Research on retinopathy of prematurity (ROP) focuses mainly on the abnormal vascularization patterns that are directly visible for ophthalmologists. However, recent findings indicate that children born prematurely also exhibit changes in the retinal cellular architecture and along the dorsal visual stream, such as structural changes between and within cortical areas. Moreover, perinatal sustained systemic inflammation (SSI) is associated with an increased risk for ROP and the visual deficits that follow. In this paper, we propose that ROP might just be the tip of an iceberg we call visuopathy of prematurity (VOP). The VOP paradigm comprises abnormal vascularization of the retina, alterations in retinal cellular architecture, choroidal degeneration, and abnormalities in the visual pathway, including cortical areas. Furthermore, VOP itself might influence the developmental trajectories of cerebral structures and functions deemed responsible for visual processing, thereby explaining visual deficits among children born preterm. This paper proposes that retinopathy of prematurity (ROP) is just the tip of the iceberg of an entity we call visuopathy of prematurity (VOP). VOP comprises the abnormal vascularization of the retina and visual processing abnormalities experienced by children born prematurely, even in the absence of ROP.This article contributes with a new perspective on the existing literature concerning visual abnormalities among children born prematurely.This article presents a new idea regarding the cause of visual abnormalities seen among children born premature, which will guide further research on the topic. Immaturity at birth is arguably one of ROP’s most critical risk factors, and the incidence of ROP increases with decreasing gestation and birth weight. In general, >50% of preterm infants weighing <1250 g at birth show evidence of ROP, and about 10% develop severe disease3. In our own previous work, we have explored the hypothesis that perinatal inflammation is associated with an increased risk for ROP6. We8 and others11 have provided empirical evidence in support of this concept, buttressed by experimental data14.Retinopathy of prematurity (ROP) is a disease of abnormal neovascularization of the retina that occurs predominantly among very preterm infants. Four major risk factors are immaturity at birth  and birth weight), exposure to fluctuating oxygen levels, perinatal/neonatal infection, and sustained systemic inflammation (SSI)15. Some of these neurovascular changes may be explored using magnetic resonance imaging (MRI), electroretinography (ERG), and optical coherence tomography (OCT).Most ROP research has focused on the abnormal retinal vascularization patterns that ophthalmologists can visualize by retinal examination. However, changes in retinal cellular architecture and relevant central pathways, including the primary visual cortex and extrastriate visual cortical areas, may also affect visual and cognitive function16. We now have evidence that ROP might not just be a vascular but a neurovascular disease that involves both the retinal and cerebral neurovascular interphase17.Already in 2006, some of us suggested to expand the concept of inflammation-associated brain damage in preterm infants to include visual dysfunctionvisuopathy of prematurity (VOP). We postulate the existence of a spectrum of inflammation-associated changes to the retina (both cellular and vascular) and the brain’s visual pathways. These changes should not be considered separate from ROP but conceptualized as an overarching, inflammation-initiated entity that explains the spectrum of visual dysfunction in preterm infants better than ROP alone.In this paper, we propose that ROP might be just the tip of the iceberg of an entity we have come to call 19, MRI21, ERG/electroencephalography (EEG)23, and OCT25. Taken together, the data support the notion that SSI in preterm newborns26 might contribute to a prolonged pathogenetic process that culminates in clinical VOP  VOP is an entity that includes the vasculogenic components of ROP as well as other retinal and cerebral abnormalities; (2) these visual abnormalities can occur among preterm infants even in the absence of ROP; and (3) prenatal and postnatal exposure to SSI is a plausible common etiological contributor to the ROP and non-ROP components of VOP. We hope that our proposal may help develop further research into the origins of visual abnormalities in children born preterm.27. Retinal and optic nerve head abnormalities seen on OCT images may be biomarkers for VOP. For example, macular edema is associated with later neurodevelopment and cerebral visual impairment in preterm infants29, the optic nerve head rim area is smaller in preterm infants than full-term peers at school-age30, and increased retinal thickness is associated with decreased visual acuity31.OCT imaging of the macula area is a reliable and useful tool to identify pathologic changes in the retina’s microstructure due to its non-invasive, real-time cross-sectional imaging of live tissue24. The RNFL consists of the unmyelinated ganglion cell axons that form the optic nerve, which extends as the optic tract into the lateral geniculate nucleus (LGN) of the thalamus. Reduced RNFL thickness is associated with more extensive brain abnormalities on MRI25, pointing toward OCT findings as a correlate and perhaps even biomarker for cerebral abnormalities in preterm infants. Findings regarding the role of RNFL thickness in the context of ROP are inconsistent. One study attributed reduced RNFL thickness at lower GA to ROP32. In contrast, another study found no such association25. Instead, RNFL thickness was associated with birth weight, GA, and MRI abnormality, suggesting that reduced RNFL thickness is a correlate of retinal immaturity rather than ROP.High-resolution spectral-domain OCT demonstrates a reduced thickness of the retinal nerve fiber layer (RNFL) in very preterm infants, which is associated with abnormal visual function and white matter injury at term-equivalent age34, and this phenomenon is even more prominent among preterm infants with ROP36. In a multiple regression analysis including GA, birth weight, neurological complications, refraction, visual acuity, ROP, and age at examination, GA was the only significant risk factor for a thicker macula among preterm infants37. However, any inference from multivariable modeling based on statistical significance should always be made with much caution because confounder constellations may change during the modeling process of adding or eliminating co-variables.Preterm infants also display increased foveal thickness compared to children born full term34. The foveal photoreceptor layer is significantly thinner among infants with GA ≤28 weeks compared to full-term infants, independent of ROP manifestation31. This suggests that the degree of immaturity indicated by GA, as well as its antecedents, correlates, and consequences, might be better indicators of abnormal retinal development than ROP alone.Inner and outer cell layer thickness is also strongly correlated with GA, and the stage of ROP has no impact on the degree of foveal development38. The ERG responses of the immature retina reflect the immaturity of photoreceptors. The ERG a-wave measures the response from photoreceptors (rods and cones), while the b-wave primarily reflects the bipolar cells’ response. Children born preterm display lower amplitudes of the combined rod and cone responses, in addition to the peak of the isolated cone response compared to full-term infants39, which suggests a general retinal dysfunction of both the photoreceptors and the cone bipolar cells.Essential steps for retinal development occur between post-conceptual weeks 25 and 38. During this period, photoreceptors develop distinct inner and outer segments, the avascular zone in the fovea is created, and the outer plexiform layer and the retinal vasculature extend to the retinal periphery22, which suggests reduced retinal function due to retinal immaturity without an additional effect of ROP. Multifocal (mf)40 and full-field (ff) ERG studies41 have yielded similar results. The amplitude of mfERG/ffERG responses in children born preterm is significantly reduced compared to their full-term peers, even if they never had ROP. This suggests that photoreceptor function is reduced in children born preterm and that these effects on the neurosensory retina do not appear to depend on the vascular and angiogenetic characteristics of ROP41. However, in children born preterm who had ROP, a prolonged rod photoreceptor response deficit is detectable after the active ROP disease has resolved. The increased receptive field size seen in these children may compensate for the deficient receptor input to the post-receptor retinal neurons42.An ERG study of school-age children revealed that those born before the 27th week of gestation had a significantly prolonged cone-driven 30-Hz flicker ERG implicit time compared to children born at term. However, the 30-Hz flicker ERG amplitudes showed no significant differences between preterm infants with and without ROP43. One VEP study found that >25% of premature infants deemed to be at low risk for abnormal development display a slow response to motion stimuli at 3 months, consistent with visual attention and cortical processing deficits15. Moreover, this slow response is present in the visual pathways of preterm infants without appreciable retinal or neurologic impairment43. This notion is supported by a study that compared visual acuity, refraction, optic disc parameters, and VEP in moderate-to-late preterm (MLP) infants (GA between 32 and 36 weeks) to similar measures obtained from infants born at term44. Investigators saw no significant differences in the retinal measures, but VEP amplitudes were lower in the MLP infant group. Furthermore, very low birth weight infants exhibit significant changes in cortical responsiveness in the absence of morbidity, such as ROP or cerebral white matter abnormalities45, indicating an impairment of central visual processing development.Electrophysiological studies have also revealed photoreceptor abnormalities among preterm infants. Visual evoked potentials (VEPs) measure the latency of the visual signal transmission from the retina to the occipital cortex46. After an image has been formed in the retina and photoreceptors encode the image as neural signals, they are transmitted through the optic nerve and optic radiation. The majority form connections in the primary visual cortex and further transmit information through extrastriate visual areas, forming two distinct streams, the dorsal stream and the ventral stream48. Subtle visual deficits among children and adults born preterm are associated with abnormal dorsal stream function, even in the absence of major neurological disabilities50. These visual functions include motion processing, understanding spatial relations, and visuomotor control51. In addition to this dorsal stream vulnerability, preterm infants are at increased risk of cerebral white and gray matter damage due to infection and subsequent neuroinflammation52, which may affect any component of the visual pathway from the retina to the visual cortex.Central visual processing entails sensation, visual perception, visual and spatial cognition, and visuomotor processing. Even though these functions are not associated with a clear division in the interacting brain network, visual developmental pathologies in the preterm brain are related to visual functioning in different eye–brain networks53. The visual system is in the close vicinity of the white matter adjacent to the cerebral ventricles, a predilection site for brain abnormalities in preterm infants. Abnormalities in this paraventricular area occur more frequently toward the posterior parietal lobe and involve optic radiations and nearby corticospinal tracts. These white matter abnormalities seen among preterm infants are associated with neuronal and axonal disease in the brainstem, basal ganglia, thalamus, cerebral cortex, and cerebellum54. Cerebral visual impairment is also associated with lesions posterior to the optic chiasma, which may be related to ROP55. Moreover, children with ROP are more likely than their