Sweet potato is one of the most economically important crops for addressing global food security and climate change issues, especially under conditions of extensive agriculture, such as those found in developing countries. However, osmotic stress negatively impacts the agronomic and economic productivity of sweet potato cultivation by inducing several morphological, physiological, and biochemical changes. Plants employ many signaling pathways to respond to water stress by modifying their growth patterns, activating antioxidants, accumulating suitable solutes and chaperones, and making stress proteins. These physiological, metabolic, and genetic modifications can be employed as the best indicators for choosing drought-tolerant genotypes. The main objective of sweet potato breeding in many regions of the world, especially those affected by drought, is to obtain varieties that combine drought tolerance with high yields. In this regard, the study of the physiological and biochemical features of certain varieties is important for the implementation of drought resistance measures. Adapted genotypes can be selected and improved for particular growing conditions by using suitable tools and drought tolerance-related selection criteria. By regulating genetics in this way, the creation of drought-resistant varieties may become cost-effective for smallholder farmers. This review focuses on the drought tolerance mechanisms of sweet potato, the effects of drought stress on its productivity, its crop management strategies for drought mitigation, traditional and molecular sweet potato breeding methods for drought tolerance, and the use of biotechnological methods to increase the tolerance of sweet potato to drought. Rising global temperature levels as a result of climate change represent a significant challenge. Agricultural production is highly influenced by climatic factors, so it may be seriously affected in the near future if no actions are taken to accommodate and reduce the effects of abiotic stress on crops. Thus, there is an urgent need for the cultivation of crops that use water resources the most effectively. Sweet potato is considered to be one such crop, although its productivity is reduced under abiotic stress conditions. However, sweet potato has several advantages over other economically important crops that enable it to better address global food security and climate change issues, especially under the conditions of extensive agriculture seen in developing countries.Ipomoea batatas) is a basic foodstuff, fodder, and horticultural crop grown in tropical countries [Convolvulaceae family. Ipomoea batatas is the main staple crop. A few other Convolvulaceae species are localized, but many of them are noxious [I. batatas is a herbaceous liana plant with alternating leaves and tubular flowers. Its edible tuberous roots may vary in shape and color depending on its variety and environmental conditions. These root tubers are usually long, and their skin color varies from white to purple [I. batatas has a high WUE (water-use efficiency) and causes limited soil erosion during the rainy season, so it can be used as a cover crop as well as in the frost-free period of at least four months long [Sweet potato  as well as recurring low temperatures during the growing season .Salinity, low temperature, and drought are the three main environmental stressors that reduce the productivity of sweet potato worldwide . DrynessAside from its enhanced output, sweet potato’s excellent nutritional content is beneficial to farmers operating in drought-stressed areas.At the same time, drought induces a number of morphological, physiological, and biochemical alterations in sweet potatoes, which can have a detrimental effect on their agronomic and economic output. For example, drought reduces root output, branching, leaf area index, stem height and length, stomatal closure, leaf size, and photosynthesis. Furthermore, it causes oxidative stress, which results in the creation of reactive oxygen species (ROS) that are harmful to plants. The activity and synthesis of other enzymatic and non-enzymatic antioxidant compounds, such as ascorbate peroxidase (APX) , glutathA comprehensive study of the parameters connected with the drought response of sweet potato revealed several antioxidant enzymes that may manage the crop’s positive response during drought. In particular, assessing the activity of nitrate reductase (NR), free proline accumulation, and extracted chlorophyll concentration 60 days after planting was suggested as an effective method for screening genotypes associated with drought tolerance . AnotherAgronomic evaluations of the creation of new plant varieties through traditional breeding in order to improve the genetic characteristics of the germplasm have focused generally on the yield of crops, with research on improving plant tolerance/resistance to abiotic/biotic stresses being less common. Considering the importance of the impact of abiotic stress on global agriculture, and to ensure global food security, new breeding programs have begun to be developed and implemented using knowledge of the physiological responses and molecular mechanisms of plants .Drought affects several biochemical and physiological processes of plants, such as translocation, respiration, the uptake of ions, photosynthesis, nutrient and sugar metabolism, and phytohormones. Cell membranes can be destroyed, and leaf water potential can be diminished by drought. Furthermore, heavy drought causes the cessation of photosynthesis and metabolic disorders, and it can lead to the death of plants . HoweverThere are two known mechanisms that reduce the negative effects of drought stress in plants, namely stress avoidance and tolerance mechanisms. Stress avoidance refers to a plant’s ability to sustain the high water potential of its tissues under drought stress. Plants reach such levels by increasing their water uptake through deep root systems or by reducing their transpiration losses through thin or meaty leaves .Drought is associated with changes in leaf anatomy and ultrastructure for most plant species . TypicalDifferent environmental conditions influence the growth, yield, and nutritional quality of sweet potato . ThroughDrought affects sweet potato structure not only at the tissue and cellular levels but also at the subcellular level. A study by Gouveia et al. assessed the physiological responses of sweet potato samples to conditions of water shortage. Sweet potato samples that had an improved WUE were found to be the most drought resistant .In other similar studies, sweet potato samples showed the best physiological and biochemical responses to water stress treatment, showing in particular a higher ratio of above-ground to below-ground plant parts (root/shoot), lower total biomass loss, and lower stress index values . In addiAnother study found that plant signal transduction, phenylpropanoids, an isoquinoline alkaloids, and flavonoid biosynthesis play important roles in the regulation of the tolerance of plants to drought stress. According to the results of a transcriptomic analysis, the tolerance mechanisms of sweet potato varieties are very different, and occasionally some varieties respond oppositely. One drought-sensitive variety resisted drought stress by up-regulating signal production, whereas another drought-sensitive variety avoided drought stress by down-regulating isoquinoline alkaloid biosynthesis and nitrogen/carbohydrate metabolism. Moreover, on the one hand, some drought-tolerant varieties regulated flavonoid and carbohydrate metabolism or isoquinoline alkaloid biosynthesis and nitrogen/carbohydrate metabolism in response to stress; on the other hand, another drought-tolerant variety increased photosynthesis activity and carbon fixation processes. The high drought-tolerant variety was not affected by stress and responded to water deficiency by regulating the cell wall. These pathways are important indicators for selecting the breeding lines of sweet potato .A study found that the chlorophyll content index values of sweet potato exposed to drought stress 60 days after planting did not decrease significantly compared to controls under drought conditions, although a decreasing trend was observed . Zhang eFurther, significant and strong decreases in CCI levels were detected 120 days after planting in all the genotypes under drought conditions. Similar data were obtained by Nikolaeva et al. , who obsAnother study found that some varieties of sweet potato  showed significant decreases in their CCI levels compared to the control. Drought affects the photosynthetic systems of plants and may cause the growth retardation observed in crown and stem development .Chlorophyll breakdown can also affect the intensity of sweet potato’s antioxidant enzyme system, with relatively weak values having been recorded in previous studies. Heider et al.  considerCertain metabolites play leading roles in the adaptation of plants to a broad range of abiotic stressors . The accA particular feature of sweet potatoes is that they contains sufficient quantities of β-carotene, vitamin C, and antioxidants . These aIn order to reduce the negative impact of abiotic stress, plants use different signaling pathways and react by changing their