In this comprehensive review,we delve into the evolution of drug delivery systems in reproductive medicine with a focus on the emerging role of exosomes,a class of extracellular vesicles.Exosomes offer unique advantag...In this comprehensive review,we delve into the evolution of drug delivery systems in reproductive medicine with a focus on the emerging role of exosomes,a class of extracellular vesicles.Exosomes offer unique advantages in overcoming these challenges due to their inherent biocompatibility,stability,and ability to facilitate targeted delivery.This review provides a detailed examination of exosome biogenesis and their function in cellular communication,setting the stage for understanding their potential as drug delivery vehicles.We explore the mechanisms through which exosomes can be loaded with small molecule drugs and the benefits they offer over synthetic nanoparticles.The review highlights groundbreaking case studies that illustrate the successful application of exosome-mediated drug delivery in reproductive health,including enhancing fertility treatments,supporting gamete and embryo development,and facilitating maternal-fetal communication.This study aims to provide a precise un-derstanding of how exosomal drug delivery can revolutionize treatments for reproductive health dis-orders,paving the way for future therapeutic applications.Lastly,we touch upon the promising therapeutic implications of exosomal delivery for proteins and genes,offering a window into future treatments for reproductive health disorders.展开更多
Abstract： With the rapid development of assisted reproductive technology, various reproductive disorders have been effectively addressed. Acupuncture-like therapies, including electroacupuncture （EA） and transcutan...Abstract： With the rapid development of assisted reproductive technology, various reproductive disorders have been effectively addressed. Acupuncture-like therapies, including electroacupuncture （EA） and transcutaneous electrical acupoint stimulation （TEAS）, become more popular world-wide. Increasing evidence has demonstrated that EA and TEAS are effective in treating gynecological disorders, especially infertility. This present paper describes how to select acupoints for the treatment of infertility from the view of theories of traditional Chinese medicine and how to determine critical parameters of electric pulses of ENTEAS based on results from animal and clinical studies. It summarizes the principles of clinical application of EA/rEAS in treating various kinds of reproductive disorders, such as polycystic ovary syndrome （PCOS）, pain induced by oocyte retrieval, diminished ovarian reserve, embryo transfer, and oligosperrnia/ asthenospermia. The possible underlying mechanisms mediating the therapeutic effects of EA/TEAS in reproductive medicine are also examined.展开更多
Based on the macroanalysis of the unbalanced development of the"demand side"and the"supply side"of clinical medicine in China,this paper elucidates the stakeholders,resources,and ecosystem of the s...Based on the macroanalysis of the unbalanced development of the"demand side"and the"supply side"of clinical medicine in China,this paper elucidates the stakeholders,resources,and ecosystem of the strategic scientific and technological capacity-building and calls for a larger coverage,smoother supply chain,and more sustainable ecosystem to ensure the development of clinical medicine.Furthermore,focusing on the establishment and development of clinical reproductive health in China,the authors introduce the strategic scientific and technological capacity-building of reproductive medicine in Peking University Third Hospital,with an attempt to inform similar efforts in other fields and even the whole clinical medicine in China.展开更多
Spermatogonial stem cells （SSCs）, also known as male germline stem cells, are a small subpopulation of type A spermatogonia with the potential of self-renewal to maintain stem cell pool and differentiation into sper...Spermatogonial stem cells （SSCs）, also known as male germline stem cells, are a small subpopulation of type A spermatogonia with the potential of self-renewal to maintain stem cell pool and differentiation into spermatids in mammalian testis. SSCs are previously regarded as the unipotent stem cells since they can only give rise to sperm within the seminiferous tubules. However, this concept has recently been challenged because numerous studies have demonstrated that SSCs cultured with growth factors can acquire pluripotency to become embryonic stem-like cells. The in vivo and in vitro studies from peers and us have clearly revealed that SSCs can directly transdifferentiate into morphologic, phenotypic, and functional cells of other lineages. Direct conversion to the cells of other tissues has important significance for regenerative medicine. SSCs from azoospermia patients could be induced to differentiate into spermatids with fertilization and developmental potentials. As such, SSCs could have significant applications in both reproductive and regenerative medicine due to their unique and great potentials. In this review, we address the important plasticity of SSCs, with focuses on their self-renewal, differentiation, dedifferentiation, transdifferentiation, and translational medicine studies.展开更多
There has been a very rapid development in the area of preimplantation genetic testing(PGT)since the first baby applied PGT technology in the world was born in the last 30 years.As an alternative treatment of prenatal...There has been a very rapid development in the area of preimplantation genetic testing(PGT)since the first baby applied PGT technology in the world was born in the last 30 years.As an alternative treatment of prenatal diagnosis,the transfer of the fetus with normal testing result has benefited many families.PGT is mainly classified into PGT for aneuploidies(PGT-A),PGT for chromosomal structural rearrangement(PGT-SR),and PGT for monogenic/single-gene defects(PGT-M).Here,we reviewed the application,development,limitations,and challenges of the current PGT in reproductive medicine.展开更多
Single-cell multi-omics sequencing has greatly accelerated reproductive research in recent years,and the data are continually growing.However,utilizing these data resources is challenging for wet-lab researchers.A com...Single-cell multi-omics sequencing has greatly accelerated reproductive research in recent years,and the data are continually growing.However,utilizing these data resources is challenging for wet-lab researchers.A comprehensive platform for exploring single-cell multi-omics data related to reproduction is urgently needed.Here,we introduce the single-cell multi-omics atlas of reproduction(SMARTdb),an integrative and user-friendly platform for exploring molecular dynamics of reproductive development,aging,and disease,which covers multi-omics,multi-species,and multi-stage data.We curated and analyzed single-cell transcriptomic and epigenomic data of over 2.0 million cells from 6 species across the entire lifespan.A series of powerful functionalities are provided,such as“Query gene expression”,“DIY expression plot”,“DNA methylation plot”,and“Epigenome browser”.With SMARTdb,we found that the male germ cell-specific expression pattern of RPL39L and RPL10L is conserved between human and other model animals.Moreover,DNA hypomethylation and open chromatin may collectively regulate the specific expression pattern of RPL39L in both male and female germ cells.In summary,SMARTdb is a powerful platform for convenient data mining and gaining novel insights into reproductive development,aging,and disease.SMARTdb is publicly available at https://smart-db.cn.展开更多