peers to have cognitive and psychomotor development below the expected mean at 2 years of age21.Cerebral visual impairment is the impairment of visual acuity due to damage to visual cortical areas and accounts for nearly 30% of all bilateral visual impairments among young children57. Diffusion tensor imaging studies have revealed significant differences in several white matter regions between preterm and full-term infants, but only a few differences between preterm infants with and without ROP20. However, structural network analyses have revealed a significant difference in brain connectivity between those with and without severe ROP, indicating that while preterm birth may be more strongly associated with white matter maturation than ROP, severe ROP may still be associated with decreased structural connectivity. Moreover, compared to full-term infants, there are remarkable differences in the degree of diffusion between regions and overall mean diffusivity values in preterm infants regardless of ROP20. This suggests that delayed maturation of the dorsal and ventral pathways in infants with ROP might be attributed to immaturity rather than ROP alone.Significant differences in white matter density exist between children born preterm and their full-term peers51. The dorsal stream, connected with the parietal cortex, has a more protracted developmental course than the ventral stream, which is connected with the temporal cortex, and could thereby provide an extensive opportunity for atypical exposure to affect cortical areas’ function in this system. Brain regions within the dorsal stream are particularly vulnerable to the diffuse white matter injury among preterm infants58. Some preterm infants without ROP have white matter abnormalities associated with dorsal stream dysfunction59, pointing to the parietal lobe as a core cortical region for abnormal visual processing in preterm infants. Moreover, the degree of immaturity at birth appears to be essential in determining the degree of visual global processing deficits later on50.This notion is further supported by studies examining global visual processing in the dorsal stream. Preterm infants display difficulties with global visual processing attributed to the dorsal stream60, and also for the augmentation and utilization of glucose across neural cells in the brain56. The insufficient availability of IGF-1 may be associated with increased levels of inflammatory cytokines produced in the context of prenatal and sustained postnatal inflammation61. For example, increasing IL-6 levels are associated with decreasing IGF-1 levels during the first months after preterm birth, and infants treated for ROP have continuously higher postnatal levels of IL-6 than infants with no history of ROP, indicating a negative correlation between IGF-1 and pro-inflammatory cytokines among preterm infants, regardless of ROP62.These visual processing abnormalities among preterm infants could be explained by the fact that both the retina and brain regions in the dorsal stream may be vulnerable to the insufficient availability of trophic factors. For example, insulin-like growth factor 1 (IGF-1) is critical for both vascular and neural development, at least in part by modifying the systemic levels of vascular endothelial growth factor (VEGF), which plays a crucial role in the pathogenesis of ROP64. Recent clinical reports have indicated that some anti-VEGF agents can leak from the eye into the systemic circulation in ROP infants and consequently inhibit neurodevelopment65. VEGF is an essential developmental molecule, and therefore VEGF inhibition may have long-term effects on central nervous system development, including visual processing. Extremely preterm infants at 18 months treated with anti-VEGF injections have lower motor scores and higher rates of severe neurodevelopmental disabilities than preterm infants treated with laser ablation63. Moreover, an experimental study has demonstrated that even a single injection of intravitreal anti-VEGF in mice with ROP inhibits their weight gain, suggesting that it can impair the systemic development of infants with ROP.66. The blood–brain barrier and blood–retina barrier may prevent anti-VEGF agents from spilling over into extravascular space, reducing the impact on brain vessels. Therefore, anti-VEGF leakage may have a more considerable impact on preterm infants with severe zone 1 ROP because they have a more immature avascular retina65.Another area of concern is the current strategy to treat ROP with intravitreally injected anti-VEGF agents due to its potential effects on the preterm brainA rapid systemic inflammatory response is an effective defense mechanism against microbial invasion that usually resolves after the infection is cleared. However, sustained and dysregulated inflammation may damage organs and contribute to chronic autoimmune diseases in adults when it fails to resolve.68 and are likely to be involved in ROP etiology and visual abnormalities among preterm infants70. These inflammatory responses may be a result of oxidative stress, and vice versa. Oxidative stress is the consequence of an imbalance between pro-oxidants and antioxidants. Antioxidants  protect the cells against the harmful effect of oxidants . Preterm infants are more prone to oxidative stress because they are often exposed to high oxygen, infection, or inflammation and also have limited antioxidant defenses. Several pathological consequences of immaturity at birth associated with visual processing, such as ROP and white matter abnormalities, appear to be related to oxidative stress. Moreover, oxidative stress and inflammation are closely related in the form of a vicious circle. For instance, an inflammatory microglial response in cerebral white matter can generate free radicals, which in turn may induce pro-inflammatory cytokine production72.Among preterm infants, inflammatory responses are common before and after birth73. For example, both can lead to stress-induced premature senescence (SIPS), the premature loss of cellular replication capability that is a hallmark of the natural aging process74. At the same time, increased production of pro-inflammatory cytokine interleukin (IL)-6 and chemokine IL-8 is a key characteristic of oxidative stress-induced SIPS in retinal pigment epithelial cells75. We speculate that SIPS in the retina and/or elsewhere in the central visual system may be among the pathogenetic mechanisms contributing to long-term visual dysfunction in individuals born preterm.Furthermore, inflammation and oxidative stress are closely intertwined stress responses implicated in the pathogenesis of retinal diseases, including ROP18. This prolonged inflammatory response is associated with (1) a substantial delay in retinal vessel growth, (2) long-lasting thinning of the choroid, and (3) long-term morphological and functional alterations of the retina, including outer retinal dysfunction 18. Because preterm infants with ROP often have higher systemic concentrations of inflammatory cytokines that may affect the choroid , ROP should no longer be considered only a vasculopathy of the inner retina19. We are aware that any potential discrepancies between systemic and tissue levels of mediators of inflammation might be perceived as weakening our argument. On the other hand, evidence continues to accumulate in support of the notion that systemic inflammation does contribute to tissue abnormalities in the brain26 and eye6.Recent findings suggest that exposure to the pro-inflammatory cytokine IL-1β is associated with choroidal degeneration in the early stages of retinopathy and that fetuses exposed only to IL-1β display a persistent postnatal infiltration of inflammatory cells61. Pro-inflammatory cytokines are overexpressed and insufficiently balanced by immunosuppressive elements, causing neuroinflammation and visual function deficits through three main cell types, i.e., astrocytes, microglia, and immune cells76.Preterm infants are predisposed to sepsis and other conditions that can contribute to the onset of SSI. Elevated concentrations of inflammatory mediators (such as tumor necrosis factor (TNF)-α, IL-1β, and IL-6) during the first postnatal month predict the occurrence of ROP77. The vasculogenic process facilitated by growth factors such as the VEGF produced by astrocytes and retinal ganglion cells in the low oxygen environment in utero results in retinal neovascular abnormalities78. While VEGF is essential for physiological retinal angiogenesis, elevated VEGF in ROP contributes to pathological angiogenesis79. Retinal microglia can negatively affect the retina by producing IL-1β and TNF-α in response to hypoxia. In mice with oxygen-induced ROP, IL-1β is indirectly related to both the retina’s microvascular degeneration and the involution of choroidal vessels, resulting in subretinal hypoxia and disturbance of photoreceptor cell integrity19.Glia cells such as astrocytes are present in large parts of the retina during development and produce vasculogenic growth factors80. In the retina, microglial cells remodel retinal vasculature during development by clearing excessive vessels and participating in vessel anastomosis. However, excessive microglial activation is associated with hypomyelination80. Severe systemic perinatal inflammation provokes microglia activation within the retina, leading to aberrant vascular development with excessive anastomosis, associated with long-term deficits in visual function14. For example, microglia are a source for IL-1β, and activated microglial cells in the hypoxic neonatal retina produce increased TNF-α and IL-1β, which may induce retinal ganglion cell layer death and consequently affect the visual capabilities of the child81. Furthermore, microglial cells respond to signals from the peripheral immune system inducing neuroinflammation and releasing proinflammatory cytokines. One of these cytokines, Gro1, triggers premature senescence in the newly developing neurons, which may lead to irreversible growth arrest of this cell population83. We therefore consider it likely that glia cells, and microglia cells in particular, play an important role in VOP pathogenesis.Microglia helps establish and mature neuronal circuitry during development, maintains neuronal cells, and mediates changes in synaptic circuitry and activity by regulating synapse and receptor expression59. However, abnormalities identified by ERG/EEG, OCT, and MRI seem to be more frequent and/or prominent among preterm infants with ROP42. What we call visuopathy of prematurity is a pathological entity among preterm infants that includes ROP, abnormal photoreceptor function, and subretinal abnormalities such as choroidal thinning, as well as abnormalities further down the visual tract. Retinal abnormalities in preterm infants with and without ROP revealed by ERG and OCT studies are associated with cerebral and visual acuity dysfunction44, suggesting that ERG and OCT findings might be biomarkers not only for ROP but also for VOP in general.The empirical and experimental studies discussed above provide evidence that neurovascular visual abnormalities and visual processing deficits are frequent among preterm infants, even in the absence of ROPBoth ROP and non-ROP components of VOP are associated with SSI, which may explain why some of the retinal and visual processing abnormalities of VOP also exist in preterm infants without ROP. We consider it likely that prenatal and sustained postnatal systemic inflammation is a core contributor to the neurovascular visual abnormalities, causing both retinal and cerebral dysfunctions. The exact mechanisms of how inflammation contributes to VOP remain to be elucidated.In sum, we propose that (1) VOP is an entity that includes the vasculogenic components of ROP as well as other retinal and cerebral abnormalities, (2) these visual abnormalities can occur among preterm infants even in the absence of ROP, and (3) prenatal and postnatal exposure to SSI is a plausible common etiological denominator for the ROP and non-ROP components of VOP. We hope that our proposal will contribute to further research into the origins of visual abnormalities in children born preterm, thereby facilitating the design of therapeutic and preventive interventions.