growth patterns, accumulating compatible solutes, activating antioxidants, and producing chaperones as well as stress proteins. ROS comprise radical and nonradical oxygen species generated by partial oxygen reduction . A commoBetaines are non-protein amino acids that possess a quaternary ammonium group and a carboxylic group in their structure. These compounds effectively stabilize the quaternary structures of enzymes, complex proteins, and membrane systems, such as the photosystem 2 complex . The synAgrobacterium tumefaciens-mediated transformation with a gene from spinach (Spinacia oleracea) called betaine aldehyde dehydrogenase (BADH). Transgenic sweet potato plants overexpressing this transgene were shown to have increased glycine betaine synthesis and an improved tolerance to multiple abiotic stress conditions, including oxidative, salt, and low-temperature conditions [Spinacia oleracea chloroplasts have enhanced tolerance to osmotic, low temperature, and oxidative stressors [A study subjected embryogenic suspensions of sweet potato to an nditions . It has tressors .I. batatas (IbTPS) and found that the overexpression of this gene in transgenic plants improved their resistance to salinity compared to control plants [Trehalose, a sugar consisting of two glucose molecules, functions as an osmoprotectant and plays a protective role against different adverse environmental conditions in both plants and animals . It has l plants .FSPD1 from Cucurbita ficifolia showed higher levels of spermidine in their tissues and an increased tolerance to heat-mediated damage, chilling, and oxidative stress compared to wild-type plants [Polyamines are small polycations that play various important roles in all organisms. Polyamines, which are positively charged at physiological pH, interact with various negatively charged molecules, such as membrane phospholipids, nucleic acids, and certain proteins, which activate and stabilize them under abiotic stress . Putresce plants .IbMIPS1 gene from I. batatas and found that its overexpression greatly impacted the salinity and water stress tolerance of transgenic sweet potato plants in field conditions [Inositol is a well-known osmolyte, and its phosphorylated derivatives function as secondary messengers in signal transduction pathways under various stressors. A key limiting stage of myo-inositol biosynthesis is catalyzed by the enzyme l-myo-inositol-1-phosphate synthase (MIPS). A study isolated the nditions .Proline (Pro) accumulation is associated with abiotic stress tolerance mechanisms in plants. It helps to stabilize proteins and membranes as well as neutralize free radicals. Proline plays a role in supporting plants affected by stress conditions . As an oIbP5CR gene isolated from I. batatas enhanced salt tolerance in transgenic sweet potato plants [The key enzyme involved in proline biosynthesis is pyrroline-5-carboxylate reductase (P5CR). A study found that the overexpression of the o plants . In a nuo plants ,74,75.Laurie et al.  identifiWater stress has been found to cause a significant increase in APX activity, especially when treated with high drought stress. For instance, Zhang et al.  recordedA study observed an increase in the superoxide dismutase activity of different sweet potato varieties subjected to water stress. This ranged from 0.350 units/mg protein under the control conditions, to 0.85 units/mg protein under the drought treatment. These findings were similar to those made by Zhang et al.  and MasoA study found that glutathione reductase (GR) levels were increased in varieties subjected to drought stress at both 60 and 120 days after planting compared to the control group. Although the increase in GR was similar in the control and heavy stress treatment groups for each variety, the simultaneous increase in SOD activity confirmed the possibility of drought tolerance . GR acti3 assimilation and N-fixation, which are associated with the modulation of photosynthesis. The impact of drought was severe, meaning that no significant differences were observed among different genotypes. The rapid decrease in the enzyme’s activity in these trials was theorized to have a negative effect on plant growth. Reduced photosynthesis also has negative effects on nitrate reductase, which is consistent with the authors of [2 g−1h−1 under control conditions to 0.0016 µmol NO2 g−1h−1 under drought conditions. No considerable differences in NR activity were found among varieties under conditions of severe stress at 60 or 120 days after planting when the activity was already at an extremely low level as a result of protein degradation [Xia et al.  investigthors of ’s reasonradation . Such a radation .During breeding, the study of plant protection mechanisms under stress is important for the development of plant resistance and tolerance. This, in turn, is important for improving the productivity and yield quality of sweet potato and other crops . ResearcWater stress is a worldwide obstacle to high sweet potato yields because most sweet potato plants grow in semi-arid regions. Because of the complexity of the genetic and physiological mechanisms of water deficiency resistance, a greater emphasis on increasing our genomic understanding of sweet potato’s reaction to stress will help us develop strategies for maintaining its productivity under stressful conditions.Laurie et al.  found thAgili et al.  identifiIn addition to its direct impact on yields, drought can also reduce the potential benefits of crop management practices, such as fertilizer application and pest and disease management. Drought requires additional periods of irrigation, which increases overhead production costs . A lack Sweet potato yield is also significantly affected by stunted growth as a result of drought conditions. A study that exposed sweet potato to a medium level of water stress found that this had a negative effect on all of its characteristics, but that it still allowed for different genotypes to be distinguished; exposure to high stress had the opposite effect. The study showed  that a gThe main objective of sweet potato breeding in many regions of the world, especially those affected by drought, is to obtain varieties that combine drought tolerance with a high yield. In this regard, the study of the physiological and biochemical features of certain varieties is important for the implementation of drought tolerance measures. In addition, it is necessary to carry out yield modeling to reduce the time and costs associated with repeating trials in larger areas.There are two options for crop management methods under conditions of water limitation: agronomic and genetic. The selection and improvement of genotypes adapted for a particular environment can be carried out with suitable equipment and through the use of selection indicators related to water deficiency tolerance. The creation of drought-tolerant varieties is a low-cost genetic management strategy that may be well-suited to small farms .In order to develop an effective selection method for assessing water deficiency tolerance, indicators such as SOD activity, NR activity, and APX activity, stomatal conductance, leaf area, chlorophyll content, leaf water content, free proline content, and WUE should be considered at the beginning of the growing season. Various studies have assessed these parameters in a number of crops, such as sugar beet , potato Several approaches, such as the measurement of potential relative humidity, diffusion pressure shortage, chlorophyll stability index, and carbon isotope discrimination, have been used to assess the drought tolerance and WUE of crops ,97,98,99Although there have been few studies on the development of methods for evaluating the drought tolerance of sweet potato, a significant number of researchers have contributed greatly towards finding the optimal process for developing useful methods for selecting tolerant sweet potato germplasm. Ekanayake and Collins  used a sThe optimal solution for developing a methodology to assess the drought tolerance of sweet potato is to grow the plant under field conditions where irrigation is applied without the interference of normal precipitation. Apart from field experiments, the adoption of strategies such as efficient water use, the proper selection of drought-tolerant genotypes, mass screening, conventional and molecular assisted selection (MAS), the exogenous application of hormones, the use of osmoprotectants on seeds or plants, and the development of genetic engineering methods for drought tolerance are recommended.The most important factors limiting productivity must be considered when breeding crops. As shown above, drought is one factor that limits sweet potato yield, resulting in an annual yield loss. This is due to unfavorable changes at the morphological, biochemical, physiological, and molecular levels . These cSweet potato growing conditions differ greatly. Therefore, selecting the sweet potato germplasm based solely on the crop’s root yield for storage under optimal conditions may be disadvantageous for growers when soil conditions are poor. The impact of climate change around the world has made the choice of drought-tolerant varieties a priority for growers. Producers, especially small growers, need to consider several