Reproductive health encompasses the entire spectrum of reproductive processes and functions throughout a person’s life,playing a vital role in the harmonious development of populations,economies,and societies.This cr...Reproductive health encompasses the entire spectrum of reproductive processes and functions throughout a person’s life,playing a vital role in the harmonious development of populations,economies,and societies.This critical aspect has garnered increasing global attention.Ensuring sexual and reproductive health stands as a fundamental step toward achieving the United Nations Sustainable Development Goal(SDG)by 2030[1].Despite extensive efforts,both China and the world at large confront a multitude of reproductive challenges.These challenges encompass declining fertility rates[2,3],high prevalence of birth defects,and the presence of various reproductive diseases that threaten fetal development.These issues contribute to emotional distress,relationship problems,social stigmatization,and an increased risk of adult-onset diseases,imposing a significant burden on individuals and society[2].In the realm of human reproductive health research,epidemiological approaches have played a pivotal role.展开更多
Stromal vascular fraction(SVF)is a complex mixture derived from adipose tissue,consisting of a variety of cells.Due to its potential for tissue repair,immunomod-ulation,and support of angiogenesis,SVF represents a pro...Stromal vascular fraction(SVF)is a complex mixture derived from adipose tissue,consisting of a variety of cells.Due to its potential for tissue repair,immunomod-ulation,and support of angiogenesis,SVF represents a promising frontier in regenerative medicine and offers potential therapy for a range of disease condi-tions.In this article,we delve into the mechanisms through which SVF exerts its effects and explore its potential applications in treating both male and female reproductive disorders,including erectile dysfunction,testicular injury,stress urinary incontinence and intrauterine adhesion.展开更多
Collagen-based biomaterials(CBB) are highly esteemed by researchers in materials science and biomedicine due to their extensive applications across various biomedical disciplines.In recent years,owing to advancements ...Collagen-based biomaterials(CBB) are highly esteemed by researchers in materials science and biomedicine due to their extensive applications across various biomedical disciplines.In recent years,owing to advancements in developmental biology techniq ues,this superior biomaterial has seen increasing utilization in 3D in vitro tissue culture.Three-dimensional cell cultures,often referred to as organoids,have emerged in response to technological advancements in biomaterials and the growing need in the field of medical research.They serve as important models for simulating normal physiological activities in vivo,addressing limitations in experimental material sources,and resolving ethical issues.In this review,we discuss the material characteristics of CBBs commonly used for organoid culture,integrating aspects such as Matrigel and decellularized ECM as culture matrices.We also analyzed the development prospects and directions of various materials in the context of biology,clinical medicine,and partic ularly reproductive medicine.Currently,despite the FDA approval and clinical research incorporating numerous CBBs,existing challenges in multiple studies indicate a significant unmet need in the development of key tissue models for both medical research and clinical applications.In summary,CBBs are swiftly broadening their applicability in the realms of organoid nature and medical research,serving as a versatile and high-performing material for 3D in vitro tissue culture.展开更多
Ovarian aging is characterized by a progressive decline in oocyte quality and quantity with age.Icariin(ICA),a flavonoid compound derived from Epimedium species,has demonstrated potential as an agent for ovarian resto...Ovarian aging is characterized by a progressive decline in oocyte quality and quantity with age.Icariin(ICA),a flavonoid compound derived from Epimedium species,has demonstrated potential as an agent for ovarian restoration.In this study,a subcutaneous implantation system using gelatin methacryloyl(GelMA)hydrogel embedded with ICA was developed to restore ovarian function in aged female mice.Mice were assigned to receive subcutaneous implantation of GelMA alone(GelMA group),GelMA containing ICA(GelMA/ICA group),or a sham operation.Ovarian morphology,serum hormone levels,follicle counts across developmental stages,and reproductive outcomes were evaluated.In vitro fertilization(IVF)and embryo culture assays were performed to assess oocyte developmental potential,while a 10 day natural mating trial was conducted to determine fertility restoration.RNA sequencing(RNA-seq)and RT-qPCR were performed to elucidate the underlying molecular mechanisms.Results showed that GelMA/ICA treatment significantly increased ovarian index(0.19±0.01 vs.0.13±0.01,P<0.0001)and follicle numbers at all developmental stages,including primordial(383.33±151.65 vs.107.14±32.26,P<0.0001),primary(203.33±83.22 vs.91.43±27.04,P=0.003),and secondary follicles(154.17±52.00 vs.59.28±20.50,P=0.029)compared to the sham controls.Hormonal analyses revealed a significant reduction in serum follicle-stimulating hormone(FSH,11.97±3.53 vs.53.10±17.89 ng/mL,P=0.0008),accompanied by elevated anti-Müllerian hormone(AMH,22.97±2.26 vs.5.54±1.56 ng/mL,P<0.0001)and estradiol(E2,315.30±37.62 vs.168.5±14.78 pg/mL,P<0.0001).Oocyte yield and developmental potential improved significantly,as reflected by the increased number of superovulated MII oocytes(17.83±5.15 vs.4.83±4.79,P=0.0002),and higher proportions of two-cell(85.90%±6.16%vs.50.00%±10.00%,P=0.0009),four-cell(81.67%±9.76%vs.50.00%±10.00%,P=0.0061),and blastocyst stage embryos(64.25%±10.55%vs.23.33%±15.28%,P=0.0067).Live birth numbers were significantly increased following GelMA/ICA treatment(6.90±3.21 vs.1.72±2.05,P=0.0001).Transcriptomic analysis revealed up-regulation of genes associated with cytoskeletal organization(Vil1,Tubb3),lipid storage(Soat2,Plin4),oocyte maturation(Oosp2),and cytokine secretion(Cxcl12).Collectively,these findings suggest that GelMA/ICA hydrogels effectively reverse key hallmarks of ovarian aging and restore reproductive function in aged mice,offering a promising platform for fertility preservation and a novel therapeutic for future investigations into ovarian aging.展开更多
Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its s...Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its significant therapeutic potential in cancer immunotherapy and the substantial attention it has received from academia and industry,the molecular mechanisms of LAG3-mediated immunosuppression remain poorly understood,primarily because of its unique ligand-binding characteristics and intracellular domains[1].展开更多
V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating ene...V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.展开更多
In vitro maturation(IvM)of human oocytes offers cost efficiency and minimal invasiveness,serving as a valuable supplementary tool in assisted reproduction for fertility preservation,ovarian hyperstimulation syndrome p...In vitro maturation(IvM)of human oocytes offers cost efficiency and minimal invasiveness,serving as a valuable supplementary tool in assisted reproduction for fertility preservation,ovarian hyperstimulation syndrome prevention,and other reproductive strategies.Despite its availability for three decades,the clinical use of IVM remains limited due to efficacy and safety concerns.This study examines the DNA methylation profile of IVM oocytes collected during laparoscopic/hysteroscopic surgeries compared to in vivo matured oocytes via reduced representation bisulfite sequencing.Results indicate IVM oocytes exhibit a higher global methylation level.Differentially methylated regions(DMRs)analysis reveals that the in vitro group displays more hypermethylated and fewer hypomethylated DMRs compared to the in vivo group.Additionally,the in vitro group exhibits a higher level of non-CpG methylation than the in vivo group.However,no significant correlation between methylation levels and transcriptional activity in these oocytes is found,especially for those specific imprinted genes or genes related to embryonic development.These findings shed light on the epigenetic landscape of IvM oocytes,contributing to the ongoing assessment of their clinical feasibility and safety in assisted reproduction.展开更多
Background:Chronic endometritis(CE)is an important pathological factor contributing to female infertility and recurrent pregnancy loss.Although antibiotics are the primary clinical treatment for CE,they do not effecti...Background:Chronic endometritis(CE)is an important pathological factor contributing to female infertility and recurrent pregnancy loss.Although antibiotics are the primary clinical treatment for CE,they do not effectively improve pregnancy outcomes.Wen Yang Hua Zhuo(WYHZ)is a clinically employed classical formula known for its effects in warming yang,tonifying the spleen and kidneys,and resolving dampness.However,its underlying mechanisms remain unclear.This study aimed to elucidate how WYHZ modulates the immunometabolic microenvironment at the maternal-fetal interface in CE by targeting the MCT/HIF-1α/LDHA pathway to promote embryo implantation.Methods:In vivo,the model of CE was established by intrauterine injection of lipopolysaccharide(LPS)(1 mg/mL)into female C57/BL mice,followed by WYHZ treatment for 3 weeks to evaluate its effects on embryo implantation.Mechanistic studies were further conducted using the MCT-1 inhibitor AZD3965 and adeno-associated virus-mediated HIF-1αknockdown.In vitro,an in vitro CE model consisting of M1 macrophages and Ishikawa,as well as an in vitro embryo implantation model mediated by JAR cells,were constructed using Transwell,and the therapeutic mechanisms of WYHZ was validated using AZD3965 and lentiviral sh HIF-1αintervention.Metabolic enzyme activity assays,protein antibody microarrays,immunofluorescence,Western blotting,Seahorse analysis,and ELISA were employed.Results:WYHZ improved the immune-inflammatory microenvironment at the maternal-fetal interface by reducing pro-inflammatory cytokines and increasing anti-inflammatory factors.In parallel,WYHZ reprogrammed endometrial metabolism by enhancing glycolysis and suppressing mitochondrial oxidative phosphorylation,thereby improving endometrial receptivity and embryo implantation.Mechanistically,WYHZ activated the MCT/HIF-1α/LDHA pathway in endometrial epithelial cells,alleviating inflammatory stress and restoring receptivity.Both AZD3965 intervention and HIF-1αknockdown impaired endometrial receptivity and implantation,effects that were reversed by WYHZ.Conclusion:WYHZ modulates the immunometabolic microenvironment of the endometrium in the context of CE by targeting the activation of the MCT/HIF-1α/LDHA pathway,which improves endometrial receptivity and promotes embryo implantation.展开更多
Varicocele(VC)is widely recognized as a prevalent and clinically significant cause of male infertility.However,the comprehensive pathogenic mechanisms underlying VC development and progression remain incompletely unde...Varicocele(VC)is widely recognized as a prevalent and clinically significant cause of male infertility.However,the comprehensive pathogenic mechanisms underlying VC development and progression remain incompletely understood,creating an important knowledge gap in the field of andrology.This review establishes that VC pathogenesis centers on abnormal vascular remodeling and integrates multiple contributing elements,including anatomical abnormalities,biochemical disturbances,genetic factors,low body mass index(BMI),age,and specific sports habits,while secondary varicoceles are primarily induced by compressive pathologies.Through a systematic synthesis of current evidence and recent advances,this review aims to elucidate the complex pathogenic network of VC and provide valuable insights to guide future research directions and inform the development of targeted clinical applications.展开更多
Optical tweezers technology has the characteristics of noncontact manipulation in three dimensions and steerable separation in solutions,and could be applied to obtain a separated sperm with high quality for intracyto...Optical tweezers technology has the characteristics of noncontact manipulation in three dimensions and steerable separation in solutions,and could be applied to obtain a separated sperm with high quality for intracytoplasmic sperm injection(ICSI).However,the effects of optical tweezers on sperm motility are still unclear.To elucidate the effects on sperm motility for optical tweezers,we systematically investigated the correlation between motility parameters and the parameters of optical tweezers(wavelength,power,trapping duration,and trapping orientation).Under three systems of optical tweezers with different laser wavelengths(1064,850,and 785 nm),the nine motility parameters of free swimming were mainly affected by trapping orientation(vertical/horizontal)and trapping duration.When 850 nm laser and 1064 nm laser are used,vertical trapping significantly reduces sperm free-swimming capability with prolonged exposure time,whereas horizontal trapping exhibits relatively minor interference on sperm motility.Notably,the 785 nm laser does not induce statistically significant changes in key parameters of sperm motility under any experimental conditions(trapping orientation and duration).For the rolling frequency of trapped sperm,horizontal trapping for three wavelengths has a negligible effect compared with vertical trapping,especially for the 785 nm laser.In conclusion,horizontal trapping can preserve sperm motility under low power(below 140mW at 1064 nm,below 100mW at 850nm,below 60mW at 785 nm)and short duration(below 4 min).This trapping duration is suffcient for the separation procedure of single live sperm in ICSI.This study provides critical parameter optimization guidelines for the safe application of optical tweezers technology in reproductive medicine.展开更多