They further found a tackykinin-expressing subset of MeA GABAergic neurons that project to the medial preoptic area in the promotion of this behaviour.uch Fig. . However5 Interestingly, Liu et al. found that a previously uncharacterized subpopulation in the laminae II of the spinal cord that uniquely expresses prokineticin receptor 2 (PROKR2).1Because affective touch mediated by unmyelinated C fibers is a show process, the authors hypothesized that pleasant touch is encoded by slow-acting neuropeptides in C fibers and their associated excitatory G protein –coupled receptors (GPCRs) in the spinal cord, which together forms microcircuits to convey discrete sensory information from the skin to the brain.Prokr2+ neurons, Liu et al. applied an intersectional genetic strategy to specifically ablate spinal Prokr2+ neurons in Prokr2-Cre mice, hereafter referred to as ABL mice.1 Surprisely, ABL mice did not display a statistically significant difference in response to diverse pain stimuli and itch-related behaviours, compared with the control mice.1 Numerous studies have implicated that the spinal cord play essential roles in the encoding and conveying of sensory information, including touch, pain and itch.5 Thus, the authors next sought to examine the role of spinal Prokr2+ neurons in touch sensation. As known, affective pleasant touch is considerably challenging to accurately infer and assess the affective state of mice. Liu et al. began to develop an unbiased two-chamber pleasant touch–conditioned place preference (PT-CPP) apparatus. They applied this apparatus to find that ABL mice could not develop the preference for stroking coupled chamber, suggesting that Prokr2+ neurons are required for transmitting pleasant touch.1 Moreover, optogenetic activation of Prokr2+ neurons could generate a strong place preference to the stimulation-coupled chamber in a real-time place preference test, demonstrating that Prokr2+ neurons encode reward.1To investigate the behavioural function of spinal Prokr2+ neurons in response to gentle stroking applied to the hairy skin of the hindlimb of ChR2-expressing Prokr2cre; Ai32 mice.1 They found that spinal Prokr2+ neurons respond most vigorously to gentle stroking in a manner that depends on stroking speed and that these neurons also exhibited comparable response strength, independent of stroking directions.1 The authors next examined whether spinal Prokr2+ neurons behave gradually attenuated responses to repeated stroking stimuli within seconds. The firing rate of spinal Prokr2+ neurons displayed fatigue to repeated brush stroking,1 indicating that the firing features of Prokr2+ neurons recapitulate the hallmarks of human CT fibers reinforces the notion that neural mechanisms of pleasant touch are conserved between humans and rodents. Together, these electrophysiological results further support the important role of spinal Prokr2+ neurons in the conveying and encoding of pleasant touch-related information.To explore neural correlates of pleasant touch, Liu et al. used an in vivo extracellular opto-tagging recording approach to investigate the neuronal dynamics of spinal Prok2 conditional knock-out mice (Prok2 CKO mice). The authors first generated floxed Prok2 mice and then bred them with Nav1.8Cre mice to acquire Prok2 CKO mice, which allows us to delete Prok2 in Nav1.8Cre neurons of dorsal root ganglions (DRGs). The results showed that mice with conditional knockout of Prok2 in DRGs could not develop preference to stroking-coupled chamber in PT-CPP but nonetheless displayed normal pain and itch behaviours, highlighting the unique role of Prok2 in pleasant touch rather than pain and itch.1Liu et al. next examined the role of PROK2 in pleasant touch by the generation of Prok2 CKO but not ABL mice exhibited heightened stress response and anxiety-like behaviours,1 highlighting the importance of maternal touch in the development and health of offspring and further supporting the notion that early tactile experience plays an essential role in shaping the resilience of offspring in response to diverse stress.5Pleasant social touch exhibits remarkable emotional benefits through indirectly activating brain reward-related circuits to release neuropeptides and neurotransmitters that encode prosocial value and anti-stress, thus serving to strengthen and maintain social bonding and helping to console distressed conspecifics. Thus, it is interesting and important to investigate whether a loss of pleasant touch sensation developmentally or in adult mice may lead to abnormal stress response. Liu et al. demonstrated that 1 Notably, there are two major contributions of this research to the field. First, due to the lack of methodologies that allow us to accurate infer and assess of the affective state of animals experiencing pleasant touch, the development of the PT-CPP test in this study helps us overcome a major obstacle in the comprehensive understanding of neural basis of pleasant touch. Second, Prok2 CKO mice generated in this research might serve as an invaluable animal model that can be used for studying the long-term effects of maternal touch on the development and health of offspring. Together, this study by Liu et al. not only provides us insights into understanding how pleasant touch information is encoded and transmitted from sensory neurons to the spinal cord across multiple levels, but also helps us develop alternative strategies for the innervations and treatment of neurological disorders associated with impaired social development and touch avoidance.To sum, using a combination of approaches, including establishment of an unbiased behavioural paradigms, physiological tests, electrophysiology recording, optogenetics and genetics, and behavioural analysis, Liu et al. dissected the function of the PROK2-PROKR2 signalling within the spinal circuit in pleasant touch sensation.Still, many questions need to be answered. Does it exist other neuropeptides and/or molecules specifically for mediating pleasant touch? What are the spinal microcircuits that underlie pleasant touch sensation? How do neuropeptides synergically or independently mediate diverse somatosensory information  in the spinal cord? Is it possible to develop more effective new systems for studying pleasant touch? Addressing these questions represents challenging but interesting future research directions in the field.


Lipocalins form an ancestral protein family found in all kingdoms of life, except for Archaea. From a small number of family members, Lipocalins rapidly evolved through duplication and divergence in the vertebrate genome, giving rise to nineteen different proteins in humans. Despite a high sequence diversity of homologous Lipocalins, their tertiary structure displays a resilient fold of eight beta-barrels delimiting a binding pocket where they can accommodate different ligands, mostly hydrophobic.A close-to-linear accrual of publications marks the knowledge accumulation on Lipocalins since the family name was coined in 1985, but an inflection point appears in the literature after 2006, when the last comprehensive review of this protein family was collected. Since then, an explosion of association studies of Lipocalin expression with many human diseases has taken place, ranging from metabolic and endocrine syndromes to cancer, cardiovascular, neurodegenerative and psychiatric conditions. Regardless of this wealth of correlational data, with their understandable practical use as disease biomarkers, an analysis of publications devoted to Lipocalin biological function was needed.Diez-Hermano et al.), where the use of unbiased selection of animal species, have yielded a phylogenetic tree with strong support of previously elusive relationships. On this evolutionary pattern, we can now map the Lipocalin functions , uncover an interesting pattern where the common Lipocalin structure provides a basic biochemical tool put to work in an amazingly varied set of physiological and pathological contexts. Specializations are combined with shared properties, and labour division with functional redundancy. The Research Topic starts with a novel view of Lipocalins evolution in chordates ], or rather “promiscuous” [AGP or Lcn1 being capable of binding many endogenous or exogenous molecules ].The family name was adequately chosen to highlight a prominent feature of Lipocalins: the pocket within the calix that can bind ligands. Ligand binding properties can be highly specific  or the removal of toxic molecules  are genuine transporter functions of Lipocalins. However, ligand-managing is not reduced to transport; Lipocalins can use the ligand to transform it , to prevent its oxidation [A1M heme quenching ], or to retain a ligand in intra- or extracellular fluids . Moreover, the ability of abundant Lipocalins to bind xenobiotics  must be considered when analysing the pharmacokinetics and expected outcome of a treatment (Ruiz).Ligand binding can fulfil different purposes and have different spatial scales. Transport of ligands to target tissues to perform a function . Indeed, surface residues potentially involved in ligand-independent functions are found as traces in the evolution of the different Lipocalin clades  paralleling their large functional divergence.As relevant as ligand-binding in the pocket can be for a Lipocalin, important functions have been demonstrated that employ interactions with high molecular weight partners, such as protein-protein interactions, or are unrelated to the ligand. Examples are the ligand-independent activation of TLR2/4 signalling in immune system cells by RBP4 (Sawyer). Also, variation in glycosylation patterns are observed in various Lipocalins that can condition their interactions  and are worth further analysis.Finally, most Lipocalins are glycosylated and the oligosaccharides provide the basis of functional interactions of the Lipocalin, like the lectin-like binding of Gd to cell surfaces of endometrial decidua, oocyte and spermatozoa (2 (Urade)] or control the availability of small immunomodulating molecules . They can either promote inflammation [PGDS or Lcn2 ], restrain its extent or duration , or have immunosuppressive functions . They can control bacterial infections by scavenging precious iron-containing siderophores , transport lipids with antibacterial or antiviral activity or even degrade microbial DNA [Lcn1 (Glasgow)]. This general defensive function is part of the ancestral toolkit of Lipocalins ].A prominent function of Lipocalins is their role as acute response proteins upon harmful stimuli  where up-regulation of Lipocalin expression is part of the general response. Lipocalins can synthesize immune system mediators  vital for cell survival-death fates.This Research Topic highlights yet another function also predicted to be ancestral in the family: regulation of barriers, so important for biological compartments protection ; 2) by scavenging oxidized molecules or radicals that propagate oxidation ; 3) or by direct antioxidant activity, like Met-based lipid reduction by ApoD or Cys-based reduction by A1M .It has become clear that antioxidant functions are also shared properties of Lipocalins  and theyBergwik et al.; Ruiz; Sanchez and Ganfornina; Antioxidant effects of Lipocalins can be exerted on small free ligands (A1M), or on higher order lipidic structures by direct interaction with membranes  or lipoprotein particles   and the involvement in ER-stress, fat deposition and obesity of A1M . Metabolic response to cold stress is shared by RBP4, PGDS and Lcn2 , a trait curiously present in the distant plant lipocalins (Sanchez and Ganfornina), ApoM , ApoM ].Stopková et al.; Urade)], prevention of oxidative stress in placenta [A1M ], nutritive and protecting properties of milk [BLG (Sawyer)], fertilization, implantation and endometrial homeostasis [Gd (Sawyer)], or long-range sex-specific signal communication by MUPs and OBPs . Indeed, the control of microbiota by OBPs not only influence host physiology, but also the perception of health state by putative mates .Lipocalins also play key roles in reproductive organ development and function, as well as in behaviours conditioning reproductive success. They influence various physiological processes like development or maintenance of reproductive organs , but also unrelated mechanisms like angiogenesis or chondrogenesis [ApoD (Sanchez and Ganfornina)], or myelin development and maintenance [ApoD and PGDS ]. Also, various Lipocalins have roles in the functional maintenance of specific organs upon aging .The well-known roles of retinoic acid in embryonic development place RBP4 as a major player in developmental processes , liver  or cartiSteinhoff et al.; Urade)] or to perform their function there [ApoD (Sanchez and Ganfornina)]. They can also bind to mitochondria in damaged cells [A1M ].All vertebrate Lipocalins have a signal peptide that, except for ApoM , is cleaSteinhoff et al.); A1M-IgA complex ], lipoprotein particles . Lipocalin dynamics within extracellular fluids or intracellular organelles have an important dependence not only on the format used, but also on their glycosylation “coat” that conditions their interactions, stability against proteases, or renal clearance .Furthermore, extracellular Lipocalins appear in different formats: bound to protein partners  or exosBhusal et al.; Ruiz; Steinhoff et al.; Urade)]. 2) Labour division: similar functions are performed by different lipocalins in different body compartments . 3) Functional convergence: the enzymatic activity of PGDS is shared by the hematopoietic PGD2-synthase (Urade).Not a single Lipocalin-KO animal model results in lethality, but no null-mutation for a Lipocalin is reported in humans. This paradox can be solved by three Lipocalins facts: 1) Functional redundancy: several Lipocalins can cooperate in the same physiological process [e.g., AGP-RBP4, Lcn2-AGP, RBP4-PGDS  or if they are conditionally essential in particular environmental or internal stressful situations. Nevertheless, we can conclude that the proper response of an organism to disease or damage clearly depends on optimal performance of Lipocalins.The functional map collaboratively built from this Research Topic can be a good starting point guiding future research on previously unpredicted functional properties of particular Lipocalins. It should help to increase our knowledge on important physiological processes and expand the applicability of Lipocalins to improve therapies for many pathological conditions.