factors in order to achieve successful production . Namely,I. batatas varieties have reduced flowering and fertility or do not bloom. As a result of high levels of male sterility and self- and inter-specific incompatibility, sweet potato plants do not mix well in breeding programs [Traditional breeding has several limitations in terms of improving sweet potato properties. Most programs . The hexprograms .In addition, breeding sweet potato for drought tolerance requires an understanding of the consequences of drought stress, the availability of genetic diversity, and effective crossing and breeding methods that can lead to the identification and development of potential clonal varieties .Drought is often a serious environmental barrier to the cultivation of sweet potato when it is grown in non-irrigated agricultural areas . DiffereThe development of genetic management technology requires reliable, reproducible, simple, and rapid field and laboratory screening methods. These would enable researchers to identify drought-tolerance characteristics in the sweet potato germplasm and to include these in high-yielding varieties tolerant to drought stress .Several researchers, such as Ekanayake and Collins  and NeduThe use of drought and yield indices for the selection of derived germplasm for different production environments has produced encouraging results, and it should be carried out at the early stages of the breeding cycle .Plant breeders must consider the crucial phases of plant growth and development. To increase sweet potato yield, particularly in Kenyan conditions, farmers have been advised to plant tubers early in the rainy season so that they are not subjected to water shortage conditions during the first four months of growth .Omotobora et al.  researchI. batatas produce storage roots or have been found to be drought tolerant compared to cultivated sweet potato, it is likely that focusing on these species is the best option to improve the yield and drought tolerance of sweet potato.Nhanala and Yencho  found thVarious mechanisms of plant tolerance to stress at the molecular and genetic levels appear to be interrelated, with environmental factors influencing the strength of their connections. Such molecular and genetic mechanisms have not been studied enough with regards to the phenotyping and genotyping of water stress resistance. In addition, epigenetic mobility and genetic element modifications are sources of variability in a plant’s stress resistance . DespiteThe above information may be useful for the general screening of sweet potato sensitivity or drought tolerance as well as for the adaptation of sweet potato to climate change using selection and breeding programs.Sweet potato is a hexaploid (2n = B1B1B2B2B2B2 = 6x = 90), and therefore, its gene expression has certain features. On the one hand, polyploidy introduces certain difficulties; on the other hand, the identification of genomes facilitates the study of gene expression in sweet potatoes.Agrobacterium-mediated transformation [I. batatas, raising the prospect of adopting cis-genic approaches [As an alternative to traditional breeding, gene transfer technologies and genome-editing techniques are promising tools for the improvement of the environmental stress tolerance of sweet potato . The relormation ,114,115.proaches . ImplemePlant heat shock proteins play key roles in conferring abiotic stress tolerance. Most of these stress proteins are molecular chaperones that assist in protein folding and transport and that prevent cellular functions from occurring under stressful conditions .P3B, which encodes one of the ribosome-associated chaperones in Arabidopsis thaliana, improves the tolerance of transgenic plants [Sap1 gene from Xerophyta viscosa encodes one such stress protein. A study exploited the XvSap1 gene for the genetic engineering of sweet potato. The induced expression of this transgene resulted in transgenic plants that grew better than wild-type plants under drought stress conditions [The overexpression of stress protein-encoding genes can promote transgenic plant survival under abiotic stress conditions. The overexpression of the cDNA gene Atc plants . Cell wanditions .IbLEA14, induces enhanced tolerance to drought and salt stress, which is expressed in various tissues  under different water stress conditions. The expression of the IbLEA14 gene is highly induced by water deficiency, salt stress, and ABA treatment in plants. The overexpression of IbLEA14 in transgenic calli enhanced tolerance to drought stress. The IbLEA14 gene regulates the increase in lignin, which has a crucial role in the drought stress response of plants. New studies will be required to study the role of lignin accumulation under stress conditions [The genes of late-embryogenesis-abundant (LEA) stress proteins are expressed during seed maturation. LEA proteins are small and hydrophilic polypeptides that play essential roles in the abiotic stress response and stress tolerance of plants by acting as molecular chaperones . The LEAnditions .+/H+ antiporters are transmembrane proteins located in plasma or vacuolar membranes that operate to transport sodium out of the cytosol against a concentration gradient. These transport proteins maintain ion homeostasis, preventing the excessive accumulation of Na+ in the cytosol [I. batatas vacuolar Na+/H+ antiporter gene (IbNHX2) has been found to be associated with a significantly higher salt and drought tolerance in transgenic sweet potato plants than non-transgenic ones [The Na cytosol . The ovenic ones .+/H+ anti-transporter gene from Arabidopsis thaliana into the genome of sweet potato plants has been found to increase their resistance to cold and salt [Similarly, the introduction of the Naand salt .The importance of ROS production as a response to abiotic stress has already been mentioned. However, it is also important to consider the role of ROS regulation at the molecular-genetic level. ROS are constantly generated in mitochondria and chloroplasts, as well as in response to different stress conditions. These compounds are highly reactive and dangerous, and they can directly damage cellular components and cause oxidative cell death . A plantIbNFU1 gene, which encodes the iron–sulfur cluster scaffold protein, from a salt-tolerant I. batatas variety and found that its overexpression resulted in a higher tolerance to salinity in transgenic sweet potato plants than in wild-type plants [A study isolated the e plants . Iron–sue plants .I. batatas showed that the transgenic plants had a stronger ability to deactivate ROS compared to control plants [A study used the genes of two ROS scavenging enzymes, Copper/Zinc (CuZn) superoxide dismutase (Cu/Zn-SOD) and APX, to increase the resistance of transgenic sweet potato plants to oxidative stress. The overexpression of these transgenes in l plants .LOS5/ABA3 gene, which encodes low osmotic stress 5 (LOS5) molybdenum cofactor sulfurase, is one of the key regulators of abiotic stress tolerance in plants [Arabidopsis thaliana LOS5/ABA3 gene in sweet potato results in an enhanced salt tolerance [Abscisic acid (ABA) is a plant hormone that regulates a plant’s growth, development, and responses to various stressors. It plays a crucial role in enhancing plant resistance to abiotic stressors. The level of ABA in plants significantly increases under adverse conditions . The moln plants . The oveolerance .IbMas, which encodes the maspardin protein, regulates osmotic balance in I. batatas. Furthermore, the overexpression of this gene was shown to improve tolerance to salinity in cultivated sweet potato compared to wild-type plants [A study showed that the α/β-hydrolase gene e plants .The resistance mechanisms of plants are extremely complex, as plants must balance their growth and stress responses under stressful conditions. Because plants face many environmental stress factors, they have evolved complex resistance mechanisms for their balanced growth and development . SeveralI. batatas (27 SWEETs), I. triloba (25 SWEETs), and I. trifida (27 SWEETs), and are named “Ib”, “Itb”, and “Itf”, respectively [IbSWEETs. Dai et al. [I. batatas, I. triloba, and I. trifida under drought and salt treatment conditions, induced by polyethylene glycol (PEG) and NaCl treatments, respectively. Four IbSWEETs , six ItbSWEETs , and seven ItfSWEETs  were found to be caused by both drought and salinity. Altogether, these results show that SWEET is expressed in different ways in response to various abiotic stressors in sweet potato and its two diploid relatives. Each SWEET gene plays a different, vital role in plant growth and development, hormone crosstalk, carotenoid accumulation, and responses to abiotic stress. This research provides valuable information on the structure and function of SWEET genes in sweet potato and its two diploid relatives. The results also indicate that high expressions of these IbSWEETs are involved in adaptations to abiotic stress in sweet potato. These IbSWEETs genes may be used as candidate genes to improve abiotic stress tolerance.Sugar will eventually be exported transporters (SWEET) are key transporters in sugar transportation. A total of 79 SWEETs have been identified in ectively . They arectively , DREcoreectively , and MYCectively , have