Despite its crucial importance in numerous physiological processes, iron also causes oxidative stress and damage which can promote the growth and proliferation of leukemic cells. Iron metabolism is strictly regulated and the related therapeutic approaches to date have been to restrict iron availability to tumor cells. However, since a new form of iron-catalyzed cell death has been described, termed ferroptosis, and subsequently better understood, iron excess is thought to represent an opportunity to selectively kill leukemic cells and spare normal hematopoietic cells, based on their differential iron needs. This review summarizes the physiology of iron metabolism and its deregulation in leukemia, the known ferrotoposis pathways, and therapeutic strategies to target the altered iron metabolism in leukemia for the purposes of initiating ferroptosis in these cancer cells. Among these processes is the Fenton reaction, in which a ferrous iron donates an electron to hydrogen peroxide to yield hydroxyl radicals, thereby inducing highly reactive oxygen species (ROS) , DNA synthesis (ribonucleotide reductase), oxygen transport, antioxidant defense , oxygen sensing factors (hypoxia-inducible factor – HIF – and prolyl hydroxylases), and many others. The ability of iron to gain and lose electrons between its oxidized Fees (ROS) . The abeAcute myeloid leukemia (AML) results from oligoclonal proliferations arising from the transformation of immature myeloid hematopoietic cells, characterized by a differentiation blockage and acquisition of a survival advantage and proliferation gain. AML displays high heterogeneity at the phenotypic, genetic and molecular levels . RecurreTo enable growth, leukemic cells exhibit an increased iron demand compared with normal cells . Accumul3+) is absorbed in the duodenum via divalent metal transporter 1 (DMT1) after the action of a ferric reductase, duodenal cytochrome b (Dcytb), which converts Fe3+ to Fe2+. Alternatively, heme iron is imported into enterocytes through an unknown mechanism and is thereafter, degraded by heme oxygenase 1 (HO-1), liberating Fe2+. Iron exits the basolateral surfaces of the enterocytes across the sole iron efflux pump yet known, ferroportin (FPN), along with hephaestin which oxidizes Fe3+ to Fe2+, and then is loaded onto transferrin (Tf). The holo-transferrin complex Tf – Fe3+ circulates in the plasma to deliver iron to its sites of utilization, mostly to the bone marrow to enable erythropoiesis. After binding to transferrin receptor 1 (TFR1), the Tf-Fe3+/TFR1 complex is subsequently taken into cells by receptor-mediated endocytosis, reduced to Fe2+ by the six-transmembrane epithelial antigen of prostate 3 (STEAP3), and transported into the cytosol by DMT1. The Tf/TFR1 complex is finally recycled to the cell surface. Recycling from senescent red blood cells by macrophages is by far the main source of iron, whereas dietary intake is marginal and compensates for iron losses only. The released Fe2+ constitutes the labile iron pool (LIP) and is either stored in ferritin (FTH) or used for metabolic needs, or even exported into the circulation via FPN after being re-oxidized by ceruloplasmin (Iron homeostasis is a highly tuned process. Dietary iron (predominantly in the form of Feoplasmin .The predominant pathway for iron output into the cytosol from ferritin is controlled by nuclear receptor coactivator 4 (NCOA4)-mediated selective autophagy, whereby NCOA4 binds ferritin to traffic it to the lysosome where it is degraded and iron is then released for use by the cell . Non-stoin vivo experiments  . NotablyIron markers of intake, storage and export are commonly concurring to iron overload. TFR1 expression, known as CD71, is generally increased in leukemic cells compared to normal counterparts and its level may be directly correlated to the degree of differentiation as AML, whether minimally differentiated or not, has the highest level of CD71 expression . The proRegarding the iron storage counterpart, serum ferritin is also frequently increased in leukemic patients and is a pejorative factor in overall and relapse-free survival in chemotherapy-treated patients –40 as weDysregulation of the ferroportin-hepcidin axis is a common feature in AML, entailing reduced iron efflux. Notably, low ferroportin expression in AML seems to correlate with improved outcomes and greater chemotherapy sensitivity, and is consistently found in core binding factor (CBF) AML subsets . HepcidiThe ability of tumor cells to fuel iron availability that enables sustained proliferation, ROS accumulation and evasion of adaptative host immunity has prompted research into iron chelation strategies. Moreover, such strategies became of paramount interest in the context of iterative blood transfusions in leukemic patients, in whom chronic iron overload leads to secondary hemochromatosis responsible for cardiac, hepatic, or endocrinal damage.in vitro  and deferasirox (DFX), by lowering LIP and hampering ROS production and iron-dependent enzymes such as ribonucleotide reductase –53, exerin vitro , althougin vitro .2+ in the tumor microenvironment to activate drug release  from an alkoxyl or an hydroxyl radical via the Fenton reaction in the presence of peroxide (H2O2). These reactions are not mutually exclusive and can operate together, especially since the LOXs are iron-containing enzymes  prevents the experimental induction of ferroptosis , although it cannot do so once ferroptosis is launched . In addiin vitro or murine in vivo models (©), an FDA approved intravenous iron nanoparticle for treating iron deficiency in patients with chronic kidney disease, showed anti-leukemic effects in vitro and in murine models bearing leukemia cells with low FPN expression (in vitro anti-leukemic properties via ferroptosis or necroptosis (Ferroptosis has gained considerable interest as a potential