Native West African (WA) taurine (Bos taurus) cattle are trypanotolerant; i.e., they have the ability to suppress the establishment of trypanosomes. Cattle trypanotolerance is a heritable trait—partially additive in nature—that can share mechanisms with tick resistance. Copy Number Variations (CNVs) are genomic alterations affecting gene structure, gene expression, and performance. However, the relationship between CNV regions and trypanotolerance and tick resistance in WA taurine cattle has not been approached thusfar. Here, we identify and characterize CNV regions in a sample of WA taurine cattle using WA zebu as an outgroup. The CNV regions identified spanned genes that are mainly involved in innate immunity. However, their relationship with genomic regions, previously reported to be associated with trypanotolerance and tick resistance, was not clear. Therefore, CNV alterations may not be the main genomic features underlying such traits.A total of 106 West African taurine cattle belonging to the Lagunaire breed of Benin (33), the N’Dama population of Burkina Faso (48), and N’Dama cattle sampled in Congo (25) were analyzed for Copy Number Variations (CNVs) using the BovineHDBeadChip of Illumina and two different CNV calling programs: PennCNV and QuantiSNP. Furthermore, 89 West African zebu samples  were used as an outgroup to ensure that analyses reflect the taurine cattle genomic background. Analyses identified 307 taurine-specific CNV regions (CNVRs), covering about 56 Mb on all bovine autosomes. Gene annotation enrichment analysis identified a total of 840 candidate genes on 168 taurine-specific CNVRs. Three different statistically significant functional term annotation clusters (from ACt1 to ACt3) involved in the immune function were identified: ACt1 includes genes encoding lipocalins, proteins involved in the modulation of immune response and allergy; ACt2 includes genes encoding coding B-box-type zinc finger proteins and butyrophilins, involved in innate immune processes; and Act3 includes genes encoding lectin receptors, involved in the inflammatory responses to pathogens and B- and T-cell differentiation. The overlap between taurine-specific CNVRs and QTL regions associated with trypanotolerant response and tick-resistance was relatively low, suggesting that the mechanisms underlying such traits may not be determined by CNV alterations. However, four taurine-specific CNVRs overlapped with QTL regions associated with both traits on BTA23, therefore suggesting that CNV alterations in major histocompatibility complex (MHC) genes can partially explain the existence of genetic mechanisms shared between trypanotolerance and tick resistance in cattle. This research contributes to the understanding of the genomic features of West African taurine cattle. Bos taurus) cattle are the result of a unique process of natural adaptation to the challenging environmental conditions of the biogeographic zones south of the Sahel, including the presence of different diseases, such as trypanosomiasis )More important, The current analysis used a significant number of zebu samples as a reference to ensure that the genomic features identified are unique for the West African taurine cattle genomic background. In this respect, a recent study reported that introgression due to between-population gene flow shapes the distribution of structural variations in cattle, allowing us to identify CNVs introgressed from zebu cattle in N’Dama cattle . TherefoBos indicus than in African taurine cattle [The number and mean length of CNVRs identified in West African taurine cattle were significantly higher than in zebu cattle. Previous literature reported that CNV alterations are more frequent in e cattle ,47. TherStudies focusing on CNVR identification are not directly comparable: they may differ due to the techniques used to obtain genomic data and both the genome assembly and number and performance of the calling platforms used ,48,49. FBos taurus) and zebu (Bos indicus) cattle cannot be considered model representatives of their subspecies [In any case, studies reporting higher CNVR variability in zebu cattle used zebu samples of Asian or East African origin. Present East African zebu cattle are closely related to Asian zebu  due to abspecies ,53; SNP There is consensus that CNVs in cattle are highly enriched in the immune function and olfactory receptor genes, suggesting that Copy Number alterations contribute to their high variability ,54. ThisThe current results do not depart from expectations. Taurine-specific CNVRs identified on BTA15 are mainly enriched for genes coding olfactory receptors . Two CNVHowever, our results suggest that the candidate genes spanned by the taurine-specific CNVRs identified are mainly involved in innate immunity.Genes belonging to ACt1 encode lipocalins, transport proteins delivering small hydrophobic ligands  to cell surface receptors of specific cells. With highly diverse physiological functions, lipocalins are involved in the modulation of immune response and allergy . FurtherACt2 is formed by genes coding B-box-type zinc finger proteins, with most of them belonging to the tripartite motif (TRIM) encoding proteins and butyrophilins. TRIM proteins are upregulated by type I and type II interferons and they are well known to be involved in innate immune processes due to their role in the regulation of pathogenrecognition ,59. InteREG3A and REG3G) are candidates forplaying a role in regulating the cattle sensitivity to environmental variation under tropical conditions. The REG3A gene would be associated with wound repair after skin injury and with homeostasis of the skin, thus contributing to immune defense, whereas the REG3G gene would play a role in the antimicrobial defense of the intestine.Finally, ACt3 includes nine genes belonging to the C-type lectin receptors family, such as OLR1, involved in the immune response via regulating the inflammatory responses to pathogens and promoting B-cell differentiation and antigen-specific T-cell responses . CarvalhBOLA-DRA, GABBR1, or MOG, belonging to MHC.Other reasons contribute to relating taurine-specific CNVRs with immune function. CNV analyses in cattle paid major attention to BTA23, on which the major histocompatibility complex (MHC) genes are located. The major histocompatibility complex has a highly polymorphic nature , is wellBOLA-DRA, the macrophage-stimulating 1 receptor (MST1R) gene, butyrophilin coding genes such as BTNL2, or the interferon-induced transmembrane protein 3 (IFITM3) gene, therefore suggesting that the main function of this set of genes may be related to immunity.Furthermore, a high proportion of the candidate genes spanned by taurine-specific CNVRs belonged to a functional annotation cluster (ACt30) enriched for membranes and transmembranes. Although membrane and transmembrane genes represent a significant fraction (20–30%) of the total genes, at least in the human genome, their functionality is still poorly understood . ACt30 iAlthough trypanotolerance is a heritable trait unique to West African taurine cattle, and the taurine-specific CNVRs identified are likely to be representative of their genomic background, the overlap between candidate genes spanned by these CNVRs and trypanotolerance-related QTL traits was not particularly high.In principle, the existence of a high number of chromosomal regions putatively associated with cattle trypanotolerance  would fiBos taurus × Bos indicus experimental population. The general importance of BTA23 in the genetic basis of host resistance to parasites can be explained by the action of MHC genes including BOLA-DRA. This gene has been previously suggested to be under selection in West African cattle [In any case, the QTL regions associated with trypanotolerance may not be exclusive to regulating this trait. Some of the CNVRs identified on BTA23 of taurine cattle overlapped with the QTL regions reported by Machado et al.  and Otton cattle ,68 and iCXCR4 [ARHGAP15 [INHBA [TICAM1 [CARD11 [CFH, CRBN, TRNT1, and IL5RA) were not identified within CNVRs either (Within CNVRs, our research failed at identifying the most proposed candidate genes for trypanotolerance in West African taurine cattle such as CXCR4  and ARHGARHGAP15  on BTA2,5 [INHBA  on BTA4, [TICAM1  on BTA7  [CARD11  on BTA25 [CARD11  reporteds either . AlthougThis research contributes to the understanding of the genomic features of West African taurine cattle. Our results suggest that the role of CNVs in the genomic history of these unique cattle is not negligible. Taurine cattle significantly differ in CNV variation of West African zebu. Furthermore, the identified CNVRs spanned genes that are mainly involved in innate immunity. This fits well with the expectation of a costly process of natural adaptation to the challenging environment of humid West Africa and its reflection on the cattle genome. The determination of the way in which CNVs have contributed to cattle trypanotolerance and resistance to parasites remains an issue. However, the study of CNVs on BTA23 appear to be a target for future research.