bei et al.  analyzedLHCSB6 and SLAC1 single-copy orthologs was observed in both varieties at both time points [Arabidopsis. Thus, Lau et al. [Lau et al.  demonstre points ,134. Theu et al.  presenteu et al. ,135. On IbHPPD gene affects sweet potato’s resistance to various stressors. Transgenic sweet potato plants overexpressing IbHPPD were more resistance to herbicides, salinity, drought, and oxidative stress than non-transgenic plants [Many studies on sweet potato have investigated changes in p-hydroxyphenylpyruvate dioxygenase (HPPD) gene expression levels induced by other abiotic stressors during oxidative stress ,137. Kimc plants ,137.Genes encoding TFs have attracted significant attention in recent years because of their ability to activate drought stress-resistance genes . DREB/CBDUF668 members are still unknown [DUF668) is a gene family that plays a vital role in plant responses to negative stressors associated with forcing. However, the function of the DUF668 gene family in sweet potato has not been fully studied [DUF668 show specificity and differential expressions under cold, heat, drought, salt, and particular hormonal conditions in sweet potato . The study’s expression analysis showed that IbDUF668-6, IbDUF668-7, IbDUF668-11, and IbDUF668-13 play important roles in the response of sweet potato to drought and salt stresses. The results suggest that the DUF668 gene family is involved in drought and salt tolerance in sweet potato and also provide key information about the mechanism of DUF668 genes in plants [In recent years, the number of superfamily members with a domain-unknown function (DUF) has increased rapidly as research has progressed . Althoug unknown . The dom studied . A studyn plants .IbWRKY under exposure to abiotic stressors and hormones is needed to clarify the signaling pathways associated with sweet potato responses to abiotic stress. Multiple IbWRKYs induced by stress may be closely related to the transcriptional regulation of abiotic stress responses in sweet potato, and a variety of interactions among IbWRKYs have been identified. The complex co-expression of IbWRKYs in response to abiotic stress is, therefore, predictable [IbWRKY candidate genes involved in drought tolerance is also needed.The WRKY TF family, initially isolated from sweet potato and named Sweet Potato Factor1 , forms odictable . FurtherIbGRAS genes of sweet potato that had an irregular distribution and were isolated on 15 chromosomes and divided into 12 subfamilies. An RNA-seq analysis under salt stress conditions and the qRT-PCR determination of 12 selected IbGRAS genes demonstrated their significant and differing induction characteristics under exposure to multiple abiotic stressors  and hormonal influences . Consequently, the IbGRAS gene promoter regions were shown to contain several cis-acting elements related to stress and hormones. Among these, IbGRAS71, a potential candidate for plant tolerance selection, was characterized as having transactivating activity against yeast. The results of this study laid the foundation for the further functional identification of IbGRAS genes, and many members can serve as potential regulators for molecular selection for sweet potato tolerance [GRAS plant-specific TFs play key roles in a variety of unfavorable environmental conditions. Zhang et al.  studied olerance .IbPIF3.1 has been found to be induced by abiotic stressors, such as drought, salinity, cold, and heat, as well as biotic stressors, such as Fusarium wilt tolerance [Phytochrome-interacting factors (PIFs) are key regulators of plant responses to different abiotic stressors. The expression of olerance .Or), carrying the same mutation, resulted in high total carotenoid and beta-carotene contents and an increased resistance to abiotic stress in sweet potato crops [IbOr-R96H), which carries a single-nucleotide polymorphism responsible for replacing arginine with histidine at the 96th amino acid position, significantly increased the carotenoid content and antioxidant activity in the storage roots as well as the abiotic stress resistance in the storage roots and leaves of transgenic sweet potato plants compared to cells overexpressing the wild-type IbOr gene (IbOr-WT) [A study found that the overexpression of the orange gene (to crops . AnotherIbOr-WT) .IbOr-R96H under the control of the 35S promoter of the cauliflower mosaic virus (CaMV) through an Agrobacterium-mediated transformation. The carotenoid content was higher in the stocking roots of the IbOr-R96H plants than in the stocking roots of the non-transgenic plants. In addition, the IbOr-R96H plants showed a greater resistance to heat stress than the non-transgenic plants and IbOr-WT, possibly as a result of their higher DPPH radical removal activity and ABA content [IbOr-R96H represents a promising strategy for the development of new sweet potato varieties with increased carotenoid content and an improved tolerance to abiotic stress. Overall, the IbOr-R96H gene can help us cope with global food and nutritional security problems as well as create sustainable agricultural practices under climate change.Kim et al.  establis content . These rAgrobacterium tumefaciens-mediated transformation to regenerate transgenic sweet potato IPT lines. The overexpression of the IPT gene resulted in a significant increase in the drought tolerance of sweet potato, demonstrating the potential for developing drought-resistant varieties of this crop. The pathway involves the transfer of an isopentenyl group from dimethylallylldiphosphate to N6 adenosine monophosphate, resulting in the formation of isopentenyladenosine-5-monophosphate (iPMP). This reaction is catalyzed by dimethylallyl diphosphate and adenosine monophosphate isopentenyl transferases [Nawiri et al.  used Agrsferases .Tang et al.  identifi+ [Overall, plants produce signal molecules, such as abscisic acid (ABA) , Ca2+ [3+ , inosito+ , cyclic + , and NO + , in resp+ , glycine+ , soluble+ , late em+ ,119, and+  are exam+ , bZIP [1+ , WRKY [1+ , AP2/ERF+ , MYB [13+ , calcium+ , mitogen+ , and HD-+ ,156, canNumerous plant responses to drought are controlled by several genes with different functions. Many regulatory processes are initiated when plant cells lose water to help regulate cellular metabolism and induce changes in gene expression. Whether these genes perform an adaptive role under drought conditions is completely unknown and, therefore, requires further investigation.Our understanding of the genetic control of plant mechanisms in order to overcome abiotic stressors has advanced in recent decades. The identification and cloning of candidate genes has enabled private and public researchers to create plants that can tolerate the adverse effects of these stressors without affecting their yields ,150,151.Various experiments by Nawiri et al.  involvedGenetic engineering methods are one class of methods used to increase the resistance of plants to several negative environmental factors simultaneously, which, in turn, increases the rate of proline biosynthesis and decreases the rate of its biodegradation in plant cells . ExcludiArabidopsis plants, which increased their resistance to frost and elevated salt content in the environment [Plants may synthesize proline in the cytosol via either the ornithine or glutamate pathways. However, the glutamate pathway of proline synthesis is mainly activated during plant adaptation to various stressors . The genironment .Among the many gene transfer technologies, the use of agrobacterial transformation continues to be the most effective strategy, and it could be a potential extension of classical breeding through which foreign genes can be introduced into plants via genetic transformation .Despite being the seventh most common food crop in the world and having a yearly yield of 115 million metric tons , the impThe development of the diversity of the sweet potato germplasm is important for ensuring food security worldwide because sweet potato is an important food in developing countries that are characterized by high populations and persistent malnutrition ,170,171.Drought severely affects the survival and yields of crops and also increases the costs of crop production. Today, research on plant drought tolerance is becoming increasingly important, as it focuses on minimizing the impact of global climate change on agriculture. Sweet potato has attracted much interest from researchers interested in addressing the problems of drought tolerance in plants. Recent achievements in sweet potato genomics and metabolomics highlight the potential for using new, fundamental knowledge to carry out the practical breeding of the crop. To achieve the faster development of drought-tolerant sweet potato varieties, a combination of traditional and new techniques will be required. At the same time, it is necessary to improve the agronomic techniques used for specific soil and climatic conditions. Among the basic food crops, sweet potato has the greatest potential for adaptation to semi-arid and drought-prone areas. Developing drought-resistant varieties of sweet potato will increase farmers’ profits by reducing their irrigation and related production costs. Therefore, this crop can ensure food security for the increasing population of the developing world.


