Systems Biology in Reproductive Medicine最新文献

{"title":"SBiRM 2026.","authors":"Stephen A Krawetz","doi":"10.1080/19396368.2025.2605839","DOIUrl":"https://doi.org/10.1080/19396368.2025.2605839","url":null,"abstract":"","PeriodicalId":22184,"journal":{"name":"Systems Biology in Reproductive Medicine","volume":"72 1","pages":"1-2"},"PeriodicalIF":2.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioethics in assisted reproduction and embryology.","authors":"George Anifandis, Helen G Tempest, Dimitrios Ioannou, Peter Sutovsky, Christina Messini, Katerina Chatzimeletiou, Eleni Zagelidou, Georgia Kokkali","doi":"10.1080/19396368.2026.2618252","DOIUrl":"10.1080/19396368.2026.2618252","url":null,"abstract":"<p><p>The use of assisted reproductive therapies, advances in embryo research, and developments in scientific fields such as gene editing and <i>in vitro</i> gametogenesis have attracted the attention of bioethicists for years. On one side, the 14-day rule has faced criticism from embryo researchers advocating for its extension. On the other side, the increasing number of cryopreserved embryos worldwide has raised practical and ethical concerns about their fate. While advancements in scientific research, especially gene editing and in-vitro gametogenesis (IVG), are not yet fully applicable, their potential future use appears to pose significant bioethical questions. In this review, we examine the evolving bioethics of embryo research, focusing on the 14-day rule, the challenges surrounding surplus cryopreserved embryos, and the future dilemmas posed by CRISPR-based gene editing, IVG, and preimplantation genetic testing for polygenic risk (PGT-P). We also highlight the critical role of multidisciplinary, patient-centered counseling in ART practice, to foster informed consent, realistic expectations, and psychosocial well-being. Finally, we underscore the need for anticipatory ethical frameworks and open-society engagement that integrate public deliberation with scientific progress to ensure that reproductive innovation proceeds responsibly, preserving both human dignity and social justice.</p>","PeriodicalId":22184,"journal":{"name":"Systems Biology in Reproductive Medicine","volume":"72 1","pages":"87-100"},"PeriodicalIF":2.0,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant epithelial differentiation may contribute to endometrial polyp formation: insights from single-cell analysis.","authors":"Amruta D S Pathare, Ankita Lawarde, Katrin Täär, Sergio Vela Moreno, Apostol Apostolov, Vijayachitra Modhukur, Darja Tarassova, Alberto Sola-Leyva, Andres Salumets, Merli Saare, Maire Peters","doi":"10.1080/19396368.2026.2628916","DOIUrl":"10.1080/19396368.2026.2628916","url":null,"abstract":"<p><p>Endometrial polyps (EPs) are benign overgrowths of the endometrium causing abnormal uterine bleeding and infertility. Despite their clinical significance, the molecular mechanisms underlying their development and recurrence remain poorly understood, warranting comprehensive transcriptomic investigation. We hypothesized that transcriptomic differences, particularly at the single-cell level as revealed through cellular trajectory analysis, distinguish EPs from adjacent endometrium. To investigate this, paired EP and adjacent endometrium (adEN) samples were collected from 12 women undergoing hysteroscopic polypectomy (proliferative phase, <i>n</i> = 9; secretory phase, <i>n</i> = 3) and analyzed using bulk and single-cell RNA sequencing (scRNA-seq). Bulk RNA-seq revealed high transcriptional similarity between EPs and adENs, with only a few differentially expressed genes (FDR < 0.05) in proliferative-phase EPs, including upregulation of <i>KMT2B</i> and <i>DLEC1</i> and downregulation of <i>COL9A1</i> and <i>RAB3C</i>, potentially reflecting epigenetic regulation and protective mechanisms against tumorigenesis. scRNA-seq identified eight major cell clusters namely stromal, epithelial, endothelial, immune, perivascular, macrophage, B cell, and ciliated populations in both tissues. Pseudotime analysis revealed a mid-transcriptional arrest and enrichment of <i>MECOM/EYA2</i>-positive intermediate epithelial states in EPs, in contrast to the late, mature epithelial stage seen in the adENs. This aberrant epithelial maturation may be associated with impaired perivascular and endothelial differentiation, potentially contributing to defective vascular remodeling and polyp persistence. In conclusion, while EPs exhibit global transcriptomic similarity to adENs, single-cell and pseudotime analyses suggest subtle but significant disruptions in epithelial differentiation and vascular remodeling that might be involved in EPs development. Study limitations include scRNA-seq restricted to the proliferative phase, which may limit generalizability. Nevertheless, future functional studies using primary epithelial organoids derived from EPs may provide a physiologically relevant model to evaluate targeted therapeutic strategies including hormonal interventions with potential applications in infertility management.