Insulin resistance is linked to impaired cell metabolism and survival in the peripheral tissues, as well as increased oxidative stress and activated inflammatory responses. Chronic High fat diet insulin resistant to exposure results in liver damage,impaired glucose homeostasis, hyperinsulinemia, late pancreatic-cell failure to generate insulin due to cell exhaustion, and subsequent hyperglycaemia, all of which are hallmarks of Type 2 Diabetes Mellitus (T2DM). Therefore, it is of intrest todocument a short review on the impact of a high-fat diet with insulin resistance. Impaired Triglycerides TG deposition and increased lipolysis result in an excess of circulating TG and FFAs Free fatty acids, which contributes to ectopic lipid accumulation in the liver and skeletal muscle, resulting in hepatic steatosis and insulinresistance -2. CLDs It is also known that the composition of FA (Fatty acid) intake could influence the characteristics of cell membranes and their FA components. Changes in the FA composition of the sarcolemma could modify membrane fluidity and stiffness .The effHyperglycemia and hyperinsulinemia has a significant effect on gluconeogenic genes, such as Pck1 andG6pc by double triumph of the insulin receptor substrates (IRS) namely, Irs1 and Irs2 in liver . The actInsulin signalling via phosphorylation of FOXO1 by AKT contributes to the reported decrease in steady-state mRNA levels for gluconeogenic genes such G6pc and Pck1. FOXO1 causes the derepression and/or activation of the GLUT4 gene, which leads to improvedinsulin sensitivity . A fundaIt is interest to document the effect of fat metabolism linked with insulin. Insulin resistance, is caused by lipid metabolic abnormalities and elevated levels of circulating fatty acids that accumulate in insulin-sensitive organs such muscle, liver,and adipose tissues. Severe diseases such as diabetes, obesity, stroke, and heart attack are developed, as a result of high fat diet, where insulin resistance is a risk factor that can be managed with therapeutic lifestyle changes and pharmacological therapy.


Furthermore, metabolic systems are highly complex, connected, and interactive, and consequently, one’s metabolic fluxes (“motion pictures”) should not be understood as individual components but as a whole system2. Unfortunately, most modern metabolic studies heavily depend on the measurements of static, snapshot information, so-called “statomics”  of individual components of the whole system, which often fail to reflect actual metabolic status4. Without simultaneous considerations of metabolic flux, sole dependence on “statomics” can lead to incorrect conclusions regarding metabolic status. In this Special Feature, experts in the field of tracer methodology or fluxomics provide the basic principles and applications of the methodologies determining metabolic fluxes to various metabolic conditions. The incorporation of these state-of-the-art methodologies into metabolic research will guide researchers to a better understanding of dynamic metabolic systems with which to better dissect underlying molecular mechanisms of physiology or pathophysiology.Since Rudolf Schoenheimer’s pioneering metabolic tracing work in the 1930s6. While a great number of methods determining metabolic flux rates are currently used, any calculation of those metabolic fluxes (or kinetics) must be predicated on one of four tracer model structures or combinations: tracer dilution in (1) single-pool or (2) multiple-pools and tracer incorporation with (3) single precursor or (4) multiple precursors in steady or nonsteady states. In this Special Feature, Kim et al.7 discuss the importance of obtaining kinetic information on the in vivo metabolism of compounds and then the fundamental principles of tracer methodology and their use to assess in vivo metabolic flux rates. The authors focus on the basic model structures of tracer methodology that apply to a wide range of applications with emphasis on stable isotope tracers.Currently, various tracer methodologies are employed to assess metabolic fluxes in vivo and in vitro, including rates of synthesis, breakdown, oxidation, conversion, and/or transport across the membrane8. The recommended dietary allowance (RDA) for protein, defined as 0.8 g protein/kg/day, is in fact the minimal amount of protein intake that leads to net protein balance at the whole-body level, regardless of age, exercise training status, or clinical condition7. However, many physiological circumstances may require greater protein intake to maintain lean body mass (more importantly muscle mass). It is of critical importance to use an appropriate and accurate methodology to assess the optimal rate of dietary protein or amino acid intake. In this Special Feature, Wolfe et al.9 discuss stable isotope tracer methodology that enables a variety of approaches to assess the optimal dietary protein intake in humans. The authors primarily focus on tracer methods for estimating dietary protein and essential amino acid requirements for humans under different physiological conditions and discuss key methodological approaches, along with the advantages and limitations of each tracer method.Dietary protein intake plays many physiological roles, particularly in the maintenance or gain of body protein stores, the largest storage site of which is skeletal muscle. Gains in muscle mass  are accomplished through stimulation of net positive protein synthesis , called an anabolic response10. Furthermore, lactate plays a number of key roles in metabolism, specifically being involved in intermediary metabolism , redox biology, allosteric regulation of lipolysis, mitochondrial biogenesis and energetics, angiogenesis, gene expression (via histone lactylation), and brain metabolism11. In this Special Feature, Brooks et al.12 discuss the historical background related to the discovery of the lactate shuttle, concepts that describe the roles of lactate in the delivery of oxidative carbon energy and gluconeogenic precursors as well as in cellular signaling. These discoveries have been largely based on stable isotope tracer methodology.Once thought to be a dead-end waste product of anaerobic glycolysis due to the lack of oxygen, we now know that lactate is formed under fully aerobic conditions, and the formation stems from the imbalance between the rates of production and disposal (via oxidation and other pathways)1. Over the past decades, there have been further advances in stable isotope tracer techniques and mass spectrometry that have advanced our current understanding of lipid metabolism, particularly in humans, regarding normal conditions and pathophysiology, such as obesity, fatty liver disease, and dyslipidemia. In this Special Feature, Salvador et al.13 discuss the advances in the quantitative approaches to determining lipid flux rates using stable isotope-labeled substrate tracers or 2H2O, including tracing flux rates of various fatty acid species and the entry of dietary fats and their fates . The authors discuss how advances in fluxomics can be combined with recent advances in lipidomics to bring about further advancement in our understanding of lipid metabolism with an additional discussion on the potential use of data science .We now know that various lipids are in constant states of rapid flux to achieve overall “dynamic” homeostasis in the body thanks to earlier studies using tracer methodology15. Described briefly by other contributors12 in this Special Feature, Bae et al.16 provide a more comprehensive overview regarding arteriovenous metabolite gradient measurement, including the historical perspectives on the development of A-V balance measurements, and discuss the advantages and limitations of the techniques with key examples of studies that have uncovered dynamic exchanges of numerous metabolites between organs in the contexts of various pathophysiological conditions.The combination of arteriovenous balance  techniques and (stable) isotope tracer methodologies enables quantification of metabolic kinetics of multiple metabolites across or between organs  in steady state as well as nonsteady state Altogether, tracer methodology, particularly stable isotope tracers, can provide in-depth information on dynamic metabolic status , which can serve as a kinetic basis for the molecular mechanisms. The arteriovenous balance technique in conjunction with tracer methodology with advancements in powerful mass spectrometry enables the quantification of substrate kinetics across and between organs, with additional information on intracellular kinetics. Furthermore, multidisciplinary approaches, including multiomics and data science , integrated into metabolic fluxomics can aid the advances in metabolic research that enables a better understanding of the metabolic status of living organisms and thus leads to the discovery and development of effective drugs against various pathologies.