In recent years, significant strides have been made in the field of genomics, with the commencement of large-scale studies aimed at collecting host mutational profiles and microbiome data. The amalgamation of host gene mutational profiles in both healthy and diseased subjects with microbial abundance data holds immense promise in providing insights into several crucial research questions, including the development and progression of diseases, as well as individual responses to therapeutic interventions. With the advent of sequencing methods such as 16s ribosomal RNA (rRNA) sequencing and whole genome sequencing, there is increasing evidence of interplay of human genetics and microbial communities. Quantitative trait loci associated with microbial abundance (mbQTLs), are genetic variants that influence the abundance of microbial populations within the host.Here, we introduce mbQTL, the first R package integrating 16S ribosomal RNA (rRNA) sequencing and single-nucleotide variation (SNV) and single-nucleotide polymorphism (SNP) data. We describe various statistical methods implemented for the identification of microbe–SNV pairs, relevant statistical measures, and plot functionality for interpretation.https://bioconductor.org/packages/mbQTL/.mbQTL is available on bioconductor at  With the advent of sequencing methods such as 16s ribosomal RNA (rRNA) sequencing and whole genome sequencing, there is increasing evidence of the interplay between human genetics and microbial communities  is that there exists co-abundant bacterial operational taxonomic units (OTUs) associated with particular genotypes. As an example, Bifidobacterium and Acinetobacterioum genera. Finally, our third approach (C) assumes particular SNVs are associated with the presence or absence of specific taxa. Implemented are three approaches for microbe–host interaction testing. Our first approach (A) is based on the hypothesis that a particular SNV is associated with increases or decreases of bacterial abundance. Assuming abundance of every taxa is similar to gene expression quantitatively, the abundance of a taxa can be associated with the presence of a SNV. As an example, The first approach (A) employs multiple linear regression to examine the relationship between bacterial abundance and host SNVs. The user can design their own model matrix for each microbe–SNV pair to control for phenotypes of interest .x, y, by the goodness of fit estimates (The second approach (B) is a correlation-based method, scaling the correlation (The correlation-based approach (approach B) allows us to demonstrate the relationships between SNVs and various microbes, as well as identify SNVs that are in linkage disequilibrium with each other and their expression patterns affect similar microbes as seen in In our final approach (approach C), we assume a binary relationship between each microbe and SNV pair and use a logistic regression model to determine the significant microbe–SNV relationships (User input includes three objects: (i) microbial abundance in the form of a MRexperiment object, (ii) a SNV matrix, which should be in the heterozygous format , and lastly (iii) a phenotype matrix to include covariates for multiple regression adjustment. For logistic regression, abundance thresholds are required.P-values for the linear model, in addition to FDR and Bonferroni P reporting. In approach B, as the method reports on the strength of the SNV-taxa and taxa-taxa relationships, we provide functions for flexible cutoff selection for the highest probability correlation estimates. This enables users to evaluate the method’s performance using various cutoffs, allowing to correct for the occurrence of false positives. The package is on the Bioconductor platform to allow extended use and maximum reproducibility of results from various labs that use this package in the research community.Main functions for linear and logistic regression analysis are linearTaxaSnp, histPvalueLm, qqPlotLm and logRegSnpsTaxa, logitPlotSnpTaxa. For the correlation based analysis the following functions are implemented, coringTaxa, allToAllProduct, taxaSnpCor, and mbQtlCorHeatmap for easy visualization of SNVs in linkage disqeuilibrium, e.g. chr15 in the package example dataset.mbQTL users can evaluate the performance of their analysis in approach A and C using the qqplot function, which compares expected versus observed Finally, the mbQTL package allows for the explanation of linear, correlative and binary investigations of microbe–SNVs estimation.We present mbQTL, an R package designed to provide a convenient method for microbe-SNV association analysis and visualization. Our approach incorporates three different models to identify significant microbe–SNV relationships: linear regression, correlation estimation (


Editorial on the Research TopicCytokines, novel cell death models and pathways in cardiovascular diseasesCardiovascular disease (CVD) persists as a major global health issue and remains one of the leading causes of mortality worldwide. Cell deaths, especially programmed cell deaths, are critical processes in the development of various CVDs . RecentlCytokines also play an essential role in CVD development. They are considered to have crucial regulatory roles in CVDs through autocrine, paracrine, and endocrine actions , 6. For Building on this, the research topic “Cytokines, Novel Cell Death Models, and Pathways in Cardiovascular Diseases” published in Frontiers in Cardiovascular Medicine aimed to discuss recent advances and offer insights in this field.Li et al. presented a comprehensive review on the pivotal role of ferroptosis in CVDs. Ferroptosis, an iron-dependent form of cell death characterized by phospholipid peroxidation, was first identified in 2012  and insulin-like growth factor binding protein 2 (IGFBP-2) in patients with acute coronary syndrome (ACS) and found that IGFBP-2 levels were associated with a poor prognosis after ACS. Yu et al. demonstrated that combining Lp(a) levels with carotid intima-media thickness could provide a favorable predictive value for CHD. Wali et al. identified that early atrial remodeling could predict hospitalization for cardiovascular events in patients with new-onset metabolic syndrome. Tong et al. conducted a bioinformatics study and revealed that circRNAs  possess promising predictive capabilities for CHD. Liu et al. conducted a mendelian randomization analysis to investigate the genetic causal relationship between whole-body iron status and CHD development.Another area of focus in the research topic was coronary heart disease (CHD), a prevalent cardiovascular disorder primarily caused by atherosclerosis and narrowing of the coronary arteries. CHD can lead to severe outcomes such as myocardial infarction, ischemic cardiomyopathy, and heart failure, resulting in significant morbidity and mortality rates. Several studies in this research topic examined different aspects of CHD. In conclusion, this special issue of Frontiers in Cardiovascular Medicine sheds light on the intricate interplay between cell death modalities, cytokines, and their involvement in CVDs. It underscores the importance of further researches on the crosstalk between cell death pathways and cytokine regulation, as it holds significant promise for developing more effective preventive and treatment strategies to address the increasing burden of CVDs worldwide.


Thirty-five years ago, the flexible endoscopic evaluation of swallowing (FEES) was described for the first time. FEES is a gold standard instrumental assessment of oropharyngeal swallowing function using flexible laryngoscopy. FEES usually includes a part 1, in which the anatomy of the pharynx/larynx is observed and movements of structures are evaluated through motor tasks. These often include the pharyngeal squeeze maneuver (sustained/pressed phonation “eee”), velopharyngeal closure , base-of-tongue retraction , glottic closure/vocal fold and arytenoid mobility ; as well as the observation of epiglottic inversion during a dry swallow. These tasks allow the clinician to build their working hypotheses regarding intact and problematic components of the pharyngeal phase of swallowing i.e. pharyngeal constriction for bolus clearance and vocal fold closure for airway protection. Voice and swallowing share neural and musculoskeletal substrates. Yet, the strength of evidence for motor and speech tasks predicting swallowing function is variable making it hard for clinicians to confidently build working hypotheses during part 1 of their FEES. This results in some clinicians leaving this part of their FEES out and missing valuable clinical information about their patient. What is the evidence for these motor speech tasks components of the FEES procedure?One of the most validated motor tasks, with the greatest potential to predict swallowing function, is the pharyngeal squeeze maneuver (PSM), which is considered a substitute measure of pharyngeal strength during FEES. Recently published, Miles and Hunting report on 222 inpatients referred for FEES and demonstrated a correlation between PSM and pharyngeal constriction during videofluoroscopy (in those who had both assessments) and a strong association between PSM and accumulated secretions, aspiration, residue and diet on discharge from hospital.Recently, a modification of PSM, called the Velopharyngeal Squeeze Maneuver (VPSM), has been studied in patients with dysphagia.Glottic closure is essential for airway protection during swallowing and coughing, thus, dysphagia/aspiration often occurs in patients with vocal fold paralysis, with an estimated prevalence of 55%–69%.Recently, a study by Jijakli et al. evaluated the association between epiglottic inversion (observed during FEES) with the biomechanical events of swallowing (observed during videofluoroscopy) in a small cohort of 25 patients with dysphagia. The researchers wanted to know whether reduced hyoid and laryngeal excursion on videofluoroscopy would be associated with absent epiglottic inversion on FEES. Patients were divided into three groups: complete, reduced, and absent epiglottic inversion. The study demonstrated that the reduction of base-of-tongue retraction, reduction of hyoid excursion, reduction of laryngeal elevation and reduction of pharyngeal constriction contribute to the decrease of epiglottic inversion observed in FEES. However, the assessment of epiglottic inversion was unable to discriminate between patients with normal versus impaired hyolaryngeal elevation. This small pilot study perhaps suggests that observations of epiglottic inversion should be interpreted with caution, and cannot infer the specific movement of the hyolaryngeal complex.Base-of-tongue retraction, while often included in a FEES protocol, has little scientific evidence to relate task performance to swallowing function. Langmore et al. studied the relationship between pre-swallowing tasks assessed during the part 1 of the FEES (including base-of-tongue retraction) and functional swallowing outcomes in patients with post-extubation dysphagia. The only task that showed a significant relationship with aspiration was decreased pharyngeal squeeze. No association was observed between base-of-tongue retraction and swallowing impairments in this specialized population.https://pubs.asha.org/doi/10.1044/2021_AJSLP-20-00348). While some motor tasks may not been researched extensively, these tasks assess swallowing related actions in isolation and support clinician diagnostic decision-making. Knowing there is a vocal fold paralysis or poor pharyngeal squeeze provides valuable information about how a patient may perform during oral trials, as well as what the underlying biomechanical cause of functional deficits during oral trials. A deficit observed during a motor or speech task that has little evidence may need to be interpreted with caution. For example, if a clinician observes absence of epiglottic inversion or base of tongue retraction during part 1 of their FEES procedure, they might pay focused attention to these structures during oral trials during the FEES and may recommend a videofluoroscopy study to further investigate pharyngeal function. It is also recommended that clinicians stay current and adapt their clinical practice as new evidence becomes available over time.Despite limitations in current evidence, researchers and clinicians recommend that pre-swallowing tasks are included during FEES  for all pre-swallowing tasks is warranted.The authors declare no conflicts of interest.No funding.