</p>","PeriodicalId":22184,"journal":{"name":"Systems Biology in Reproductive Medicine","volume":"72 1","pages":"131-148"},"PeriodicalIF":2.0,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146228785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multielement male nutritional supplement (AlphaSperm®) induces novel epigenetic changes in sperm DNA.","authors":"Seth Parks, Ryan Miller, Lily Millar, Berlin Barnett, Timothy Jenkins, Kristin Brogaard, Paul J Turek","doi":"10.1080/19396368.2026.2722986","DOIUrl":"10.1080/19396368.2026.2722986","url":null,"abstract":"<p><p>Male fertility supplements reduce oxidative stress, but whether they improve fertility is controversial. Since sperm epigenetic patterns correlate with fertility potential, we investigated whether a male fertility supplement (AlphaSperm^®) impacts semen parameters or sperm epigenetics. In a prospective, multi-institutional, within-subject study, 3 groups were evaluated: young healthy men < 25 years old (C, <i>n</i> = 11), young infertile men < 40 years old (YI, <i>n</i> = 10), and older infertile men > 40 years old (OI, <i>n</i> = 10). While on daily AlphaSperm^® supplementation, subjects provided serial semen samples. Conventional WHO semen parameters, sperm DNA fragmentation, and sperm DNA methylation were assessed at baseline and after 9 months of treatment. Beta values were generated from methylation array data, and differences in regional sperm DNA methylation with treatment were reported as differentially methylated regions (DMRs) by paired sliding-window analyses. The Stanford GREAT gene ontology tool revealed biological pathways associated with DMRs. SpermQT, a clinical diagnostic, was performed on all subjects. AlphaSperm^® supplementation did not significantly alter semen parameters or sperm DNA fragmentation within groups. Regional sperm DNA hypermethylation was observed in all groups (eFDR < 0.0001), and mean methylation changes at DMRs ranged from 0.1% to 4.3%. Gene ontological analysis revealed 29 biological pathways significantly altered with treatment in the OI group (adjusted <i>p</i> < 0.05), though their functional significance needs validation. Supplement-induced DMRs included 5 genes whose methylation statuses are correlated with male infertility that were hypermethylated in the OI group; 1 was hypermethylated in the C group. Thus, although semen parameters and DNA fragmentation were largely unaltered, male fertility supplementation induced novel regional sperm DNA hypermethylation, most obvious in older infertile men. This study provides novel insights into the potentially large epigenetic effects of nutritional supplements occurring independent of semen analysis changes. Limitations include small sample size and lack of placebo controls.</p>","PeriodicalId":22184,"journal":{"name":"Systems Biology in Reproductive Medicine","volume":"72 1","pages":"299-314"},"PeriodicalIF":2.0,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomic analysis of follicular fluid in women with unexplained infertility.","authors":"Durva Panchal, Aishani Bose, Grishma Desai, Priyanka Vora, Priyanka Parte","doi":"10.1080/19396368.2026.2637454","DOIUrl":"10.1080/19396368.2026.2637454","url":null,"abstract":"<p><p>Unexplained infertility (UI) affects ∼10% of infertile couples, yet standard diagnostic protocols fail to identify a cause. Follicular fluid (FF), which supports oocyte development, contains metabolites that may reflect underlying molecular disturbances. In this exploratory study, we investigated the FF metabolome of women with UI and compared it with controls to explore metabolic alterations associated with UI. FF was collected during oocyte retrieval from 20 women undergoing IVF (ten with UI, ten with male factor infertility), matched for age, BMI, stimulation, and fertilization protocols. Metabolomic profiling was performed using hydrophilic interaction and reversed-phase liquid chromatography coupled to Q-TOF-MS/MS, followed by metabolite identification (XCMS Online and MetaboAnalyst) and KEGG pathway analysis. Approximately 2000 features were detected. Differential metabolites were