Prenatal maternal psychological distress,particularly depression,has been increasingly recognized as a factor that influences fetal growth;however,its impact on early childhood development remains less well understood...Prenatal maternal psychological distress,particularly depression,has been increasingly recognized as a factor that influences fetal growth;however,its impact on early childhood development remains less well understood.The present study investigated the association between prenatal depression and children's growth trajectories,as well as the odds of overweight and obesity from 1 to 36 months,while also accounting for maternal anxiety and stress.We analyzed data from 4710 mother-child dyads in the Jiangsu Birth Cohort,assessing maternal psychological distress across trimesters and categorizing participants into groups with mild,moderate,and severe depressive symptomatology.Children's weight-for-length z-scores(WLZ)were used to assess overweight/obesity prevalence,and growth patterns were identified through trajectory models.The results from the generalized estimating equations analysis showed that greater depressive symptomatology during pregnancy was associated with a 28%to 41%increase in the odds of childhood overweight/obesity across all three trimesters,compared with mild depressive symptomatology.We identified five distinct WLZ growth trajectory patterns,and found that mothers with greater depressive symptomatology were 39%–47%more likely to have children who followed a very-high-stable growth trajectory,compared with mothers with mild depressive symptomatology.These findings highlight the significant impact of prenatal depression on adverse growth patterns and childhood overweight/obesity,underscoring the need for early intervention.展开更多
Mammalian fertilization involves the migration of spermatozoa through the female reproductive system.Early embryonic development is a consequence of several steps and signaling pathways being activated,as well as bioc...Mammalian fertilization involves the migration of spermatozoa through the female reproductive system.Early embryonic development is a consequence of several steps and signaling pathways being activated,as well as biochemical and morphological modifications of spermatozoa that enable them to penetrate the membrane of mature oocytes.There are some crucial steps known to clearly explain the process of fertilization,starting with hyperactivation of spermatozoa,mutual recognition,and binding of gametes mediated by receptors located on the surface membranes of both gametes.The final step is followed by oocyte activation,which is primarily triggered via sperm-derived factors,inducing a sharp increase in intracellular calcium levels,eventually leading to polyspermy block.This review integrates current knowledge of the molecular and physiological events governing fertilization,emphasizing how ion regulation and signaling pathways converge to enable sperm function and oocyte activation.Special attention is given to sperm-derived factors such as phospholipase C zeta(PLCζ)and post-acrosomal sheath WW domain-binding protein(PAWP),which play essential roles in triggering calcium release and supporting early embryonic development.展开更多
Ferroptosis,a type of cell death that mainly involves iron metabolism imbalance and lipid peroxidation,is strongly correlated with the phagocytic response caused by bleeding after spinal cord injury.Thus,in this study...Ferroptosis,a type of cell death that mainly involves iron metabolism imbalance and lipid peroxidation,is strongly correlated with the phagocytic response caused by bleeding after spinal cord injury.Thus,in this study,bulk RNA sequencing data(GSE47681 and GSE5296)and single-cell RNA sequencing data(GSE162610)were acquired from gene expression databases.We then conducted differential analysis and immune infiltration analysis.Atf3 and Piezo1 were identified as key ferroptosis genes through random forest and least absolute shrinkage and selection operator algorithms.Further analysis of single-cell RNA sequencing data revealed a close relationship between ferroptosis and cell types such as macrophages/microglia and their intrinsic state transition processes.Differences in transcription factor regulation and intercellular communication networks were found in ferroptosis-related cells,confirming the high expression of Atf3 and Piezo1 in these cells.Molecular docking analysis confirmed that the proteins encoded by these genes can bind cycloheximide.In a mouse model of T8 spinal cord injury,low-dose cycloheximide treatment was found to improve neurological function,decrease levels of the pro-inflammatory cytokine inducible nitric oxide synthase,and increase levels of the anti-inflammatory cytokine arginase 1.Correspondingly,the expression of the ferroptosis-related gene Gpx4 increased in macrophages/microglia,while the expression of Acsl4 decreased.Our findings reveal the important role of ferroptosis in the treatment of spinal cord injury,identify the key cell types and genes involved in ferroptosis after spinal cord injury,and validate the efficacy of potential drug therapies,pointing to new directions in the treatment of spinal cord injury.展开更多
Prostate cancer(PCa)remains a major cause of cancer-related mortality in men,largely due to therapy resistance and metastatic progression.Increasing evidence highlights the tumor microenvironment(TME),particularly can...Prostate cancer(PCa)remains a major cause of cancer-related mortality in men,largely due to therapy resistance and metastatic progression.Increasing evidence highlights the tumor microenvironment(TME),particularly cancer-associated fibroblasts(CAFs),as a critical determinant of disease behavior.CAFs constitute a heterogeneous population originating from fibroblasts,mesenchymal stem cells,endothelial cells,epithelial cells undergoing epithelial-mesenchymal transition(EMT),and adipose tissue.Through dynamic crosstalk with tumor,immune,endothelial,and adipocyte compartments,CAFs orchestrate oncogenic processes including tumor proliferation,invasion,immune evasion,extracellular matrix remodeling,angiogenesis,and metabolic reprogramming.This review comprehensively summarizes the cellular origins,phenotypic and functional heterogeneity,and spatial distribution of CAFs within the prostate TME.We further elucidate the molecular mechanisms by which CAFs regulate PCa progression and therapeutic resistance,and critically evaluate emerging strategies to therapeutically target CAFmediated signaling,metabolic,and immune pathways.By integrating recent advances from single-cell and spatial transcriptomics(ST),our objective is to provide a holistic framework for understanding CAF biology and to highlight potential avenues for stromal reprogramming as an adjunct to current PCa therapies.展开更多
基金NGS assistant and Beijing Chipstone co.for their copy editing service.