widespread anti-cancer strategy, although most of the research thus far has been restricted to o models –98. GPX4o models , as for o models . Hence, pression . Iron saroptosis . Notablyroptosis . Ferroptroptosis  in RAS-mroptosis . Erastinroptosis . Furtherroptosis . Recentlroptosis . A putatRecent insights into iron metabolism along with the recent discovery of ferroptosis have opened new avenues in the field of anti-tumor therapies. Metabolism rewiring between glycolysis and mitochondrial oxphos respiration in tumors has proven to be an anchor for new and effective therapeutic combination strategies such as the association of the BCL2-BH3 mimetic and hypomethylating agents, which are able to specifically target the LSC compartment. Additionally, iron metabolism dysregulation toward increased iron demands is a specific feature of tumor cells which has been considered almost exclusively until now as an opportunity to test iron deprivation approaches against the tumor cells, whether than using it as an Achilles heel. Opportunities to tailor new strategies that also utilize ferroptosis will arise in the coming years.in vitro and murine AML models are required to assess the feasibility of such strategies. Data are currently lacking in this regard for hematological malignancies and specifically for AML, thus hindering further therapeutic perspectives. Second, in addition to the iron supplementation or iron metabolism actor modulation, combination strategies using ferroptosis inducers are probably desirable to lower the sensitivity threshold of cancer cells to ferroptosis and thus avoid iron-mediated off-target damage. This point is of major interest since great efforts have been made to identify and develop ferroptosis triggers over the past decade. Hence, a widespread introduction of iron-based treatments into the mainstream oncology arsenal in a personalized fashion and with the purpose of inducing iron-catalyzed death is a promising anti-cancer strategy.Because non-targeted iron supplementation could increase tumorigenicity and cause deleterious systemic effects, feeding tumor cells with iron or reshaping iron metabolism mechanisms to trigger ferroptosis will be a complex problem to solve. First, because of the heterogeneous sensitivity to iron-catalyzed necrosis among cancers, thorough analyses using EG and DB contributed conception and design of the review. RB and NC provided critcial revisions to the content. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Spinal muscular atrophy (SMA) is an autosomal recessive condition that results in pathological deficiency of the survival motor neuron (SMN) protein. SMA most frequently presents itself within the first few months of life and is characterized by progressive muscle weakness. As a neuromuscular condition, it prominently affects spinal cord motor neurons and the skeletal muscle they innervate. However, over the past few decades, the SMA phenotype has expanded to include pathologies outside of the neuromuscular system. The current therapeutic SMA landscape is at a turning point, whereby a holistic multi-systemic approach to the understanding of disease pathophysiology is at the forefront of fundamental research and translational endeavours. In particular, there has recently been a renewed interest in body composition and metabolism in SMA patients, specifically that of fatty acids. Indeed, there is increasing evidence of aberrant fat distribution and fatty acid metabolism dysfunction in SMA patients and animal models. This review will explore fatty acid metabolic defects in SMA and discuss how dietary interventions could potentially be used to modulate and reduce the adverse health impacts of these perturbations in SMA patients. Spinal muscular atrophy (SMA) is a debilitating neuromuscular disorder, which predominantly affects children within the first months of life, affecting 1:10,000 live births .survival motor neuron 1 (SMN1) [SMN2 [SMN2, humans would not live to develop the condition. There are only five nucleotides that are different between the paralogues, which does not alter coding for amino acids but does affect pre-mRNA splicing [SMN2 gene [SMN2 is extremely important in the context of SMA as gene copy number is a positive modifier of the condition. Indeed, it has been shown that disease severity is inversely proportional to the number of SMN2 copies [SMN1 is compensated for, to a greater or lesser extent, by the number of SMN2 copies a person possesses and thus the amount of SMN that can still be produced. SMA, therefore, results from the complete loss of SMN1 and the concurrent retention of at least one copy of SMN2  protein. In >90% of SMA patients, there is homozygous loss of the gene encoding this protein: 1 (SMN1) ,4. This 1 (SMN1) . Interessplicing . The subMN2 gene  primarilMN2 gene , leading2 copies . In esse of SMN2 .SMN2 gene copy number is the major disease modifier, as a greater number of SMN2 copies results in a larger amount of functional full-length SMN protein being produced [SMN2 copies, type II patients 2–4 copies, type III patients 2–5 copies and type IV patients 4–6 copies [SMA is clinically classified into types based on severity and age of onset, whereby produced . Type I,produced . Type IIproduced . Patientproduced . Type IIproduced . Type IIproduced . Type IVproduced . Type IVproduced . In gene6 copies . The ove6 copies .SMN is ubiquitously expressed  and the By conventional body mass index (BMI) measurements, SMA patients often appear normal or underweight . HoweverOne possible contributor to the increased fat mass in SMA patients is an imbalance between dietary intake and energy expenditure. The degenerative nature of SMA makes this scenario quite plausible as progression of the disease leads to increasing immobilisation. In 2015, a retrospective study was conducted based on clinical data from 