identified by OPLS-DA (VIP > 2) and validated using univariate metrics such as fold change (|log₂FC| > 1), statistical significance (<i>p</i> < 0.05), and ROC analysis (AUC > 0.8). Twelve metabolites, including diacylglycerols, phosphatidic acids, vitamin D3 derivatives (VitD3-glucosiduronate, 1α-hydroxy-2β-(5-hydroxypentoxy)-VitD3), asparaginyl-asparagine, 3α-hydroxy-6-oxo-5β-cholan-24-oic acid, Leu-Pro-Ala-Ser-Phe, triacylglycerols, phosphatidylcholine, and lactosyl-ceramide were significantly decreased, while Ile-Lys-Val-Val was increased in women with UI. Pathway analysis highlighted disruptions in glycerophospholipid, glycerolipid, steroid, and linoleic acid metabolism. Consistent with the untargeted findings, targeted analysis demonstrated significantly reduced levels of follicular 25-hydroxyvitamin D [25(OH)D] in women with UI despite uniform oral supplementation, indicating dysregulated follicular vitamin D availability. Whilst the study was limited by sample size, the metabolome analysis was performed in triplicate for each sample, thus providing preliminary insights into the metabolic disruptions in FF from women with UI.</p>","PeriodicalId":22184,"journal":{"name":"Systems Biology in Reproductive Medicine","volume":"72 1","pages":"168-184"},"PeriodicalIF":2.0,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Future directions in infertility research: the role of generative AI and large language models.","authors":"Hasan M Jamil","doi":"10.1080/19396368.2026.2627889","DOIUrl":"10.1080/19396368.2026.2627889","url":null,"abstract":"<p><p>Male infertility remains an understudied yet significant contributor to global reproductive health challenges, with up to 50% of infertility cases involving a male factor and a large proportion still classified as idiopathic. Recent advances in generative artificial intelligence (AI), particularly large language models (LLMs), offer a transformative opportunity to tackle persistent gaps in understanding the genetic, epigenetic, and environmental determinants of male infertility. This chapter explores the scientific potential of LLMs and related AI technologies in accelerating discov-eries across the male reproductive research continuum - from interpreting complex genomic data and identifying novel gene - environment interactions to enhancing sperm quality assessment and predicting an unborn child's long-term health risks stemming from paternal factors. Real-world examples and emerging case studies illustrate how generative AI can help fertility researchers learn rapidly, synthesize massive volumes of literature, generate hypotheses, design experiments, and reveal patterns that conventional analyses may miss. The narrative further reflects on the implications of using AI to forecast offspring health <i>via</i> polygenic risk scoring and in silico developmental simulations, highlighting both technical promise and ethical considerations. Written from the perspective of a computational scientist collaborating with fertility experts, this chapter demonstrates how interdisciplinary approaches, amplified by LLMs, can lower barriers between computer science and reproductive biology. By embracing generative AI responsibly - with attention to data quality, interpretability, and social responsibility - male infertility researchers stand poised to unlock novel insights that will benefit not only current patients but also future generations.</p>","PeriodicalId":22184,"journal":{"name":"Systems Biology in Reproductive Medicine","volume":"72 1","pages":"185-210"},"PeriodicalIF":2.0,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147469103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The biology and clinical aspects of female infertility.","authors":"Mitko Madjunkov, Svetlana Madjunkova, Clifford Librach","doi":"10.1080/19396368.2025.2593345","DOIUrl":"10.1080/19396368.2025.2593345","url":null,"abstract":"<p><p>Female infertility is a multifactorial condition with complex biological and clinical underpinnings. Biologically, female-related infertility may stem from disruptions in the hypothalamic-pituitary-ovarian (HPO) axis, impaired folliculogenesis, oocyte maturation defects, uterine abnormalities, endometrial dysfunction, and fallopian tube abnormalities. This review highlights key genetic mechanisms contributing to reproductive dysfunction and their relevance to diagnosis and treatment. Chromosomal abnormalities, including Turner syndrome and X-autosome translocations, also contribute to infertility and recurrent pregnancy loss (RPL). Age-related declines in oocyte quality and