文摘In this comprehensive review,we delve into the evolution of drug delivery systems in reproductive medicine with a focus on the emerging role of exosomes,a class of extracellular vesicles.Exosomes offer unique advantages in overcoming these challenges due to their inherent biocompatibility,stability,and ability to facilitate targeted delivery.This review provides a detailed examination of exosome biogenesis and their function in cellular communication,setting the stage for understanding their potential as drug delivery vehicles.We explore the mechanisms through which exosomes can be loaded with small molecule drugs and the benefits they offer over synthetic nanoparticles.The review highlights groundbreaking case studies that illustrate the successful application of exosome-mediated drug delivery in reproductive health,including enhancing fertility treatments,supporting gamete and embryo development,and facilitating maternal-fetal communication.This study aims to provide a precise un-derstanding of how exosomal drug delivery can revolutionize treatments for reproductive health dis-orders,paving the way for future therapeutic applications.Lastly,we touch upon the promising therapeutic implications of exosomal delivery for proteins and genes,offering a window into future treatments for reproductive health disorders.
基金Project supported by the Special Research Fund for the Public Welfare Industry of Health of China(No.201302013)
文摘Abstract： With the rapid development of assisted reproductive technology, various reproductive disorders have been effectively addressed. Acupuncture-like therapies, including electroacupuncture （EA） and transcutaneous electrical acupoint stimulation （TEAS）, become more popular world-wide. Increasing evidence has demonstrated that EA and TEAS are effective in treating gynecological disorders, especially infertility. This present paper describes how to select acupoints for the treatment of infertility from the view of theories of traditional Chinese medicine and how to determine critical parameters of electric pulses of ENTEAS based on results from animal and clinical studies. It summarizes the principles of clinical application of EA/rEAS in treating various kinds of reproductive disorders, such as polycystic ovary syndrome （PCOS）, pain induced by oocyte retrieval, diminished ovarian reserve, embryo transfer, and oligosperrnia/ asthenospermia. The possible underlying mechanisms mediating the therapeutic effects of EA/TEAS in reproductive medicine are also examined.
文摘Based on the macroanalysis of the unbalanced development of the"demand side"and the"supply side"of clinical medicine in China,this paper elucidates the stakeholders,resources,and ecosystem of the strategic scientific and technological capacity-building and calls for a larger coverage,smoother supply chain,and more sustainable ecosystem to ensure the development of clinical medicine.Furthermore,focusing on the establishment and development of clinical reproductive health in China,the authors introduce the strategic scientific and technological capacity-building of reproductive medicine in Peking University Third Hospital,with an attempt to inform similar efforts in other fields and even the whole clinical medicine in China.
文摘Spermatogonial stem cells （SSCs）, also known as male germline stem cells, are a small subpopulation of type A spermatogonia with the potential of self-renewal to maintain stem cell pool and differentiation into spermatids in mammalian testis. SSCs are previously regarded as the unipotent stem cells since they can only give rise to sperm within the seminiferous tubules. However, this concept has recently been challenged because numerous studies have demonstrated that SSCs cultured with growth factors can acquire pluripotency to become embryonic stem-like cells. The in vivo and in vitro studies from peers and us have clearly revealed that SSCs can directly transdifferentiate into morphologic, phenotypic, and functional cells of other lineages. Direct conversion to the cells of other tissues has important significance for regenerative medicine. SSCs from azoospermia patients could be induced to differentiate into spermatids with fertilization and developmental potentials. As such, SSCs could have significant applications in both reproductive and regenerative medicine due to their unique and great potentials. In this review, we address the important plasticity of SSCs, with focuses on their self-renewal, differentiation, dedifferentiation, transdifferentiation, and translational medicine studies.
文摘There has been a very rapid development in the area of preimplantation genetic testing(PGT)since the first baby applied PGT technology in the world was born in the last 30 years.As an alternative treatment of prenatal diagnosis,the transfer of the fetus with normal testing result has benefited many families.PGT is mainly classified into PGT for aneuploidies(PGT-A),PGT for chromosomal structural rearrangement(PGT-SR),and PGT for monogenic/single-gene defects(PGT-M).Here,we reviewed the application,development,limitations,and challenges of the current PGT in reproductive medicine.
基金supported by the Young Elite Scientists Sponsorship Program by China Association for Science and Technology(Grant No.2020QNRC001)the research start-up funding from Nanjing Medical University,China(Grant No.KY116RC20200007).
文摘Single-cell multi-omics sequencing has greatly accelerated reproductive research in recent years,and the data are continually growing.However,utilizing these data resources is challenging for wet-lab researchers.A comprehensive platform for exploring single-cell multi-omics data related to reproduction is urgently needed.Here,we introduce the single-cell multi-omics atlas of reproduction(SMARTdb),an integrative and user-friendly platform for exploring molecular dynamics of reproductive development,aging,and disease,which covers multi-omics,multi-species,and multi-stage data.We curated and analyzed single-cell transcriptomic and epigenomic data of over 2.0 million cells from 6 species across the entire lifespan.A series of powerful functionalities are provided,such as“Query gene expression”,“DIY expression plot”,“DNA methylation plot”,and“Epigenome browser”.With SMARTdb,we found that the male germ cell-specific expression pattern of RPL39L and RPL10L is conserved between human and other model animals.Moreover,DNA hypomethylation and open chromatin may collectively regulate the specific expression pattern of RPL39L in both male and female germ cells.In summary,SMARTdb is a powerful platform for convenient data mining and gaining novel insights into reproductive development,aging,and disease.SMARTdb is publicly available at https://smart-db.cn.