60 SMA patients  in order to assess nutrient intake and establish nutritional status . AnthropFats have multiple roles within the body, from membrane components to signalling molecules, but they are most commonly associated with energy metabolism. In the form of triglycerides, they are the primary source of energy storage as they contain a higher energy content per gram  than both proteins and carbohydrates  . In the Oxidation of fatty acids predominantly occurs by beta oxidation in the matrix of mitochondria, following activation of fatty acids through thioester bonding with Co-enzyme A (CoA). This process removes a hydroxyl group from the fatty acids, forming highly polar thioesters called acyl-CoA molecules. Long chain acyl-CoA molecules (10+ carbons) cannot freely pass through mitochondrial membranes and require shuttling in the form of carnitine derivatives, referred to as acylcarnitines or esterified carnitines, whereby an ester bond links the fatty acyl-CoA to the carnitine molecule . Once inWhile the majority of beta oxidation takes place in the mitochondria, additional beta oxidation also occurs inside peroxisomes. Peroxisomes are double membrane-bound organelles found in eukaryotic cells and they are responsible for the catabolism of various types of molecules as well as the exclusive site of alpha oxidation of fatty acids  that othOne of the earliest accounts associating SMA with potential fatty acid metabolic abnormalities is a case report by Kelley and Sladky in 1986 , where aFatty acid metabolism defects have since been regularly reported in SMA such as in a study of 14 SMA patients that displayed dicarboxylic aciduria, high excretion of urinary acylcarnitines and carnitine deficiency in both muscle and serum . A deficFasting and non-fasting fatty acid profiles revealed similar abnormalities in serum and urine samples from 50 SMA patients when compared to healthy controls and infants suffering from a denervating condition that is not caused by loss of SMN . The SMAThere is therefore consistent evidence of disruption of fatty acid metabolism in SMA patients . What isAs discussed above, there is a need to better understand the relationship between fatty acid metabolism defects, aberrant fat accumulation and diet in SMA. SMA mouse models are well established, display the canonical hallmarks of the disease and have been invaluable to our understanding of pathological mechanisms and therapeutic development . NotablyThe importance of nutrition and its impact on SMA disease progression was first highlighted following the observation that severe SMA mice lived 2–4 days longer when maintained on a 9% fat diet compared to a 5.2% fat diet . InteresBoth 9% and 5.2% fat-containing diets were found to have no effect on spinal cord motor neuron loss, onset of body mass loss or overall body weight. There were however differences noted when looking at energy metabolites. In general, wild type (WT) mice had higher blood glucose levels than SMA mice. The 5.2% fat diet-fed mice (both WT and SMA) were found to have higher blood glucose than 9% fat diet-fed mice. Additionally, ketone levels were higher in SMA mice compared to WT animals and this was most evident in SMA mice fed the 5.2% fat diet. These results suggest that some dietary component is affecting the SMA phenotype, which may be fat content but also additional dietary elements that differed between both diets .In a more recent study, a high-fat diet (HFD)  and low-fat diet (LFD)  were compared to normal chow (NC) in SMA mice . SimilarThe contradictory conclusions between both studies, whereby one favours a HFD  and the SMN2 transcripts, was administered to mice either on a Picolab20 or Harlan diet [While diet alone can have a profound effect on the health of an organism, in the context of medical care, it is also very important to consider its interaction with a drug treatment. Indeed, the bioavailability and pharmacokinetics of pharmacological compounds are especially influenced by diet and body composition ,55. D158lan diet . A 15% iA further example of drug and diet interaction in SMA mice is demonstrated in a study evaluating the therapeutic potential of Trichostatin (TSA), a histone deacetylase inhibitor . This drOverall, while these studies in pre-clinical models clearly demonstrate a role for dietary interventions in the management of SMA symptoms and disease progression, there remains a lack of clear identification of the key specific dietary constituents and their levels. A better understanding of these components is essential for the development of nutritional guidelines for SMA patients .The current nutritional guidelines for SMA patients recommend dietary adjustments based on assessments of swallowing, dysphagia, weight, gastrointestinal function, glycaemic control and bone health  but not However, patients and their families have nevertheless developed and adopted elemental diets. Elemental diets are amino acid based and low in fat feeds, meant to provide nutrition in the simplest elements to reduce the energy cost of digestion . Diets sIt is important to note, however, that diets that are low in fat, such as elemental diets, are at risk of being deficient in essential fatty acids and may require particular attention to ensure an adequate intake of all nutrients and essentials acids . In an oThere is thus a clear need for more in-depth pre-clinical and clinical studies on dietary interventions in SMA to help inform clear and evidence-based nutritional guidelines aimed at reducing the impact of aberrant fatty acid metabolism on whole-body health.The first account of fatty acid metabolism defects in SMA was in the late 1980s . Since tMost tissues are involved in fatty acid metabolism, however, adipose tissue, skeletal muscle and liver are quantitatively more important than others. Each of these tissues has a store of