quantity-due to increased aneuploidy significantly impact fertility after the mid-30s. Clinical causes such as polycystic ovary syndrome (PCOS), luteal phase defects, and endometriosis contribute to infertility through hormonal imbalance, inflammation, and impaired implantation. Environmental and lifestyle factors-like endocrine-disrupting chemicals, obesity, smoking, and stress-further influence reproductive function. Evaluation requires a multidisciplinary approach combining hormonal profiling, imaging, and genetic diagnostics. Ovarian reserve assessment using anti-Müllerian hormone (AMH) and antral follicle count (AFC), hormonal evaluation along with ultrasound and hysterosalpingography, are central to clinical workups. Next-generation sequencing is enhancing the role of genetic screening in unexplained infertility and specific conditions like POI and endometriosis. Treatment options-ranging from ovulation induction to surgery and assisted reproductive technologies (ART)-are increasingly personalized based on underlying causes and patient profiles. Despite advances, many cases remain idiopathic, highlighting the need for deeper molecular research and refined phenotyping. This review emphasizes the importance of precision medicine and an evidence-based, patient-centered approach to improve fertility outcomes across a broad spectrum of infertility etiologies.</p>","PeriodicalId":22184,"journal":{"name":"Systems Biology in Reproductive Medicine","volume":"72 1","pages":"23-54"},"PeriodicalIF":2.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145960291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global oxidative stress estimation using chemiluminescence for evaluating semen quality in boars with different fertility indices.","authors":"Sunil Kumar, R Islam, Prantik Deka, P J Das, V K Gupta","doi":"10.1080/19396368.2026.2748991","DOIUrl":"https://doi.org/10.1080/19396368.2026.2748991","url":null,"abstract":"<p><p>Oxidative stress (OS) in ejaculates is a key indicator of semen quality. The aim was to estimate global OS using chemiluminescence and malondialdehyde (MDA) based methods in fresh (0h) and extended preserved (48h and 96h) semen of boars with different fertility indices. Based on the boar fertility index (BFI >10, ∼7-8 and <6), boars (n = 6) with three fertility (high, medium and low) levels were used to collect semen (n = 72). Routine semen evaluation tests along with OS estimation by MDA and chemiluminescence methods were done in fresh (0h) and extended semen at 48, 96 h of preservation. In results, routine assessment tests were not significantly (p > 0.05) reliable in determining fertility according to the corresponding BFI. Only low (BFI < 6) fertile boar's extended ejaculates at only 96 h of preservation could be distinguished using MDA-based OS estimation (p < 0.05). There was a significant (p < 0.05) difference between the OS levels measured by chemiluminescence in fresh (5.81 ± 0.16 vs 7.36 ± 0.15 vs 9.05 ± 0.24 RLU/s) and extended ejaculates (48h, 96h) of high (BFI > 10), medium (BFI∼7-8) and low (BFI < 6) fertile group boars. A weak (r = -0.12) to moderately (r = -0.29) negative correlation was observed between routine semen quality assessment and OS estimated by chemiluminescence. However, the initial capital cost of the chemiluminometer was the major limitation apart from the study over larger population and samples. In conclusion, the chemiluminescence method was a more accurate method than MDA to assess global OS level in the semen and can be used to predict the boar fertility grades.</p>","PeriodicalId":22184,"journal":{"name":"Systems Biology in Reproductive Medicine","volume":"72 1","pages":"345-359"},"PeriodicalIF":2.0,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HDAC6 interacting-microtubule associated proteins (HMAPs) identified in human sperm.","authors":"Veena Chawan, Aniket Patankar, Smita Yevate, Rahul Gajbhiye, Sinetra Kushte, Kedar Ganla, Priyanka Parte","doi":"10.1080/19396368.2026.2631565","DOIUrl":"10.1080/19396368.2026.2631565","url":null,"abstract":"<p><p>Sperm flagellar axoneme comprises microtubules (MT) and associated machinery and is an integral determinant of sperm motility. Reports from our lab show reduced levels of acetyl α-tubulin, and HDAC6, along with compromised axoneme polymerization in sperm of asthenozoospermic men. These observations prompted us to identify the sperm repertoire of HDAC6-interacting proteins(HIPs) associated with the MTs. HIPs and Microtubule associated protein (MAP) fractions, respectively, were isolated from sperm of normozoospermic individuals, subjected to tandem mass spectrometry(MS) using a bottom-up approach and proteins in the two groups were identified. 