Transcatheter aortic valve replacement (TAVR), as an alternative to open heart surgery, has revolutionized the treatment of severe aortic valve stenosis (AVS), the most common valvular disorder in the elderly. AVS is now considered a form of atherosclerosis and, like the latter, partly of inflammatory origin. Patients with high-grade AVS have a highly disturbed blood flow associated with high levels of shear stress. The immediate reopening of the valve during TAVR leads to a sudden restoration of a normal blood flow hemodynamic. Despite its good prognosis for patients, TAVR remains associated with bleeding or thrombotic postprocedural complications, involving mechanisms that are still poorly understood. Many studies report the close link between blood coagulation and inflammation, termed thromboinflammation, including monocytes as a major actor. The TAVR procedure represents a unique opportunity to study the influence of shear stress on human monocytes, key mediators of inflammation and hemostasis processes. The purpose of this study was to conduct a review of the literature to provide a comprehensive overview of the impact of TAVR on monocyte phenotype and subset repartition and the association of these parameters with the clinical outcomes of patients with severe AVS who underwent TAVR.  Aortic valve stenosis (AVS) represents the most common heart valve disease in the elderly and is associated with significant morbidity and mortality when left untreated . This chToday, surgical or transcatheter aortic valve replacement (TAVR) is the only available treatment option in patients with severe AVS . In lessThe historical view of the biology of monocytes has been overhauled in recent times, including their phenotypic and functional heterogeneity as well as their high sensibility to changes in their environment ,13. MoreThe aim of this review is to highlight recent advances regarding the effects of TAVR on monocyte functions and subset repartition as well as the prognostic value of these parameters on clinical outcomes in patients with severe AVS undergoing TAVR. To our knowledge, this is the first review of the literature on the relationship between circulating monocyte subset distribution and phenotype in the context of TAVR in patients with severe AVS. Given the important prevalence of this pathology and the significant rate of complications occurring after TAVR, this review aims to help with the prediction and understanding of these complications. At the same time, therapeutic strategies that modulate monocyte phenotype, for example, to reduce their recruitment to atherosclerotic plaques, have recently been proposed to be efficient on atherosclerosis in both animal models and a few clinical experiments . An incrAVS is the most prevalent valve disease in the elderly with an estimated prevalence from 2 to 7% in the population aged 65 years or over worldwide ,18. ThisAVS was previously regarded as an age-related degenerative process caused by passive calcium deposition in the valve. However, recent data challenged this concept and the valve calcification is now understood as an active inflammatory process developing through an initial endothelial injury induced by high shear stress, leading to infiltration of a large number of monocytes in the aortic valve tissue, where they differentiate into macrophages able to oxidize lipids and secrete inflammatory cytokines, chemokines and growth factors, such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), IL-6, transforming growth factor β1 (TGF-β1), vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMPs), leading to matrix remodeling and neovascularization ,20. MoreCardiac valves are dynamic and closely interact with the surrounding hemodynamic and mechanical environment. In normal conditions, the aortic valve opens and closes with every heartbeat, maintaining the blood velocity and pressure gradient between the aorta and the left ventricle, experiencing the maximum shear stress during the peak systole . The incThese hemodynamic disorders also increase Von Willebrand factor (VWF) susceptibility to proteolytic cleavage by its main protease, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) ,28. VWF Symptomatic severe AVS is associated with high mortality rates, up to 50% within one year, when left untreated . No pharTAVR is a minimally invasive procedure that consists of the implantation and deployment of a new biological valve through the femoral artery into the stenosed valve with a stent. The restoration of the valve opening and thus of the blood flow leads to an instantaneous normalization of the shear stress. The replacement of the stenosed valve also allows the immediate correction of the VWF alterations  with theHowever, despite a clear improvement in the patient’s prognosis and quality of life, TAVR remains associated with significant bleeding or thrombotic postprocedural complications and the management of patients after TAVR needs to be optimized. The major preoccupation is the risk of cerebral vascular accident that occurs in 3.5% of cases in the 30 days after TAVR ,40 and 7For TAVR perioperative risk assessment, scores such as the Society of Thoracic Surgeons (STS) risk-score for predicting mortality and the European system for cardiac operative risk evaluation (EuroSCORE II), based on clinical parameters, are routinely used . HoweverAs a systemic inflammation response occurs within 48 h after TAVR procedure in approximately 50% of patients in the absence of clinical infection and has been associated with adverse outcomes in TAVR patients, some teams tried to predict the short- and long-term TAVR complications  by measuring circulating biomarkers related to inflammation . Thus, sMonocytes are known for their very important role in tissue homeostasis and the innate immune system. Originating from bone marrow, they continuously enter the blood circulation, where they constitute 8 to 10% of the total leukocyte population in humans. During infection or damage, they are recruited into tissues where they rapidly differentiate into macrophages or dendritic cells to exert their role in inflammation, immune defense, phagocytosis or tissue repair . Human monocytes are now classified into three functionally different subsets, based on the expression of superficial cluster differentiation CD14 (a cell co-receptor for lipopolysaccharide) and CD16 (the low-affinity Fc receptor III for IgG), with different phenotypes and functions in homeostasis and diseases ,67 Tabl. Classical monocytes (CD14++ CD16−) are generally short-lived cells surviving for only one day. They are rapidly mobilized into infected or injured sites and are involved in diverse functions such as phagocytosis, infection control, inflammation regulation and tissue repair. Among the three monocyte subsets, they present the greatest migration capacity in tissues . Non-classical monocytes (CD14+ CD16++) patrol endothelial cell integrity, clear dying endothelial cells, and protect vessel health. They survive for 7 days in humans and can be recruited into sites of vascular injury or infection or enter into the areas of inflammation, such as atherosclerotic plaques . A third monocyte subset has also been described. They are referred to as intermediate monocytes (CD14++ CD16+), which are variously described as closely resembling either classical or non-classical monocytes. They express a high degree of MHC class II gene presentation, conferring them a predominant role in inducing T-cell proliferation and stimulation and are recruited at a later stage of inflammation. The classical (CD16−) and intermediate/non-classical (CD16+) monocytes represent 80–90% and 10–15% of total monocytes, respectively. Although a large number of studies have focused on the differentiation of human monocyte subsets, the mechanisms regulating their recruitment into tissues and their functional and dynamic role in inflammation and immunity, there are still many aspects that need to be clarified. In this way, Cormican and Griffin , in a reMany studies report the close link between blood coagulation and the innate immune system, termed “thromboinflammation” or “immunothrombosis”. Indeed, activated monocytes express on their surface a tissue factor  that hasVariations in the repartition of the monocyte subsets have been reported several times in diverse conditions, either as a protective mechanism or as taking part in the pathological process, such as in infections, cancers, autoimmune or inflammatory diseases , althougWhile data accumulate on the key role of monocytes/macrophages in AVS and the similarity in many aspects of AVS and atherosclerosis, very few studies have reported the circulating levels of total monocyte and of monocyte subsets in AVS patients. Shimoni et al.  comparedA few teams were interested in the variation of the monocyte subset levels before and after TAVR that may have been induced by the sudden change of hemodynamic conditions. At this time, according to the best of our knowledge, only four studies reported these variations or associated the levels of a pre- or postprocedural subset with outcome after TAVR . First, It is very difficult to compare these studies as the times of study of the monocyte subset repartitions in the post-TAVR procedure as well as the follow-up periods and type of analyzed adverse events were not the same. However, all these studies reported an impact of the TAVR procedure on intermediate monocyte levels with an earlier increase in post-procedural and then a decrease under baseline a few days and months after TAVR. The mechanisms involved in the modulation of circulating intermediate monocyte levels during a TAVR procedure remain speculative. The TAVR procedure results in sudden changes in wall shear stress and flow turbulence associated with a proinflammatory response. It can be hypothesized that increased levels of circulating intermediate monocytes quickly after TAVR are the result of interplay between significant hemodynamic disturbances and inflammation response. To go deeper into the comprehension of the shear stress impact on monocyte function, Baratchi et al.  recentlyDNMT3A) and Tet-methylcytosine dioxygenase 2 (TET2) are the most frequently identified variants among patients with CHIP. Mas-Peiro et al. assessed the incidence of somatic CHIP-driver mutations in these two genes in 279 patients with critical AVS undergoing TAVR and their association with circulating monocyte subset levels evaluated before TAVR and with all-cause mortality [DNMT3A- and TET2-CHIP-driver mutations with a variant allele frequency ≥2% in a third of patients with an incidence that increases with age (from 25% in patients aged 55–79 years to 53% in those aged 90–100 years) and a three-fold increase of death risk over a median 8-month follow-up period after TAVR in patients with DNMT3A or TET2 mutations compared with a group of age-matched patients without DNMT3A and TET2 mutations. They also observed in a subset of TET2-CHIP patients, an increase of non-classical monocyte levels compared to patients without DNMT3A and TET2 mutations. As non-classical monocytes are known to secrete high levels of inflammatory cytokines [DNMT3A or TET2 mutations compared to age-matched healthy control participants without DNMT3A and TET2 mutations [DNMT3A and TET2 mutations, the effects of mutations in other driver genes on monocyte subset repartition and phenotype and the outcomes of patients with severe AVS who underwent TAVR need to be investigated. Clonal hematopoiesis of indeterminate potential (CHIP), defined by the presence of acquired somatic mutations in hematopoietic stem cells without other hematologic abnormalities, is a novel age-related risk factor for coronary artery calcification and atherosclerotic cardiovascular morbidity and mortality, independent of traditional risk factors ,98,99. Mortality . They reytokines , this dautations . As thesAs we know that a systemic inflammation response occurs after a TAVR procedure in approximately 50% of patients and that monocytes seem to play a key role in this response, introducing a preventive anti-inflammatory therapy targeting monocytes should be discussed. Recent studies provided evidence that modulating the monocyte phenotype and inflammatory processes in pre-clinical animal models of atherosclerosis could be effective in reducing lesion size, and in patients with cardiovascular diseases in reducing cardiovascular events and improving clinical outcomes ,108. TheStatins were proven to reduce morbidity and to improve overall survival in patients at high risk of cardiovascular mortality by reducing the levels of low density lipoprotein-cholesterol, as well as regressing or stabilizing coronary atheromatous plaques ,118, butPreventive therapy could be discussed in patients who have a pre-existing proinflammatory comorbidity, which could worsen TAVR consequences. For example, the presence of diabetes is associated with poor outcome after TAVR with a higher risk of stroke  or 2-yeaIn the end, very few teams reported the monocyte subset repartition during TAVR but they all confirmed that intermediate monocyte levels were impacted by the instantaneous change of blood flow pulsatility occurring during the TAVR procedure in patients with severe AVS, now considered as an active and chronic inflammatory disease. In addition, as previously described for other cardiovascular diseases, intermediate monocyte levels (measured before or after TAVR) seem to be associated with early mortality or worse cardiac function after TAVR. This biomarker could be used as a predictive biomarker for TAVR complications and constitute a decision-making aid in the management of the growing population of candidates for TAVR, but, before this parameter can be used in clinical practice, these data need to be reinforced. Moreover, even though intermediate monocyte level modulation has been reported in TAVR procedures and their prognostic values have been described in some publications, the question, whether intermediate monocytes represent a reflection or rather contribute to the TAVR outcomes remains essentially unanswered. Proving the causal role of intermediate monocytes in TAVR complications in patients with severe AVS requires large prospective and long-term studies with longitudinal assessments of monocyte subsets and is an essential step towards understanding the mechanisms involved in TAVR complications and to propose, in the future, therapeutic targets of interest in the AVS and TAVR context.