triacylglycerol that can be mobilized in a regulated way to release fatty acids. There is a clear cooperation amongst these tissues and an overlap of fatty acid metabolism pathways in order to maintain whole body homeostasis . ImportaWhilst the present review focused on fatty acid metabolism, other metabolic pathways have been implicated in SMA pathology. Indeed, glucose metabolism defects such as fasting hyperglycemia, glucose intolerance and hyperglucagonemia have been observed in SMA mice and patients ,78. MoreFrom the studies presented here, it appears that both the severity of disease and age critically impact fatty acid metabolism defects in SMA patients, which should be taken into consideration when undertaking studies to establish nutritional guidelines. Of importance is that in the current therapeutic landscape of SMN-dependent therapies, patients are living much longer and reaching milestones never before seen . Consequacyl-CoA synthetase long chain family member 5 (ACSL5) gene, whose protein regulates lipid and fatty acid metabolism pathways [There is also significant evidence that, in addition to SMA, fatty acid metabolism may play a role in the pathophysiology of other neurodegenerative and neuromuscular disorders such as amyotrophic lateral sclerosis (ALS) , multiplpathways ,88, was pathways . As suchpathways ,91, ketopathways  and acetpathways ) have bepathways . TherefoSMN gene-based therapies will be essential to better understand the nature of the metabolic perturbations and the contribution of different CNS and peripheral tissues to the fatty acid metabolism defects.In conclusion, further work is needed to determine optimal dietary practices to support the quality of life and well-being of SMA patients , which c


The skeleton is a dynamic and metabolically active organ with the capacity to influence whole body metabolism. This newly recognized function has propagated interest in the connection between bone health and metabolic dysfunction. Osteoblasts, the specialized mesenchymal cells responsible for the production of bone matrix and mineralization, rely on multiple fuel sources. The utilization of glucose by osteoblasts has long been a focus of research, however, lipids and their derivatives, are increasingly recognized as a vital energy source. Osteoblasts possess the necessary receptors and catabolic enzymes for internalization and utilization of circulating lipids. Disruption of these processes can impair osteoblast function, resulting in skeletal deficits while simultaneously altering whole body lipid homeostasis. This article provides an overview of the metabolism of postprandial and stored lipids and the osteoblast's ability to acquire and utilize these molecules. We focus on the requirement for fatty acid oxidation and the pathways regulating this function as well as the negative impact of dyslipidemia on the osteoblast and skeletal health. These findings provide key insights into the nuances of lipid metabolism in influencing skeletal homeostasis which are critical to appreciate the extent of the osteoblast's role in metabolic homeostasis. Development of the mammalian skeleton and maintenance of its structure for the life of the organism requires the coordinated actions of two specialized cells. Osteoclasts, large multinucleated cells that are derived from the monocyte/macrophage lineage of hematopoietic cells, are responsible for bone resorption. After attaching to an exposed bone surface, osteoclasts acidify a resorption lacuna to dissolve the mineral fraction of bone and then secrete proteolytic enzymes that degrade the organic matrix component . During The tremendous economic impact of osteoporotic fractures –9 and deOsteoblasts harvest energy from a number of fuel molecules. Studies performed more than 50 years ago first highlighted the avidity of osteoblasts for glucose. Isolated osteoblasts or bone tissue explants from mice, rats, rabbits, and humans all used glucose to produce lactate even under aerobic conditions –34. MoreWhile lipid metabolism yields significantly more ATP than glucose or glutamine catabolism, its role in osteoblast function remains more controversial. Recent studies have highlighted the importance of fatty acid catabolism for normal bone formation , 40, butThe lipid molecules that support cellular metabolism are primarily derived from three sources: ingested fat, lipoproteins produced by the liver, and non-esterified fatty acids released by white adipose tissue . Postprade novo lipogenesis. Lipid molecules from each of these sources can be used to generate ATP in the liver or they can be packaged along with apolipoprotein (Apo) B-100, ApoC, and ApoE into very low-density lipoproteins (VLDL) on the endoplasmic reticulum. VLDL are released into the circulation and metabolized by target tissues in a manner similar to that of chylomicrons, with LPL hydrolyzing triglycerides to fatty acids that can be imported by cells. In this case, the remaining lipoprotein particle is further metabolized to low density lipoprotein (LDL), which can be taken up by many tissues via the LDL receptor  and medium-chain (7-12 carbons) fatty acids are produced by the bacterial fermentation of dietary fiber or the ingestion of dairy products. These lipids are primarily metabolized by enterocytes or by hepatocytes and are beyond the scope of this review . Long-chn of ATP . Successn of ATP .2 produced by one round of mitochondrial β-oxidation yields 2 ATP, the electrons from FADH2 produced by peroxisomal oxidation are donated to oxygen to form H2O2. For this reason, chain shortened fatty acids can be shuttled to the mitochondria for further metabolism via β-oxidation.Very long chain fatty acids (more than 22 carbons) can also be used to generate ATP but must be chain-shortened in peroxisomes before they can enter the mitochondria . Multi-fin vivo , which should