Immunosuppressive medication therapy after organ transplantation is essential for preventing transplant rejection and minimizing the need for re-transplantations. Nonadherence to immunosuppressant therapy has been identified as a major risk factor for acute complications and allograft rejection, as well as late graft rejection, and a return to dialysis after failed renal transplantation, leading to an increase in health care costs and potentially even death.To evaluate clinical and economic outcomes of a mandatory transplant specialty pharmacy program implemented for the membership of a national commercial health plan for post-renal transplantation patients, as compared with membership using traditional retail pharmacy services. This program was delivered by a designated specialty pharmacy, which met requirements for contracted rates and provision of clinical programs and services.The study is a 1-year retrospective claims analysis after the implementation of a transplant specialty pharmacy program that, in addition to medication dispensing, includes adherence and clinical management programs, patient education, and counseling services provided by transplant pharmacology experts. Renal transplant patients using the specialty pharmacy program were matched to those using retail pharmacies utilizing a propensity score-matching technique based on logistic regression. Primary outcomes were financial, which included pharmacy medication costs, medical inpatient and outpatient costs, and overall health care costs. Patient adherence to transplant medication therapy and health care resource utilization were also evaluated. One-year outcomes post-specialty pharmacy program implementation were compared between the two groups with t-tests for continuous variables and chi-square tests for nominal variables.After propensity score matching, 519 patients were identified per group for analysis. Baseline parameters were similar between the two groups. The mean total health care cost during 1 year of follow-up was 15% lower in the specialty pharmacy program group . Similarly, the mean transplant-related medical cost was 42% lower in the specialty pharmacy program group , with lower cost, although not statistically significant, in both the dialysis-related and the nondialysis-related costs. The transplant-related office visit costs  were significantly lower for the specialty pharmacy program cohort, while the inpatient and outpatient transplant-related costs were lower but not statistically significant in the specialty program. The weighted medication procession ratio (MPR) was higher ; the number of patients with a medication gap or who discontinued was lower  in the specialty pharmacy program members than in the retail pharmacy members.This specialty pharmacy program is associated with lower transplant-related medical costs and lower overall health care costs, as well as higher transplant medication adherence within the first year of evaluation. The positive impact of health plan program design and coordinated care and oversight by transplant pharmacology experts in a specialty pharmacy program has implications for the current health care reform and requires more research.


Papuloerythroderma of Ofuji (PEO) is a rare skin disorder characterized by a distinctive pattern of pruritic, flat-topped, erythematous papules which coalesce into an erythroderma-like eruption with classic sparing of the skin folds. Although the pathogenesis of this condition is incompletely understood, previous reports have suggested a notable link between PEO and various forms of malignancy and immunocompromised states. Here, we report a case of a healthy young male with no comorbidities who presented with the classical features of PEO that responded well to combination therapy comprised of topical corticosteroids and phototherapy. Originally reported in Japan by Ofuji et al., Papuloerythroderma of Ofuji (PEO) is an eruption of flat-topped, pruritic, erythematous coalescing papules characteristically sparing the face and intertriginous skin, producing the classic ‘deck-chair sign’, which distinguishes it from ordinary erythroderma ,2. PEO iGiven its rare occurrence, the underlying etiology of PEO remains unclear. Previous reports have attempted to illustrate an association between PEO and malignancy, drugs, atopy, and infection . Of thesA 22-year-old South Asian male presented to the dermatology clinic for evaluation of a pruritic rash on his lower back. He first noticed pruritus about nine months prior and reports that a rough and scaly rash presented shortly after this. Two months prior, he visited his primary care physician who prescribed an oral prednisone taper and triamcinolone 0.1% cream. Although this slightly helped relieve the itching, the rash persisted. He had no past medical history and denied any personal or family history of asthma, atopic dermatitis, or seasonal allergy. He had not changed any soaps, detergents, or skin care products recently and does not take any medications or over-the-counter (OTC) supplements.Dermatological examination revealed an erythroderma-like eruption formed by erythematous, flat-topped, red to brown polygonal papules with a cobblestone-like appearance which coalesced into slightly scaly, velvety, hyperpigmented plaques with notable sparing of the skin folds on the lower back. The inguinal crease, popliteal fossa, and axillary folds were spared. Focal dermal elastosis was not present. Physical examination revealed left supraclavicular lymphadenopathy. Laboratory results were largely unremarkable except for elevated liver function tests, revealing an aspartate aminotransferase (AST) of 123 U/L  and alanine aminotransferase (ALT) of 64 U/L . Hepatitis B and C, rapid plasma reagin (RPR), and HIV antibody titers were within normal limits. Viral capsid antigen IgG level for Epstein-Barr virus was elevated. Serum IgE level was elevated at 2941 IU/mL and complete blood count (CBC) revealed eosinophilia. Flow cytometry was also conducted to rule out cutaneous T-cell lymphoma (CTCL) of which the results were within normal limits. A punch biopsy obtained for hematoxylin and eosin staining revealed mild spongiosis with focal parakeratosis of the epidermis, and a perivascular lymphocytic infiltrate with eosinophils and plasma cells  as PUVA was not available. The patient’s skin findings and pruritus resolved after three weeks of therapy. He was also referred to gastroenterology for upper endoscopy and further workup due to the association of PEO with gastric malignancy and lymphadenopathy on physical exam, however, the patient was lost to follow-up.Papuloerythroderma of Ofuji (PEO) remains a rare diagnosis that is seen to preferentially affect elderly males . The proTo date, the etiopathogenesis of PEO remains unknown. Previous case reports on PEO have demonstrated association with internal malignancy, atopy, drugs, and infection ,11,12. OOur patient deviated from the classic presentation of PEO as he presented as a healthy, young male with no past medical history of any underlying comorbidities or immunocompromised status. Clinical diagnosis was made after an intensive workup and exclusion of more common differential diagnoses. Thus, our case highlights the importance of considering the possibility of PEO in younger, healthy patients who may not present with the classic predisposing factors. A high index of clinical suspicion and thorough investigation is necessary to prevent misdiagnosis and to rule out likelihood of associated malignancy. Further studies are needed to investigate the causative factors of PEO and to formulate universal guidelines for effective treatment to avoid unnecessary trial and error.Papuloerythroderma of Ofuji remains a rare diagnosis with an obscure pathogenesis. Our report presents a patient who lacked the classical background of previously described PEO patients, highlighting the variability in clinical presentation. Clinicians should recognize this entity and its nuances due to its association with internal malignancy and grave consequences of misdiagnosis. Prompt recognition and treatment are generally associated with favorable outcomes in the absence of malignancy.