The skin epidermis and appendages undergo ongoing renewal throughout life. Stem cells residing in the epidermis and hair follicles are pivotal for sustaining skin homeostasis. The self-renewal ability of stem cells significantly decreases during skin aging but actively increases during wound repair. Residential stem cells reside in niches that provide spatially distinct microenvironments for stem cell maintenance and function. Cell-extracellular matrix (ECM) adhesion is essential for the establishment of niche architecture. Collagen XVII (COL17), as a transmembrane protein constituting hemidesmosomes (HDs), mediates the interactions of stem cells with surrounding cells and the matrix to regulate skin homeostasis, aging and wound repair. This review focuses on the pivotal role of the niche component COL17 in stem cell maintenance and its function in regulation of skin aging and wound repair. The transmembrane protein collagen XVII (COL17/BP180/BPAG2) is a structural component of hemidesmosomes (HDs). It was first named BP180 due to its initial discovery in bullous pemphigoid (BP) in the 1980s COL17 is mainly expressed by basal keratinocytes, and its ICD binds to keratin intermediate filaments through plectin and BP230 COL17 has been reported to be involved in multiple skin diseases. In autoimmune skin diseases, such as BP, mucous membrane pemphigoid, gestational pemphigoid, and linear IgA bullous dermatosis, COL17 acts as an autoantigen Since the skin of JEB patients is also characterized by skin atrophy and fragility, alopecia, dyspigmentation, and delayed wound healing The skin shows profound structural and functional changes with age, including epidermal and dermal thinning, loss of dermal elasticity and wrinkling, and greying and loss of hair Accumulating evidence has confirmed that cell-cell and cell-extracellular matrix adhesion is essential for the establishment and maintenance of niche architecture high ESCs are constantly outcompeting COL17A1low cells to eliminate stressed or unfit cells from the skin. Lineage tracing for aged skin presents an expanding single-type cell clone consisting of noncompetitive COL17A1-MCM2- cells in the basal layer instead of the conspicuous heterogeneity of COL17A1 expression in young skin. Cell competition is possibly driven by the two types of cell divisions mediated by differential COL17A1 expression. COL17A1low cells exhibit an increased ratio of perpendicular cell divisions to generate a basal cell and an apically located differentiating suprabasal cell, whereas COL17A1high cells divide in parallel to generate two identical basal daughter cells. Therefore, the COL17-mediated symmetric cell divisions (SCDs) mechanistically push out COL17A1low cells by causing a reduced number of hemidesmosomes allowing for microdetachment from the basement membrane. In addition to the cell competition theory, COL17 can directly increase the self-renewal capacity of epidermal cell colonies by increasing the ratio of parallel divisions The exact function of COL17 in aging was recently reported The mechanism by which COL17 regulates cell division is discussed in subsequent studies Collectively, age-induced COL17 proteolysis leads to the imbalance of SCDs and ACDs in ESCs through PKC signaling, resulting in the loss of cell competition, self-renewal capacity, and stem cell maintenance, ultimately causing age-associated epidermal atrophy and fragility and nonhealing wounds, which will be discussed in the following section.Hair loss is one of the common manifestations of skin aging HF aging features miniaturization of hair follicles and the absence of dermal papillae, sebaceous glands, and the infundibulum. Preceding HF miniaturization is stem cell dysregulation, including the loss of HFSC markers and HFSC maintenance markers. Similar to ESCs, HFSCs are committed to epidermal terminal differentiation and keratinization during aging; these cells are distributed in the junctional zone located above the bulge area; they then move to the suprabasal epidermis and eventually to the skin surface to be eliminated from the stem cell pool and from the skin The expression of COL17 in HFSCs has been observed. COL17 is specifically reduced in aged quiescent HFSCs, and the expression and distribution of non-HD COL17A1 in HFSCs changes greatly during aging, negating the contribution of HD COL17-induced skin detachment in hair loss MSCs are pigment-producing melanocytes residing around ESCs and HFSCs in the interfollicular epidermis or the follicular bulge-subbulge area COL17 deficiency induces relatively mild dyspigmentation in the tail skin, as well as hair greying. However, COL17 is not expressed in MSCs, indicating the indirect effect of COL17 on MSCs. As envisaged, differentiated melanocytes colocated with differentiated ESCs and HFSCs exist early in preaging skin and hair follicles, owing to the niche created by ESCs and HFSCs through TGF-β signaling Wound healing occurs through distinct overlapping phases: hemostasis, inflammation, proliferation, and remodeling Stem cells are mainly involved in three biological processes during re-epithelialization, including stem cell migration and proliferation, stem cell population dynamics, and stem cell plasticity Apart from preaging of skin, decreased wound closure is induced by COL17 KO and increased wound closure by inhibition of COL17 shedding high subcluster with top markers, such as COL17A1 and TP63, a gene enriched in quiescent bulge HF stem cells, is present in both wounded and unwounded skin. The COL17A1high state scores the lowest for inflammation and EMT genes but the highest for genes of a “quiescence and sternness” signature derived from tissue quiescent stem cells, which are more quiescent, persist longer and could give rise to more rapidly cycling committed progenitors with a shorter lifespan. This portion of cells differentiates directly or indirectly into spinous cells or a specific pool of proliferating basal cells, thus maintaining skin renewal during homeostasis. In wound repair, such cells differentiate into suprabasal cells at the wound periphery or convert into cells of higher motility and subsequently migrate into the wound.In single-cell analysis research Two kinds of colonies are formed in human keratinocyte culture, expanding colonies and stacking colonies The migration of epidermal basal cells requires the remodeling of the cell-cell and cell-substratum contacts to allow the cells to detach from the intact basement membrane in the unwounded epidermis. As the cells move over the wound, they degrade the provisional matrix while depositing new matrix proteins, including laminin-332. In keratinocytes, matrix proteins and their receptors are clustered into two distinct protein complexes: focal adhesions and hemidesmosomes The features of cell motility can be roughly grouped into the velocity and the directions of migration For studies in which the velocity shows no correlation with COL17, the directions of migration are considered. To migrate efficiently in a directed manner, cells must establish and maintain an asymmetric morphology with defined leading and trailing edges In addition to the different objects of regulation, whether COL17 itself or COL17 shedding plays a role in wound repair has been discussed. A scenario can be visualized in the wound in which shedding of the COL17 ectodomain loosens or releases the cell from some of its present binding partners and allows it to embark on other functions, as required Thus far, it is not clear whether the lack of soluble ectodomain, the concomitantly generated membrane-tethered endodomain of COL17 or the combination of both caused accelerated re-epithelialization in nonshedding COL17 skin. There is evidence that the released ectodomain has a direct suppressive effect on keratinocyte motility because 1) deposits of the highly stable released COL17 ectodomain are mainly found in the trails of migrating cells incorporated with laminin-332, leading to stabilization of the substrate and cell immobilization but directed cell motility In terms of the upstream regulatory mechanism of COL17, BP-IgG in BP induces the internalization of COL17 to inhibit its function and reduce cell motility As introduced above, the active restoration of stem cell pools by the use of residual intact stem cells before the irreversible advancement of tissue architectural changes may be essential for successful antiaging and tissue regeneration in the skin. COL17, as a good marker for stem cells reflecting individual cellular potential and quality for self-renewal, represents an interesting therapeutic target in antiaging and wound treatment.in vitro study showed that the forced maintenance of COL17 rescues both epidermal thinning and hair loss in aged mice for more than 24 months, suggesting that the stimulation of COL17 expression is a potential therapy for skin aging An For patients with COL17 deficiency, genetic therapy has been introduced to solve the skin aging problem Regarding wound repair, forced expression of COL17 by basal keratinocytes in mice promotes wound healing Collectively, upregulation of COL17 is a common solution for skin rejuvenation and wound healing. Therefore, studies on the mechanism of pre- and posttranscriptional regulation of COL17 set the basis for more therapeutic strategies. Moreover, the development of synthetic peptides that stimulate COL17 synthesis and high-throughput screening for drugs that upregulate COL17 and subsequent clinical trials of such drugs will promote the clinical translation of these findings.Taken together, this body of work provides previously unappreciated insights into the cellular and molecular mechanisms by which COL17 regulates skin aging and wound repair, focusing on the perspective of stem cell niches.high state in lineage tracing of wounded skin, the exploration of the function of COL17 in stem cell plasticity will be an important challenge for the future.However, many open questions remain regarding the detailed upstream mechanisms modulating COL17 level. We know little about the signaling pathway regulating the gradual or rapid decline of COL17 during aging and the high expression and distribution of COL17 to the wound edges. Downstream mechanisms also remain to be discovered. It is also necessary to elucidate how the multiple mechanisms introduced above interact with each other; for example, whether the functions of HD COL17 and non-HD COL17 overlap or are independent and the paradoxical role of COL17 in the regulation of cell migration has not yet been verified. In addition to the deepening of existing studies, the research direction can be further broadened. For instance, considering the regulation of COL17 on directed cell migration and its distribution to the wound edge, it will be interesting to further detect the potential role of COL17 in collective cell migration. Moreover, due to the dynamic change in COL17 expression and the return of cells in differentiated states to the COL17A1When the functions and mechanisms of COL17 are fully studied and corresponding clinical trials are performed, it will be possible to propose future therapeutic strategies for skin aging and wound repair.