eliminate intracellular lipolysis, but did not find a defect in either in vitro osteoblast performance or bone structure in vivo. Therefore, osteoblasts appear to require extracellular lipid sources.Although they are smaller than those evident in adipocytes, most cells contain a lipid droplet that can presumably be used to generate ATP via β-oxidation. Histological studies indicate that both mature osteoblasts and differentiating osteoblast progenitors contain stored lipid , 52, butin vivo and in vitro studies have examined the uptake of circulating lipoproteins and free fatty acids by the osteoblast and the skeleton. In perhaps the most comprehensive study, Neimeier and colleagues  requires care as studies have reported both reduced  revealed an osteopenic phenotype but there was no effect on systemic lipoprotein clearance or osteoblasts' ability to sequester fatty acids  and express Scarb1  , the majin vitro . A folloin vitro . However in vivo . Here to in vivo  suggestiOsteoblasts also express the receptors necessary to take up and metabolize free fatty acids. CD36 is a two-transmembrane glycoprotein receptor that binds long-chain fatty acids as well as oxidized low-density lipoprotein (oxLDL) and facilitates their transport into the cell , 76. Whiflox/flox; Osteocalcin-Cre) . The skeletal phenotype of the mutant mice was sexually dimorphic, with male mice fed a normal chow diet exhibiting only a transient decrease in trabecular bone volume in the distal femur and L5 vertebrae at 6 weeks of age. By contrast, female mutants exhibited defects in trabecular bone volume in the distal femur and L5 vertebrae and an expansion of cortical bone tissue area at both 6 and 12 weeks. This discrepancy between sexes appears to be related to a greater ability to adjust fuel utilization in males, as male mutants exhibited an increase in femoral glucose uptake that was not evident in female mutants. The greater inhibition of osteoblast performance and inhibition of glucose uptake in CPT2 mutant osteoblasts treated with estrogen may explain the sex differences in metabolic flexibility. Interestingly, both male and female CPT2 mutants exhibited an increase in serum free fatty acid levels, which suggests that disrupting fatty acid utilization by osteoblasts and osteocytes is sufficient to alter lipid homeostasis (The effects of specific fatty acids on the functions of the major bone cells has recently been reviewed elsewere . Direct cin-Cre) . As noteeostasis .In the second study, van Gastel et. al.  identifiPEX1- PEX26) that encode proteins necessary for either the formation of peroxisomes or the transport of cargo into the organelle. Loss of function mutations in peroxin genes, which occur at a rate of ~1 in 50,000 births, result in autosomal recessive peroxisomal biogenesis disorders (PBD) that affect a number of organ systems. Individuals with more severe PBD subtypes often exhibit craniofacial anomalies, short stature, and limb length discrepancies. Less severe subtypes have been associated with reductions in bone mineral density and an increased susceptibility for non-traumatic fractures  results in decreases in bone mineral density and vertebral trabecular bone volume (G171V) in osteoblasts produced the opposite phenotype, as the transgenic mice exhibited increases in bone volume and oxidative gene expression as well as decreases in fat mass, serum triglycerides, and fatty acids.The anabolic effects of Wnt signaling on skeletal development, repair, and homeostasis have been well-studied , 90, ande volume , Frey ete volume  found thin vivo, the generation of an inducible β-catenin knockout mouse  was necessary to examine the transcription factor's effects on fatty acid oxidation. In this model, the temporal ablation of β-catenin resulted in high-turnover bone loss as well as increased fat mass and the development of insulin resistance. Additionally, the expression of genes involved in long-chain fatty acid oxidation and the ability to oxidize oleate were reduced in β-catenin deficient osteoblasts in vitro, while serum fatty acid levels were increased in the mutants in vivo. These studies have expanded the role of canonical Wnt-signaling to influencing fatty acid utilization and coordinating whole-body energy homeostasis.Subsequent genetic studies revealed that Wnt-mediated regulation of fatty acid oxidation proceeds via a β-catenin-dependent mechanism. Frey et al.  found thAs indicated above, a number of contemporary studies suggest that Wnt signaling also regulates glucose and glutamine utilization by the osteoblast. Wnt signaling through LRP5 increased aerobic glycolysis in the ST2 bone marrow stromal cell line  and miceParathyroid hormone (PTH) is a master regulator of serum calcium that signals in the bone, kidney, and intestine to increase calcium levels. Intermittent administration of human recombinant PTH (1-34) is now used to reduce the occurrence of vertebral and non-vertebral fractures and increased bone mineral density in postmenopausal osteoporotic women . This thThe first indication that PTH might influence fatty acid oxidation were completed by Adamek et al. . In thisThe Centers for Disease Control (CDC) reports that 95 million adults age 20 and older have high cholesterol (>200 ng/dL) while about 25% have elevated triglyceride levels . The afoOver the last decade a combination of high fat diet (HFD) feeding models and hyperlipidemic mouse models have been used to investigate the effects of dyslipidemia on skeletal homeostasis. In addition to the development of hypertriglyceridemia, these models exhibit a host of metabolic defects, including but not limited to adipose hyperplasia, hyperinsulinemia, insulin resistance, central leptin resistance, and hepatic steatosis [reviewed in ], that cHistomorphometric analyses and serum measurements of bone turnover markers consistently demonstrated