文摘Reproductive health encompasses the entire spectrum of reproductive processes and functions throughout a person’s life,playing a vital role in the harmonious development of populations,economies,and societies.This critical aspect has garnered increasing global attention.Ensuring sexual and reproductive health stands as a fundamental step toward achieving the United Nations Sustainable Development Goal(SDG)by 2030[1].Despite extensive efforts,both China and the world at large confront a multitude of reproductive challenges.These challenges encompass declining fertility rates[2,3],high prevalence of birth defects,and the presence of various reproductive diseases that threaten fetal development.These issues contribute to emotional distress,relationship problems,social stigmatization,and an increased risk of adult-onset diseases,imposing a significant burden on individuals and society[2].In the realm of human reproductive health research,epidemiological approaches have played a pivotal role.
文摘Stromal vascular fraction(SVF)is a complex mixture derived from adipose tissue,consisting of a variety of cells.Due to its potential for tissue repair,immunomod-ulation,and support of angiogenesis,SVF represents a promising frontier in regenerative medicine and offers potential therapy for a range of disease condi-tions.In this article,we delve into the mechanisms through which SVF exerts its effects and explore its potential applications in treating both male and female reproductive disorders,including erectile dysfunction,testicular injury,stress urinary incontinence and intrauterine adhesion.
基金supported by funding from the projects of the National Natural Science Foundation of China(Y.Z.,Grant No.82001496)Sichuan Science and Technology Program(Sichuan Natural Science Foundation for Youth,China,NO.2022NSFSC1281)Sichuan Medical Association Foundation(China,NO.S21006)
文摘Collagen-based biomaterials(CBB) are highly esteemed by researchers in materials science and biomedicine due to their extensive applications across various biomedical disciplines.In recent years,owing to advancements in developmental biology techniq ues,this superior biomaterial has seen increasing utilization in 3D in vitro tissue culture.Three-dimensional cell cultures,often referred to as organoids,have emerged in response to technological advancements in biomaterials and the growing need in the field of medical research.They serve as important models for simulating normal physiological activities in vivo,addressing limitations in experimental material sources,and resolving ethical issues.In this review,we discuss the material characteristics of CBBs commonly used for organoid culture,integrating aspects such as Matrigel and decellularized ECM as culture matrices.We also analyzed the development prospects and directions of various materials in the context of biology,clinical medicine,and partic ularly reproductive medicine.Currently,despite the FDA approval and clinical research incorporating numerous CBBs,existing challenges in multiple studies indicate a significant unmet need in the development of key tissue models for both medical research and clinical applications.In summary,CBBs are swiftly broadening their applicability in the realms of organoid nature and medical research,serving as a versatile and high-performing material for 3D in vitro tissue culture.
基金supported by the National Natural Science Foundation of China(82271671)Nanjing Drum Tower Hospital Academic Innovation Peak Fund(2024-DF-02)+4 种基金Clinical Trials from Nanjing Drum Tower Hospital(2023-LCYJ-MS-05)Nanjing International Science and Technology Cooperation Program(202201027)to L.D.Research Project of State Key Laboratory of Reproductive Medicine and Offspring Health(SKLRM-2022D2)Changzhou Medical Center of Nanjing Medical University(CMCM202203)Clinical Trials from Nanjing Drum Tower Hospital(2022-LCYJ-ZD-02)to H.S.
文摘Ovarian aging is characterized by a progressive decline in oocyte quality and quantity with age.Icariin(ICA),a flavonoid compound derived from Epimedium species,has demonstrated potential as an agent for ovarian restoration.In this study,a subcutaneous implantation system using gelatin methacryloyl(GelMA)hydrogel embedded with ICA was developed to restore ovarian function in aged female mice.Mice were assigned to receive subcutaneous implantation of GelMA alone(GelMA group),GelMA containing ICA(GelMA/ICA group),or a sham operation.Ovarian morphology,serum hormone levels,follicle counts across developmental stages,and reproductive outcomes were evaluated.In vitro fertilization(IVF)and embryo culture assays were performed to assess oocyte developmental potential,while a 10 day natural mating trial was conducted to determine fertility restoration.RNA sequencing(RNA-seq)and RT-qPCR were performed to elucidate the underlying molecular mechanisms.Results showed that GelMA/ICA treatment significantly increased ovarian index(0.19±0.01 vs.0.13±0.01,P<0.0001)and follicle numbers at all developmental stages,including primordial(383.33±151.65 vs.107.14±32.26,P<0.0001),primary(203.33±83.22 vs.91.43±27.04,P=0.003),and secondary follicles(154.17±52.00 vs.59.28±20.50,P=0.029)compared to the sham controls.Hormonal analyses revealed a significant reduction in serum follicle-stimulating hormone(FSH,11.97±3.53 vs.53.10±17.89 ng/mL,P=0.0008),accompanied by elevated anti-Müllerian hormone(AMH,22.97±2.26 vs.5.54±1.56 ng/mL,P<0.0001)and estradiol(E2,315.30±37.62 vs.168.5±14.78 pg/mL,P<0.0001).Oocyte yield and developmental potential improved significantly,as reflected by the increased number of superovulated MII oocytes(17.83±5.15 vs.4.83±4.79,P=0.0002),and higher proportions of two-cell(85.90%±6.16%vs.50.00%±10.00%,P=0.0009),four-cell(81.67%±9.76%vs.50.00%±10.00%,P=0.0061),and blastocyst stage embryos(64.25%±10.55%vs.23.33%±15.28%,P=0.0067).Live birth numbers were significantly increased following GelMA/ICA treatment(6.90±3.21 vs.1.72±2.05,P=0.0001).Transcriptomic analysis revealed up-regulation of genes associated with cytoskeletal organization(Vil1,Tubb3),lipid storage(Soat2,Plin4),oocyte maturation(Oosp2),and cytokine secretion(Cxcl12).Collectively,these findings suggest that GelMA/ICA hydrogels effectively reverse key hallmarks of ovarian aging and restore reproductive function in aged mice,offering a promising platform for fertility preservation and a novel therapeutic for future investigations into ovarian aging.
文摘Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its significant therapeutic potential in cancer immunotherapy and the substantial attention it has received from academia and industry,the molecular mechanisms of LAG3-mediated immunosuppression remain poorly understood,primarily because of its unique ligand-binding characteristics and intracellular domains[1].