Lysophosphatidylcholine acyltransferases (LPCATs) are among the lysophopholipid acyltransferases (LPLATs) that specifically regulate the abundance of different phosphatidylcholine (PC) species in a variety of cell and tissue types, thereby playing an important role in lipid metabolism and homeostasis. Lysophosphatidylcholine acyltransferase 3  is a member of the LPCAT family that primarily regulates the levels of arachidonic PC species. LPCAT3 is regulated by the liver X receptor, which plays an important role in lipoprotein production in the liver and small intestine. Increasing lines of research have demonstrated that LPCAT3 plays important roles in the occurrence and development of many diseases, such as atherosclerosis, intestinal tumors, and nonalcoholic steatohepatitis (NASH). The development of many diseases has been linked to the proinflammatory effects of LPCAT3. This review focuses on the current knowledge of LPCAT3, including its function and mechanism in different diseases. We aim to provide a comprehensive and in-depth understanding of LPCAT3 and to provide new ideas for the treatment of some diseases. Of these phospholipids, PC is the most abundant phospholipid in mammalian cell membranes and subcellular organelles, accounting for approximately 40-50% of total phospholipids de novo synthesis pathway de novo synthesis of phospholipids, the fatty acyl chains in the sn-2 position of phospholipids are hydrolyzed by phospholipase A2 (PLA2) to produce 1-acyl lysophospholipids, which react with lysophospholipid acyltransferase (LPLAT) to incorporate another fatty acid into the sn-2 position and form a new phospholipid species.However, the acyl groups in glycerophospholipids show a high degree of diversity and are distributed in an asymmetric manner that cannot be fully explained by the Lysophosphatidylcholine acyltransferases (LPCATs) are LPLAT enzymes that specifically regulate the abundance of different PC species in a variety of cell and tissue types and thus play an important role in lipid metabolism and homeostasis. LPCATs belong to two distinct families based on their amino acid sequences. LPCAT1 and LPCAT2 are members of the acylglycerol phosphate acyltransferase family, which contains four conserved structural domains, called LPA acyltransferase motifs 1-4 LPCAT3, also known as MBOAT5, belongs to the MBOAT family. LPCAT3 contains the MBOAT motif but lacks the LPA acyltransferase motif LPCAT3 is responsible for most LPCAT activity in certain cell types Arachidonic acid (AA) is a precursor to important lipid mediators such as leukotrienes and prostaglandins that induces inflammation and is associated with the progression of atherosclerosis Atherosclerosis has been shown to be closely associated with inflammation and to exist in close association with macrophages, with macrophage-derived foam cells in the vessel wall producing many proinflammatory chemokines and cytokines In summary, in macrophages, LPCAT3 exerts a proinflammatory effect by regulating the expression of C-SRC and TLR4, thereby promoting the further development of atherosclerosis. At the same time, LPCAT3 can also regulate two inflammatory proinflammatory factors, LPC and AA, in vascular smooth muscle, thereby exacerbating atherosclerosis.Muscle weakness is one of the main features of skeletal muscle myopathy, and obesity leads to a reduction in certain lipid species in the muscle, leading to the development of muscle weakness and severe skeletal myopathy. Through a comprehensive lipid profile analysis, we found that skeletal muscle lysoPC was positively correlated with maximal force production capacity. Interestingly, previous studies have found that obesity leads to a reduction in muscle lysoPC A recent study has tested these hypotheses. This study found slight contractile dysfunction in skeletal muscle after the overexpression of LPCAT3 in the skeletal muscle of mice. In contrast, in HFD-fed skeletal-muscle-overexpressing LPCAT3 mice, significantly reduced lysoPC levels and severe myopathy were observed Recent studies have revealed certain links between LPCAT3 and the development and progression of NASH. First, LPCAT3 expression is regulated by LXR. Lpcat3 expression is increased by LXR activation, which promotes the entry of unsaturated fatty acids into PLs and reduces ER membrane saturation, thereby reducing ER stress and liver inflammation. In contrast, acute knockdown of hepatic LPCAT3 exacerbates ER stress and liver inflammation Another study also measured LPCAT3 expression in a NASH mouse model and found opposite results. The NASH mice in this study were induced by an HFDS (high fat diet + sucrose). NASH mice had significantly lower expression of LPCAT3 mRNA and significantly higher LPC content than control mice. When shRNA-mediated knockdown of Lpcat3 in Huh-7 cells (shLpcat3 cells) was treated with palmitic acid (PA), the intracellular LPC concentration and cell death were significantly higher than those in wild-type Huh-7 cells. In contrast, intracellular LPC and palmitic-acid-induced cell death were significantly lower in LPCAT3-overexpressing Huh-7 cells than in wild-type cells Although we cannot yet determine why two experiments measuring LPCAT3 expression in NASH mice yielded opposite results, it is certain that LPCAT3 expression is closely linked to the progression of NASH. The exact relationship and the corresponding mechanisms need to be further investigated.One enzyme that plays a major role in diet-induced cardiometabolic disease is group 1B phospholipase A2 (PLA2G1B), which catalyzes fat digestion in the intestinal lumen after feeding When liver LPCAT3-overexpressing mice and control mice were fed a mixed liposaccharide diet separately, the control mice showed significant glucose tolerance abnormalities, whereas LPCAT3-overexpressing mice showed improved postprandial hyperglycemia and glucose tolerance in vitro experiments yielded similar findings. Human skeletal muscle cells (HSKMCs) were collected from insulin-sensitive and lean (ln) or insulin-resistant and obese (ob) subjects, and human primary muscle cells from ob subjects were more insulin-resistant than those from ln controls in vitro. LPCAT3 knockdown also enhanced insulin signaling in HSKMCs from obese subjects Surprisingly, however, the overexpression of LPCAT3 in skeletal muscle led to the opposite result. Skeletal muscle is the site of the greatest glucose handling in humans As previously described, we learned that hepatic LPCAT3 overexpression improves glucose tolerance by reducing LPC levels and thereby enhancing mitochondrial fatty acid β-oxidation. However, LPCAT3 overexpression in skeletal muscle exacerbates glucose intolerance, and the inhibition of its expression enhances insulin signaling and improves insulin sensitivity, thereby improving insulin resistance. Modern medical research has found that patients with low glucose tolerance can develop diabetes and that 10%-50% of patients with low glucose tolerance become clinically diabetic after 10 years of follow-up. At the same time, it has been found that insulin resistance is prevalent in type II diabetes, accounting for almost 90% of cases, and may be an important initiating factor in the development and progression of type II diabetes. However, we are currently unsure whether there is a direct link between LPCAT3 and the development of diabetes, and this needs to be further investigated.The few intestinal stem cells (ISCs) in the intestinal crypts continuously divide to give rise to daughter stem cells and highly proliferative progenitor cells called transitional amplification (TA) cells min mouse model, cholesterol biosynthesis was enhanced following intestinal LPCAT3 deficiency, stimulating ISC proliferation and significantly contributing to intestinal tumorigenesis In epidemiological studies, cholesterol intake has been associated with an increased risk of gastrointestinal cancers Thus, we suggest that intestinal LPCAT3 deficiency is likely due to the promotion of cholesterol production, which induces excessive ISC proliferation and further promotes intestinal tumor formation.Within the tumour microenvironment (TME), tumor-associated macrophages (TAMs) represent one of the most abundant immune cell types and are characterised by heterogeneity and plasticity, resulting in populations ranging from anti-tumour to pro-tumour tams1. Emerging evidence suggests that dysregulated lipid metabolism not only enhances the metastatic and invasive behaviour of cancer cells in vitro and in vivo experimental models to assess the role of LPCAT3 in BCBM.Ferroptosis is a newly discovered form of non-apoptotic cell death driven by the catastrophic accumulation of iron-dependent lipid reactive oxygen species (ROS) and is morphologically, biochemically and genetically distinct from traditional cell death such as apoptosis, necrosis and autophagy With the above discussion, we find that the promise of LPCAT3's potential therapeutic role in cancer is enormous. It can exert anti-tumour effects by regulating ER stress. Meanwhile, its role in ferroptosis in addition to that of a marker, the mechanism by which LPCAT3 exerts specific anti-cancer effects needs to be further investigated.LPCAT3, as the main LPCAT in the liver, intestine and adipose tissue, especially the liver and intestine LPCAT3 is currently of most interest for its role in inhibiting tumourigenesis and progression, but little research has been done in this area. Although LPCAT3 has now been shown to inhibit ferroptosis, it is not known whether it can subsequently inhibit tumor progression. The research is still limited to its role as a marker for breast and ovarian cancer, but more research is needed to determine what role LPCAT3 plays in cancer or what its mechanism of action is. However, we are pleased that the latest research has demonstrated that LPCAT3 may exert anti-tumor effects through the IRE1-XBP1 pathway of the ERs. Even more surprisingly, that LXR, the upstream regulator of LPCAT3, may act through its agonist to increase LPCAT3 expression. Therefore, our future studies could be further investigated into the relationship between LPCAT3 and ERs and the tumorigenesis and progression associated with ERs. In particular, we know that ERs is closely related to the development of inflammation, which can further lead to the development of cancer, such as NASH-driven HCC (hepatocellular carcinoma). More importantly, we have known that LPCAT3 is the predominant LPCAT in the liver and regulates hepatic ERs contingency. Therefore, it is reasonable to wonder whether LPCAT3 can inhibit the NASH to HCC transition.This review focuses on the structural and functional characteristics of LPCAT3, especially the progress of research on the potential mechanisms involved in different diseases, such as atherosclerosis, intestinal tumors, NASH, skeletal myopathy and insulin resistance, and identifies some patterns of LPCAT3 in the development of these diseases Fig. . At the