Angiogenesis is acknowledged as a pivotal feature in the pathology of human cancer. Despite the absence of universally accepted markers for gauging the comprehensive angiogenic activity in prostate cancer (PCa) that could steer the formulation of focused anti-angiogenic treatments, the scrutiny of diverse facets of tumoral blood vessel development may furnish significant understanding of angiogenic processes. Malignant neoplasms, encompassing PCa, deploy a myriad of strategies to secure an adequate blood supply. These modalities range from sprouting angiogenesis and vasculogenesis to intussusceptive angiogenesis, vascular co-option, the formation of mosaic vessels, vasculogenic mimicry, the conversion of cancer stem-like cells into tumor endothelial cells, and vascular pruning. Here we provide a thorough review of these angiogenic mechanisms as they relate to PCa, discuss their prospective relevance for predictive and prognostic evaluations, and outline the prevailing obstacles in quantitatively evaluating neovascularization via histopathological examinations. Cancer research has undergone radical changes in recent years . The chaThe concept of “Angiogenesis” can be traced back to the work of British surgeon John Hunter 1728–1793) . In his 28–1793 .In a significant proportion of cancers, the vasculature exhibits abnormalities across various dimensions of structure and function . These aDespite the elevated expression of VEGF-A in advanced stages of PCa, therapeutic approaches aimed at inhibiting the VEGF-A pathway have not yielded substantial treatment advantages . Unlike Various alternative mechanisms for tumor angiogenesis have been observed across different types of neoplasia, including PCa. These mechanisms encompass a wide range of processes, such as sprouting angiogenesis, vasculogenesis, intussusceptive angiogenesis, vascular co-option, mosaic vessels, vasculogenic mimicry, the transformation of cancer stem-like cells into tumor ECs, and vascular pruning ,39,40. IThe primary method through which PCa secures its blood supply for growth is primarily facilitated by two processes: sprouting angiogenesis and vasculogenesis . It is worth noting that several aspects related to the blood supply in PCa have not been thoroughly explored; much of the existing research has either relied on in vitro studies or been conducted within the context of other physiological or pathological processes. The role of angiogenesis in metastatic castration-resistant prostate cancer (mCRPC) has garnered significant attention as a potentially actionable biological mechanism for drug development. However, attempts to target angiogenesis have not successfully extended OS rates among mCRPC patients, despite encouraging findings from both preclinical experiments and early-stage clinical trials. Additional research has revealed that PCa cells not only release a variety of angiogenic factors to stimulate the growth of blood vessels but also directly create tumor-associated vascular channels, a phenomenon termed as vasculogenic mimicry. Luo et al.  have docIt is also crucial to note that there exist substantial challenges in the quantitative assessment of neovascularization through histopathological analysis. These challenges stem from the complex and multifaceted nature of tumor angiogenesis, which complicates the identification of reliable markers for assessing overall angiogenic activity in PCa. As a result, efforts are ongoing to delineate these processes more precisely and identify more accurate measures for both prediction and prognosis in the realm of PCa angiogenesis.Sprouting angiogenesis is frequently identified as a pivotal method for the vascularization of tumors, thus making it a principal focus for therapies aimed at inhibiting angiogenesis ,42. This+ SCs/telocytes (TCs) was assessed in the context of two distinct processes: sprouting angiogenesis and intussusceptive angiogenesis [+ SCs/TCs serve as a vital source of SCs during reparative granulation tissue formation as well as a source for cancer-associated fibroblasts (CAFs) within tumors. Conversely, these CD34+ SCs/TCs play a less significant role as precursor cells in the context of intussusceptive angiogenesis. Malfunction of these angiogenic mechanisms is implicated in various pathological conditions, including neoplasms, thereby having therapeutic relevance. Notably, it has been reported that intussusceptive angiogenesis is resistant to anti-VEGF strategies [Intussusceptive microvascular growth (IMG), alternatively termed intussusceptive angiogenesis or vessel splitting, represents another principal mechanism of angiogenesis. This process is characterized by the creation of new vessels through vascular invagination, the formation of intra-luminal pillars, and subsequent vessel splitting ,51. Unliogenesis . In thesrategies . Initialrategies ,59,60.The concept of “vasculogenesis” refers to a principal mechanism governing the de novo formation of blood vessels, characterized by the development of a capillary-like network originating from either dispersed or monolayered populations of ECs ,62. TradIn the process of sprouting angiogenesis, the growth of vessels is facilitated by the proliferation and migration of ECs from already existing blood vessels. Contrarily, vessel co-option does not involve the formation of new blood vessels; rather, cancer cells appropriate existing vasculature for their own growth and subsequent invasion into healthy tissue ,42. The Vessel co-option serves as an alternative method for tumors to secure a blood supply . This me− vessels. Here, PAS serves to stain basement membranes, which include components like laminin, collagen, and glycogen, while CD34 functions as a marker specifically for ECs. A comprehensive systematic review that incorporated meta-analysis and covered 3062 patients across multiple types of cancer demonstrated that the presence of VM correlates with a poorer 5-year OS rate. Furthermore, VM is associated with the facilitation of more aggressive forms of the disease and an increased propensity for metastatic spread [Originally identified in the context of uveal melanoma, VM refers to the capacity of aggressive tumor cells to undergo trans-differentiation. This allows them to adopt EC behaviors, facilitating the creation of vascular networks and a microcirculation system that is autonomous from non-cancerous host cells . VM is gc spread . Thus, tAggressive neoplasms can self-sustain by generating their own vascular-like structures for blood and nutrient supply. Maniotis et al. articulated in 1999 that highly invasive melanoma cells have the capacity to transform into multiple cellular forms, including those with endothelial-like properties that enable them to construct vessel-like conduits for blood supply . These cVM has been strongly linked with the invasive and metastatic characteristics of PCa. There is a significant correlation between VM formation and various prognostic markers in high-risk PCa patients, such as the Gleason score, lymph node metastasis, and distant metastasis ,87,88. NRecent research has highlighted the role of Cancer Stem Cells (CSCs) and Epithelium-to-Endothelium Transition (EET) in the process of tumor angiogenesis . EET, a Pruning constitutes a fundamental process occurring at all levels of the vascular network, serving as a remodeling mechanism aimed at reducing the energetic demands associated with tissue perfusion ,100. UnlIn PCa, particularly with PC3/2G7 tumors, extended treatment using axitinib has revealed an apparent evasion from anti-angiogenic effects. This escape manifests as a reinitiation of neovascularization and, consequently, tumor growth resumption. Multiple mechanisms have been proposed for such evasive behavior from VEGFR-targeted anti-angiogenic treatments. One significant mechanism involves the tumor’s capacity to upregulate alternative proangiogenic molecules, thereby rendering angiogenesis VEGF-independent. This adaptation may be partially triggered by the hypoxic conditions induced by vessel pruning, which in turn activate factors promoting tumor vascularization . The hypAccording to the specific target addressed by the therapeutic agent, the approach to inhibiting angiogenesis can be categorized into two principal classifications: direct and indirect inhibition . Direct Small molecular fragments  function as direct inhibitors by curtailing EC proliferation and migration. These processes are typically induced by factors such as Vascular Endothelial Growth Factor-A (VEGF-A), basic Fibroblast Growth Factor (bFGF), Platelet-Derived Growth Factor (PDGF), and interleukins . ConversVEGF-A has been shown to be markedly overexpressed in PCa and is correlated with unfavorable outcomes and metastatic progression. As a result, the majority of clinical studies focusing on anti-angiogenic therapies in PCa have targeted VEGF-A. Notable among these therapies are Bevacizumab, a recombinant humanized monoclonal antibody designed to neutralize