that trabecular bone loss in HFD and hyperlipidemic mice is secondary to a reduction in osteoblast numbers and function as well as an increase in the abundance of osteoclasts , 132. Coin vitro culture systems wherein cultures of primary osteoblasts or osteoblast-like cell lines are treated with exogenous lipids have proven helpful , but multiple markers of bone formation were reduced which suggests that skeletal insulin resistance may contribute to bone loss associated with dyslipidemia.The importance of insulin signaling in the osteoblast is revealed by the increased risk of fracture and decreased BMD in type 1 diabetes [reviewed in –162], inPPARγ, a transcriptional regulator of adipogenesis that can be activated by elevated lipid levels. In bone, the nuclear receptor influences bone remodeling by stimulating adipogenic differentiation of mesenchymal stem cell at the expense of osteoblastogenesis and by stimulating osteoclastogenesis , the mutant mice exhibited increases in femoral bone mineral density and trabecular bone volume as well as reduced fat mass and increased energy expenditure (in vitro studies wherein the 3T3-L1 adipocyte cell line was treated with medium conditioned by PPARγ deficient osteoblasts culture media and exhibited reduced Oil Red O staining than those exposed to medium conditioned by wildtype osteoblasts (It is important to note that genetic ablation of PPARγ has beneficial effects on bone and body composition. Akune and colleagues  reportedenditure . Crosstaeoblasts . Furthereoblasts . TherefoIn this review, we have attempted to convey the necessity of lipid utilization by the osteoblast for normal skeletal homeostasis as well as the potential for dyslipidemia to impair osteoblast function and lead to an imbalance in bone remodeling. Mitochondrial long chain fatty acid oxidation is of sufficient importance for osteoblast function that [1] genetic impairments in this metabolic pathway lead to alterations in whole body lipid homeostasis and [2] signaling pathways essential to bone mass accrual influence fatty acid metabolism. Future studies should be directed toward more fully delineating the mechanisms of fatty acquisition by osteoblasts. These studies will require the development of new genetic mouse models in which transporters are disrupted specifically in the osteoblasts as global knockout models exhibit disturbances in metabolism that may indirectly influence bone remodeling. Determining the mechanisms by which osteoblasts convey their need for sufficient fatty acid supply to other tissues is equally vital. In this regard, the emergence of bone as a hormone-producing tissue is likely to provide key insights into the responsible endocrine networks. As we noted above, the detrimental effects of dyslipidemia, particularly in response to a high fat feeding in rodent models, on bone mass and the balance of bone formation and resorption are well-known, but the underlying mechanisms are still poorly understood. The increased recognition of bone as a lipid-utilizing tissue is likely to lead to a renewed interest in this area. Together these studies will provide a deeper understanding of the intimate interaction between the skeleton and metabolism and hopefully lead to treatment strategies that simultaneously reduce the burden of obesity and metabolic disease and preserve skeletal homeostasis.All authors contributed to the drafting of this manuscript and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Tumor-associated macrophages (TAMs) occupy an important position in the tumor microenvironment (TME), they are a highly plastic heterogeneous population with complex effects on tumorigenesis and development. TAMs secrete a variety of cytokines, chemokines, and proteases, which promote the remodeling of extracellular matrix, tumor cell growth and metastasis, tumor vessel and lymphangiogenesis, and immunosuppression. TAMs with different phenotypes have different effects on tumor proliferation and metastasis. TAMs act a pivotal part in occurrence and development of tumors, and are very attractive target to inhibit tumor growth and metastasis in tumor immunotherapy. This article reviews the interrelationship between TAMs and tumor microenvironment and its related applications in tumor therapy. While containing a large number of malignant epithelial cells, the tumor is also surrounded by surrounding immune cells, neovascularization and its endothelial cells, cancer associated fibroblasts (CAFs), and TAMs surrounded by the extracellular matrix, it forms a unique microenvironment Macrophages are the most inflammatory cells infiltrated into tumors, also known as tumor-associated macrophages. Their content can reach more than 50% of the mass of solid tumors, and they major involved in the inflammatory response of tumors. Studies have shown that treatment methods that target tumor cells alone are not sufficient to treat tumors. Tumor therapy should target tumor cells and their microenvironment as a common target This paper reviews the recent involvement of TAMs in tumorigenesis and its related applications in tumor therapy, in order to find new strategies for treating tumors.Solid tumors are composed of malignant cells and some non-malignant hematopoietic and mesenchymal cells The exact origin of TAMs has been controversial. Current research indicates that in mouse models, TAMs are mainly derived from bone marrow monocytesTAMs can be divided into two categories, namely pro-inflammatory M1 type and anti-inflammatory M2 type  and matrix metalloproteinase 7 (MMP-7), thereby making T cells lose the ability to distinguish or even kill tumor cells, which create an immunosuppressive microenvironment TAMs are one of the important components of tumor microenvironment + T cells is also inhibited by TGF-β. The mechanism is to inhibit the expression of some cell lysing genes, such