基金support from various sources,including the National Natural Science Foundation of China(Grant Nos.81570774,82070872,92049118,and 82370854)the Junior Thousand Talents Program of China,and the Nanjing Medical University Startup Fund(All awarded to J.L.)support provided by Jiangsu Province's Innovation Personal as well as Innovative and Entrepreneurial Team of Jiangsu Province(Grant No.JSSCTD2021)(All awarded to J.L.).
文摘V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.
基金supported by funding from the National Natural Science Foundation of China(81971349 and 81300456).
文摘In vitro maturation(IvM)of human oocytes offers cost efficiency and minimal invasiveness,serving as a valuable supplementary tool in assisted reproduction for fertility preservation,ovarian hyperstimulation syndrome prevention,and other reproductive strategies.Despite its availability for three decades,the clinical use of IVM remains limited due to efficacy and safety concerns.This study examines the DNA methylation profile of IVM oocytes collected during laparoscopic/hysteroscopic surgeries compared to in vivo matured oocytes via reduced representation bisulfite sequencing.Results indicate IVM oocytes exhibit a higher global methylation level.Differentially methylated regions(DMRs)analysis reveals that the in vitro group displays more hypermethylated and fewer hypomethylated DMRs compared to the in vivo group.Additionally,the in vitro group exhibits a higher level of non-CpG methylation than the in vivo group.However,no significant correlation between methylation levels and transcriptional activity in these oocytes is found,especially for those specific imprinted genes or genes related to embryonic development.These findings shed light on the epigenetic landscape of IvM oocytes,contributing to the ongoing assessment of their clinical feasibility and safety in assisted reproduction.
基金supported by the National Natural Science Foundation of China(grant number:82205172,82274570).
文摘Background:Chronic endometritis(CE)is an important pathological factor contributing to female infertility and recurrent pregnancy loss.Although antibiotics are the primary clinical treatment for CE,they do not effectively improve pregnancy outcomes.Wen Yang Hua Zhuo(WYHZ)is a clinically employed classical formula known for its effects in warming yang,tonifying the spleen and kidneys,and resolving dampness.However,its underlying mechanisms remain unclear.This study aimed to elucidate how WYHZ modulates the immunometabolic microenvironment at the maternal-fetal interface in CE by targeting the MCT/HIF-1α/LDHA pathway to promote embryo implantation.Methods:In vivo,the model of CE was established by intrauterine injection of lipopolysaccharide(LPS)(1 mg/mL)into female C57/BL mice,followed by WYHZ treatment for 3 weeks to evaluate its effects on embryo implantation.Mechanistic studies were further conducted using the MCT-1 inhibitor AZD3965 and adeno-associated virus-mediated HIF-1αknockdown.In vitro,an in vitro CE model consisting of M1 macrophages and Ishikawa,as well as an in vitro embryo implantation model mediated by JAR cells,were constructed using Transwell,and the therapeutic mechanisms of WYHZ was validated using AZD3965 and lentiviral sh HIF-1αintervention.Metabolic enzyme activity assays,protein antibody microarrays,immunofluorescence,Western blotting,Seahorse analysis,and ELISA were employed.Results:WYHZ improved the immune-inflammatory microenvironment at the maternal-fetal interface by reducing pro-inflammatory cytokines and increasing anti-inflammatory factors.In parallel,WYHZ reprogrammed endometrial metabolism by enhancing glycolysis and suppressing mitochondrial oxidative phosphorylation,thereby improving endometrial receptivity and embryo implantation.Mechanistically,WYHZ activated the MCT/HIF-1α/LDHA pathway in endometrial epithelial cells,alleviating inflammatory stress and restoring receptivity.Both AZD3965 intervention and HIF-1αknockdown impaired endometrial receptivity and implantation,effects that were reversed by WYHZ.Conclusion:WYHZ modulates the immunometabolic microenvironment of the endometrium in the context of CE by targeting the activation of the MCT/HIF-1α/LDHA pathway,which improves endometrial receptivity and promotes embryo implantation.
基金funded by China Postdoctoral Science Foundation(Grant Number:2025M773939)NationalNatural Science Foundation of China(Grant Number:82205131)Sichuan Science and Technology Program(Grant Number:2025ZNSFSC1798).
文摘Varicocele(VC)is widely recognized as a prevalent and clinically significant cause of male infertility.However,the comprehensive pathogenic mechanisms underlying VC development and progression remain incompletely understood,creating an important knowledge gap in the field of andrology.This review establishes that VC pathogenesis centers on abnormal vascular remodeling and integrates multiple contributing elements,including anatomical abnormalities,biochemical disturbances,genetic factors,low body mass index(BMI),age,and specific sports habits,while secondary varicoceles are primarily induced by compressive pathologies.Through a systematic synthesis of current evidence and recent advances,this review aims to elucidate the complex pathogenic network of VC and provide valuable insights to guide future research directions and inform the development of targeted clinical applications.
基金supported by the Natural Science Foundation of Anhui Province in China(2508085MF166)Research Fund of Anhui Institute of Translational Medicine(2024zh-03)+2 种基金Key Scientific Research Foundation of Education Department of Anhui Province(2023AH040083)National Natural Science Foundation of China(12404353)Cultivation Project of Training Young and Middle-aged Teachers in Universities of Anhui Province(DTR2023013).
文摘Optical tweezers technology has the characteristics of noncontact manipulation in three dimensions and steerable separation in solutions,and could be applied to obtain a separated sperm with high quality for intracytoplasmic sperm injection(ICSI).However,the effects of optical tweezers on sperm motility are still unclear.To elucidate the effects on sperm motility for optical tweezers,we systematically investigated the correlation between motility parameters and the parameters of optical tweezers(wavelength,power,trapping duration,and trapping orientation).Under three systems of optical tweezers with different laser wavelengths(1064,850,and 785 nm),the nine motility parameters of free swimming were mainly affected by trapping orientation(vertical/horizontal)and trapping duration.When 850 nm laser and 1064 nm laser are used,vertical trapping significantly reduces sperm free-swimming capability with prolonged exposure time,whereas horizontal trapping exhibits relatively minor interference on sperm motility.Notably,the 785 nm laser does not induce statistically significant changes in key parameters of sperm motility under any experimental conditions(trapping orientation and duration).For the rolling frequency of trapped sperm,horizontal trapping for three wavelengths has a negligible effect compared with vertical trapping,especially for the 785 nm laser.In conclusion,horizontal trapping can preserve sperm motility under low power(below 140mW at 1064 nm,below 100mW at 850nm,below 60mW at 785 nm)and short duration(below 4 min).This trapping duration is suffcient for the separation procedure of single live sperm in ICSI.This study provides critical parameter optimization guidelines for the safe application of optical tweezers technology in reproductive medicine.