1224 and 315 proteins were identified in the respective groups. Seven clusters of HIPs were among the top 20 significant clusters. Proteins were manually curated from these relevant clusters and overlapped with the MAPs dataset which identified 14 HDAC6 interacting proteins to be associated with MTs (HMAPs). On further analysis with MAP analyzer-LZTFL1, RAB7A, AIFM1 demonstrated low specificity toward MT whereas MYH10 and CFAP53 demonstrated high specificity. Among these HMAPs, EEF1A2, MYH10, ANXA1, TUFM, SOD1, and SRSF7 are known to interact with HDAC6 as documented in the BioGRID database. Interaction of CFAP53 with HDAC6 was validated by double immunofluorescence staining and co-immunoprecipitation in rat sperm. LFQ-DDA analysis of these HMAPs, revealed significantly lower abundance of CFAP53 and TUFM with higher abundance of MYH10 in asthenozoospermic men. Their differential expression in men with poor sperm motility as well as enrichment of acetylation on these HMAPs highlights their association with HDAC6 in maintaining axonemal stability/dynamicity and acetylation-deacetylation to the extent required for sperm motility, although interpretation is limited by the small sample size, restricted availability of human sperm for experimental validation, and reliance on <i>in silico</i> acetylation predictions.</p>","PeriodicalId":22184,"journal":{"name":"Systems Biology in Reproductive Medicine","volume":"72 1","pages":"149-167"},"PeriodicalIF":2.0,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147318285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"cPKCγ facilitates the apoptosis of mouse GC-1 spg cells by regulating the mitophagy via inhibiting the UCHL1/HIF‑1α axis.","authors":"Huajun Yang, You Tian, Shaoguang Feng, Jing Shen, Xianming Yao, Feng Lin","doi":"10.1080/19396368.2026.2700977","DOIUrl":"https://doi.org/10.1080/19396368.2026.2700977","url":null,"abstract":"<p><p>Cryptorchidism, among the most frequent congenital urogenital anomalies in male infants, has a global prevalence ranging from 1% to 9%. Characterized by failure of testicular descent into the scrotum, such a condition exposes the testes to elevated temperature, oxidative stress, and impaired spermatogenesis, significantly increasing risks of infertility and testicular cancer. Although orchiopexy is the standard treatment, long-term spermatogenic defects often persist, highlighting the need to elucidate underlying molecular mechanisms. Although the main mechanistic experiments were performed in GC-1 spg cells through genetic manipulation of cPKCγ, an additional heat-stress experiment was included to simulate the high-temperature condition associated with cryptorchidism. In the present study, the role of conventional protein kinase C gamma (cPKCγ) in regulating mitophagy and apoptosis was investigated using mouse spermatogonial GC-1 cells. Through siRNA-mediated knockdown and adenovirus-induced overexpression, cPKCγ upregulation was demonstrated to significantly induce cellular apoptosis and disrupt mitochondrial function, indicated by elevated malondialdehyde (MDA) levels, reduced superoxide dismutase (SOD) activity, decreased ATP production, increased 8-hydroxy-2'-deoxyguanosine (8-OHdG) accumulation, increased mitochondrial reactive oxygen species (ROS), and loss of mitochondrial membrane potential. Mechanistically, cPKCγ was found to inhibit the UCHL1/HIF-1α signaling pathway, suppressing mitophagy, as evidenced by a reduced LC3-II/LC3-I ratio and decreased PINK1 and Parkin expression. Importantly, adverse effects induced by cPKCγ overexpression were substantially rescued through UCHL1 or HIF-1α overexpression, or rapamycin treatment. Conversely, knockdown of UCHL1 or HIF-1α partially counteracted the protective effects of cPKCγ silencing on cell viability, oxidative stress, and mitophagy activation. Furthermore, heat stress upregulated endogenous cPKCγ and suppressed UCHL1/HIF-1α signaling and mitophagy-related proteins in GC-1 spg cells. Collectively, cPKCγ exacerbates spermatogonial apoptosis by repressing UCHL1/HIF-1α-dependent mitophagy, suggesting a potential molecular mechanism for spermatogonial vulnerability under cryptorchidism-related heat stress.</p>","PeriodicalId":22184,"journal":{"name":"Systems Biology in Reproductive Medicine","volume":"72 1","pages":"282-298"},"PeriodicalIF":2.0,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148472851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}