VEGF-A; Aflibercept, which sequesters circulating VEGF-A; and Lenalidomide, which operates through a multi-faceted mechanism that includes the inhibition of VEGF-induced PI3K-Akt pathway signaling.From both histopathological and preclinical viewpoints, substantial evidence exists to support the pivotal role of angiogenesis in the onset and advancement of PCa. For instance, the presence of VEGFR2 has been identified as a marker indicative of PCa cases that are at elevated risk for progression ,110. MorNevertheless, the heterogeneity of blood vessels within tumors has been identified as a significant contributing factor to the limited effectiveness of anti-angiogenic treatments. The results of such therapies to date have been moderately successful at best, providing only a temporary decrease in tumor growth before resistance develops. Furthermore, these treatments have typically resulted in marginal improvements in OS rates, despite a broad spectrum of medications having received approval from the U.S. Food and Drug Administration (FDA). The constrained efficacy of these anti-angiogenic strategies can be attributed to a variety of factors. Among these are the employment of alternative angiogenic pathways by the tumors themselves, as well as the onset of mechanisms that lead to treatment resistance.Currently, medical professionals are actively investigating which subgroups of PCa patients are most responsive to angiogenesis inhibition therapies. Additionally, there is a concerted effort to bridge the division between experimental research (“bench”) and clinical application (“bedside”). Clinicians and researchers are exploring the synergistic effects of combining angiogenesis inhibitors with other well-established anti-cancer compounds. Several anti-angiogenic medications have already received regulatory approval and are presently employed in the treatment of various cancers. This situation raises a couple of crucial questions. Firstly, is it feasible to target the various mechanisms by which PCa tumors secure their blood supply through a single, unified therapeutic approach, or will alternative strategies need to be devised to achieve effective treatment? Secondly, there is the unresolved issue of whether anti-angiogenic treatments could prove efficacious in cases of refractory castration-resistant PCa, a subtype for which existing treatment options are notably limited.The proposition that angiogenesis is a prerequisite for tumor growth was initially postulated in 1971 by Moses Judah Folkman (1933–2008). He articulated this concept by stating, “Once a tumor “take” has been established, every subsequent expansion in the tumor cell population must be preceded by an increase in new capillaries that converge towards the tumor” ,113. ThiNo definitive biomarkers exist that can quantify the net angiogenic activity within the tumor. This absence of specific markers imposes limitations on the formulation of targeted anti-angiogenic treatment strategies. Nevertheless, it is plausible to conjecture that a thorough quantification of various facets of the tumor’s vascular architecture might offer valuable insights into its angiogenic potential. Therefore, while we are yet to identify precise indicators of angiogenic activity in PCa, the measurement and assessment of tumor vasculature may serve as a provisional approach to gauging angiogenic processes.A frequently measured variable in the vascular system of PCa is MVD. The method for quantifying MVD within tumors was originally introduced by Weidner in 1991 . This meNonetheless, MVD is not without its drawbacks. The inconsistency in results related to PCa is plausibly attributed to variations in study methodologies, encompassing factors such as the size of the patient cohort, the characteristics of the tumor, the methodology for selecting tumor areas for examination, the endothelial markers chosen, and the techniques employed for counting vessels ,119,120.Despite its acknowledged role as a predictive indicator in untreated neoplasms, MVD has not been substantiated as a reliable metric for either guiding or assessing anti-angiogenic interventions . MoreoveCurrently, there are no explicit biomarkers for evaluating angiogenic activity in PCa. However, it is plausible to postulate that vascular density serves as an indirect measure of intra-tumoral angiogenic processes. MVD is generally accepted as a viable proxy for angiogenic activity and has been validated as a prognostic determinant in a diverse array of malignancies, encompassing breast and colon cancers as well as malignant melanomas . InitialQuantitative metrics elucidating the geometrical intricacy of various structures can indeed be extracted using fractal geometry, a mathematical framework initially put forth by Benoit Mandelbrot in 1975 ,135,136.γ, while employing the symbol D for the dimensions put forth by Hausdorff and Besicovitch. In the realm of Euclidean shapes, the dimensions represented by Dγ and D are equivalent (Dγ = D). However, this equivalency does not universally extend to all fractal entities found in nature. Specifically, the inequality D > Dγ is true in such cases. Various approaches have been devised to approximate the fractal dimension of objects. Among these, the “box-counting method”  is the smallest number of boxes of side ε required to cover the outline or the surface of the object completely. Because the zero limit cannot be applied to natural objects, the dimension was estimated by the formulaLog N(ε) against Log (1/ε). The identification of linear sections within the graphs was accomplished through the utilization of regression analysis based on the least-squares method. Additionally, the slopes of these linear sections were evaluated by employing an iterative resistant-line technique. Given the intricate structure of tumor vasculature, characterized by its spatial, temporal, and molecular diversification [Mandelbrot designated the dimension of Menger’s construct using the notation D method”  is most fication , it becop = 0.78) [In a study by Tretiakova and colleagues, the implementation of automated image analysis on both conventional and tissue microarray cross-sections in expansive, representative regions revealed no statistically significant elevations in MVD metrics when comparing PCa tissues to their corresponding normal peripheral prostatic zones . Intrigu = 0.78) . MoreoveA non-intrusive imaging modality capable of illustrating MVD would offer significant advantages for both the identification and analysis of tumors ,149. SucTherefore, evaluating vascularization through two-dimensional histological slides does not adequately capture the comprehensive vascular nature of the tissue ,134. TheAlmost a century ago, W.H. Lewis noted a striking divergence in both the density and morphological features of blood vessels in transplanted tumors, depending on the type of tumor in question. This led him to propose the seminal hypothesis that the vascular patterns within tumors are largely dictated by the tumor environment itself . While sThe vascularity of tumors in human cancers exhibits significant variability. This variation is, to some extent, indicative of the equilibrium between pro-angiogenic and anti-angiogenic factors present within the TME . The use of MVD as a standalone predictor for angiogenesis in cancer has proven to be insufficiently effective. Recent studies employing MVD for detecting angiogenesis have yielded inconclusive results. These studies have shown a decrease in mean MVD in areas infiltrated by PCa, while areas unaffected by the cancer have shown either relatively stable or preserved angiogenic activity. At present, there are no explicit markers for gauging angiogenic activity in PCa, although it is plausible to consider vascular density as an indicative measure of intra-tumoral angiogenic actions. One significant limitation is the intricate geometrical architecture of the newly developed vascular network, a complexity that is challenging to interpret through two-dimensional histological slices. Potential solutions for this could include the application of fractal geometry to estimate surface dimensions, computer-aided automated image analysis, or three-dimensional modeling. It is unequivocal that the angiogenic process in PCa is more multifaceted than initially perceived. Multiple pathways are implicated, either independently or in concert, in the evolution and progression of PCa. Furthermore, PCa constitutes a complex microenvironment, consisting of diverse cell types that can have distinct, impactful roles in the neovascularization process. It is crucial to synthesize the abundant information currently accessible regarding the molecules and pathways engaged in the angiogenic process in PCa, combining it with physical concepts and the physics of cancer. Both form and function continue to serve as the foundational elements for any biological entity, influencing its alterations across spatial and temporal dimensions.