基金supported by the National Natural Science Foundation of China(Grant No.82373581 to Yuan Lin).
文摘Prenatal maternal psychological distress,particularly depression,has been increasingly recognized as a factor that influences fetal growth;however,its impact on early childhood development remains less well understood.The present study investigated the association between prenatal depression and children's growth trajectories,as well as the odds of overweight and obesity from 1 to 36 months,while also accounting for maternal anxiety and stress.We analyzed data from 4710 mother-child dyads in the Jiangsu Birth Cohort,assessing maternal psychological distress across trimesters and categorizing participants into groups with mild,moderate,and severe depressive symptomatology.Children's weight-for-length z-scores(WLZ)were used to assess overweight/obesity prevalence,and growth patterns were identified through trajectory models.The results from the generalized estimating equations analysis showed that greater depressive symptomatology during pregnancy was associated with a 28%to 41%increase in the odds of childhood overweight/obesity across all three trimesters,compared with mild depressive symptomatology.We identified five distinct WLZ growth trajectory patterns,and found that mothers with greater depressive symptomatology were 39%–47%more likely to have children who followed a very-high-stable growth trajectory,compared with mothers with mild depressive symptomatology.These findings highlight the significant impact of prenatal depression on adverse growth patterns and childhood overweight/obesity,underscoring the need for early intervention.
文摘Mammalian fertilization involves the migration of spermatozoa through the female reproductive system.Early embryonic development is a consequence of several steps and signaling pathways being activated,as well as biochemical and morphological modifications of spermatozoa that enable them to penetrate the membrane of mature oocytes.There are some crucial steps known to clearly explain the process of fertilization,starting with hyperactivation of spermatozoa,mutual recognition,and binding of gametes mediated by receptors located on the surface membranes of both gametes.The final step is followed by oocyte activation,which is primarily triggered via sperm-derived factors,inducing a sharp increase in intracellular calcium levels,eventually leading to polyspermy block.This review integrates current knowledge of the molecular and physiological events governing fertilization,emphasizing how ion regulation and signaling pathways converge to enable sperm function and oocyte activation.Special attention is given to sperm-derived factors such as phospholipase C zeta(PLCζ)and post-acrosomal sheath WW domain-binding protein(PAWP),which play essential roles in triggering calcium release and supporting early embryonic development.
基金supported by the National Natural Science Foundation of China,No.81972073(to HZ)a grant from the Taishan Scholars Program ofShandong Province-Young Taishan Scholars,No.tsqn201909197(to HZ)+1 种基金a grant from Tianjin Key Medical Discipline(Specialty)Construct Project,No.TJYXZDXK-027A(to SF)a grant from Academic Expert International Innovation Summit,No.22JRRCRC00010(to SF).
文摘Ferroptosis,a type of cell death that mainly involves iron metabolism imbalance and lipid peroxidation,is strongly correlated with the phagocytic response caused by bleeding after spinal cord injury.Thus,in this study,bulk RNA sequencing data(GSE47681 and GSE5296)and single-cell RNA sequencing data(GSE162610)were acquired from gene expression databases.We then conducted differential analysis and immune infiltration analysis.Atf3 and Piezo1 were identified as key ferroptosis genes through random forest and least absolute shrinkage and selection operator algorithms.Further analysis of single-cell RNA sequencing data revealed a close relationship between ferroptosis and cell types such as macrophages/microglia and their intrinsic state transition processes.Differences in transcription factor regulation and intercellular communication networks were found in ferroptosis-related cells,confirming the high expression of Atf3 and Piezo1 in these cells.Molecular docking analysis confirmed that the proteins encoded by these genes can bind cycloheximide.In a mouse model of T8 spinal cord injury,low-dose cycloheximide treatment was found to improve neurological function,decrease levels of the pro-inflammatory cytokine inducible nitric oxide synthase,and increase levels of the anti-inflammatory cytokine arginase 1.Correspondingly,the expression of the ferroptosis-related gene Gpx4 increased in macrophages/microglia,while the expression of Acsl4 decreased.Our findings reveal the important role of ferroptosis in the treatment of spinal cord injury,identify the key cell types and genes involved in ferroptosis after spinal cord injury,and validate the efficacy of potential drug therapies,pointing to new directions in the treatment of spinal cord injury.
文摘Prostate cancer(PCa)remains a major cause of cancer-related mortality in men,largely due to therapy resistance and metastatic progression.Increasing evidence highlights the tumor microenvironment(TME),particularly cancer-associated fibroblasts(CAFs),as a critical determinant of disease behavior.CAFs constitute a heterogeneous population originating from fibroblasts,mesenchymal stem cells,endothelial cells,epithelial cells undergoing epithelial-mesenchymal transition(EMT),and adipose tissue.Through dynamic crosstalk with tumor,immune,endothelial,and adipocyte compartments,CAFs orchestrate oncogenic processes including tumor proliferation,invasion,immune evasion,extracellular matrix remodeling,angiogenesis,and metabolic reprogramming.This review comprehensively summarizes the cellular origins,phenotypic and functional heterogeneity,and spatial distribution of CAFs within the prostate TME.We further elucidate the molecular mechanisms by which CAFs regulate PCa progression and therapeutic resistance,and critically evaluate emerging strategies to therapeutically target CAFmediated signaling,metabolic,and immune pathways.By integrating recent advances from single-cell and spatial transcriptomics(ST),our objective is to provide a holistic framework for understanding CAF biology and to highlight potential avenues for stromal reprogramming as an adjunct to current PCa therapies.