as granzyme A, granzyme B, IFN-γ and FAS ligand. Further promotes the expansion of the Tregs cell population + T cells to Th2 type TGF-β is a kind of cytokine with immunosuppressive function, and it can inhibit the activity of immune cells such as natural killer (NK) cells, dendritic cells (DCs), and T cells 2, which regulates TAMs polarization through the EP2 and EP4 receptors IL-10 is a versatile cytokine that allows malignant cells to evade immune regulation and promote tumor growth TAMs are strictly related to angiogenesis, which is rigid in tumorigenesis and development. As we all know, angiogenesis is essential for the growth and diffusion of malignant tumors. Tumor angiogenesis is the course of generating neovascularization from now available vascular system. The appearance of neovascularization not only provides oxygen and nutrients for tumor growth, but also provides a convenient condition for tumor metastasis Furthermore, TAMs assemble in tumor hypoxic zone be marked by hypoxia tension. TAMs can convey more angiogenic genes based on its adaptation to the hypoxic environment. Hypoxia-inducible factor (HIF)-1 and-2 act a pivotal part in regulating angiogenesis + macrophages usually bind to endothelial cells expressing ANG2 , and they are associated with tumor angiogenesis and tumor ischemia. After the recovery is highly relevant In a study of PyMT mice, the figure for macrophages in area surrounding tumor was decreased by 43% in PyMT mice treated with doxycycline. Decreasing the number of macrophages through this level can delay tumor progression, reduce tumor production, reduce cancer angiogenesis, and down-regulate the expression of many pro-angiogenic genes Tumor metastasis is one of the important signs to determine the stages of tumor. Ectopic tumor formation is caused by tumor cell metastasis through blood vessels and lymphatic vessels Polarization of TAMs can affect the proliferation, migration, invasion and angiogenesis in primary tumors and metastases. In the study of breast cancer, endometrial cancer and renal cell carcinoma, it was found that the infiltration amount of type M2 TAMs in tumor tissue was positively correlated with tumor cell proliferation. M2 tumor related macrophages advance tumor invasion and metastasis by influencing tumor microenvironment. Studies have confirmed that M2 macrophages secreted EGF, which accelerate epithelial ovarian cancer metastasis by activating EGFR-ERK signaling and inhibiting the deliverance of lncRNA LIMT TAMs also produce enzymes  to regulate interstitial metabolism. The activity of these enzymes is related to tumor aggressiveness. For example, MMP-2 is connected with lymph node metastasis and tumor staging in some tumors Lymphangiogenesis is the first step in the general transfer of tumor cells, indicating that the tumor has a poor prognosis. Maintaining the body's homeostasis, normal metabolism and immune response are inseparable from the normal function of the lymphatic system. Experimental and clinical studies have shown that TAMs can markedly advance lymphangiogenesis through cellular autonomic models and paracrine. Paracrine effects include activating lots of pre-existing lymphangiogenic factors.+ macrophages can accumulate in mouse corneal stroma and express VEGF-C to promote mouse corneal lymphangiogenesis Studies have found that macrophages are involved in the production of lymphatic vessels in an inflammatory environment. In the study of TAMs on the occurrence and development of ovarian cancer, it was found that TAMs have an impact on the proliferation, migration and capillary-like vessel make up of lymphatic endothelial cells (LEC). TAMs can release VEGF-C, which not only helps tumor angiogenesis, but also promotes tumor lymphangiogenesis In view of the importance of TAMs in the regulation of tumor immunity, treatment strategies for macrophages have attracted widespread interest Figure . The trein vitro results further indicate that SACC cell-derived CCL2 is involved in TAMs recruitment, M2 polarization and GDNF expression via the CCL2 / CCR2 axis. Treatment of immunodeficient mice with CCR2 antagonists greatly inhibited TAMs infiltration and SACC cell tumorigenicity One strategy for TAMs consumption is to key off the circulating inflammatory monocyte supply. The circulating monocytes are mobilized from the bone marrow and recruited into the site of inflammation, which highly rely on CCL2-CCR2 signaling. The suppression of CCR2 preserve monocytes in the bone marrow, leading to depletion of circulating cell pools and a reduction in the number of TAMs at the primary and metastatic sites CSF-1 is a cytokine that supports the differentiation, proliferation and function of monocytes and macrophages Macrophages are functionally plastic, so changing the environmental stimulus under pathological conditions and repolarizing M2 type TAMs into a tumor suppressing phenotype is a potential clinical strategy for cancer treatment. Eliminating or reducing the inducement of M2-type TAMs expression or using certain methods to reverse the phenotype of TAMs have become an important measure to restore the killing ability of macrophages. Reversing the TAMs phenotype can also destroy the tumor immunosuppressive microenvironment, inhibit the formation of tumor blood vessels and lymphatic vessels, and ultimately achieve the purpose of inhibiting tumor proliferation, invasion and metastasis TLR is an important pathogen recognition receptor expressed by TAMs. After TLR3 stimulation, M1 type marker MHCⅡ and costimulatory molecules such as CD86, CD80 and CD40 are up-regulated. In contrast, the expression of the M2-type markers CD206, T-cell immunoglobulin, and mucin domain 3 is reduced. The use of TLR3L in mouse tumors can change M2 type macrophages to M1 type and degenerate tumor growth In a study, it was demonstrated that Lachnum polysaccharide (LEP) can reverse TAM from the tumor-promoting M2 phenotype to the anti-tumor M1 phenotype, thereby enhancing anti-tumor immunity in vivo. IL-37 inhibits the M2 polarization of TAMs by regulating the IL-6 / STAT3 pathway, and together inhibits the growth of HCC When IL-12 was administered to mice with hepatocellular carcinoma, By down regulating STAT3 and its downstream transcription factor c-myc, we can change the functional phenotype of M2 TAMs, so as to reduce the production of tumor cytokines and inhibit the growth of tumors CD47 / SIRP-α signaling pathway is an important way for tumor immune escape. Almost all human cells express CD47 on the surface, and macrophages can express the CD47 receptor signal-regulating protein α (SIRP-α), and by combining with CD47, they can help macrophages distinguish normal cells from abnormal cells. And tumor cells can express CD47 highly, so as to achieve immune escape in vivoLeukocyte immunoglobulin-like receptor subfamily B (LILRB), The LILRB family is a class of repressive receptors presented by myeloid cells, and its ligand is MHC class I molecule. MHC class I component β2-microglobulin expressed by tumor cells can straight protect it from being engulfed. This protection is mediated by LILRB1, which is up-regulated on the surface of macrophages, especially TAMs. Blocking MHC class Ⅰ or LILRB1 can enhance the phagocytosis of macrophages after blocking CD47 molecules Nowadays, anti-PD-1 / PD-L1 therapy has become an important research direction for human cancer immunotherapy. Among them, TAMs can promote the apoptosis of T cells and participate in immunosuppression by expressing PD-L1 on the cell external. Some evidence indicates that TAMs, especially M2-type TAMs, express PD-L1 on their surface TAMs are an important component of the tumor local immunosuppressive microenvironment. TAMs targeted drug delivery has also attracted widespread attention, which can be roughly divided into three categories: decreasing or depleting TAMs, promoting phagocytosis of TAMs, transforming TAMs into tumor inhibiting macrophages.in vitro-transcribed mRNA encoding M1-polarizing transcription factors to reprogram TAMs without causing systemic toxicity. In ovarian cancer, melanoma and glioblastoma models, it has been proved that can reverse the immunosuppressive effect. The tumor support status of TAMs reprograms them into a phenotype that induces anti-tumor immunity and promotes tumor regression in vitro and in vivo. Among them, it was found that compound 23a can repolarize TAM from M2 to M1 in a dose-dependent manner both in vitro and in vivo. More importantly, in vivo experiments also show that compound 23a can significantly inhibit tumor growth in LLC mouse models Among them, polarization of TAMs is a hot research topic. The targeted nanocarrier that can deliver For reducing or depleting TAMs, the study to achieve the selective elimination of specific M2 TAMs provides the possibility to eliminate TAMs that support cancer while retaining TAMs with anti-tumor potential. EnAd targeting TAMs depletion armed with T cell adaptors provides a powerful treatment that combines direct cancer cell toxicity with the reversal of immunosuppression It is also very important to promote the phagocytosis of TAMs. Studies have shown that simultaneous inhibition of CSF1-R and SHP2 signaling pathways on the activation and phagocytosis of macrophages may be an effective strategy for macrophage-based immunotherapy. Self-assembled dual inhibitor-loaded nanoparticles (DNTs) target M2 TAMs and simultaneously inhibit the CSF1R and SHP2 pathways. Compared with single drug treatment, it has better phagocytic ability This review summarizes the research progress of TAMs in cancer treatment related fields in recent years. The source is described, and the role and mechanism in tumorigenesis and development and application in tumor immunotherapy are discussed.At present, TAM-related tumor immunotherapy has achieved promising results. Research shows that TAMs as the target of anti-tumor treatment strategy mainly focuses on the inhibition of macrophage recruitment and viability, which can significantly improve the efficacy of traditional therapy and immunotherapy. Nevertheless, clinical interest and some implied early test results have not yet brought out the best treatment. Moreover, due to the complex and changeable tumor microenvironment, and the clinical evaluation of immunotherapy mainly focused on single target drugs, its efficacy is limited. Clinical trials have begun to combine the use of different immunotherapy methods, as well as clinical trials that combine immunotherapy with surgery, chemotherapy, radiotherapy, targeted therapy, and photothermal therapy to more accurately treat patients from the perspective of the immune system.The latest research has shown that macrophages differ markedly from tumor to tumor. Other studies have also analyzed the presence of multiple TAMs subgroups at the molecular level, and the study of macrophages in their primary tumors and their metastasis should be deepened. In recent years, breakthroughs have been made in immunotherapy site therapy. In 2018, it won the Nobel Prize in Physiology or Medicine, and related antibody drugs have been approved for listing. The molecular detection of macrophages has an impact on the progress of tumors, and the research prospects of mechanisms that hinder the response of anti-tumor therapy are also very promising. The reprogramming of TAMs should become the top priority of research. The therapeutic response of M2 type macrophages can be used to direct anti-tumor immune cells to tumors. To attain to this purpose, TAMs can be reshaped into M1 type, which is essential for causing important transduction in TME. The method can also be used in conjunction with other immunotherapy strategies to provide cumulative cancer suppression.