bims-simsho 2025-09-14 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–09–14
23 papers selected by
Chun-Chi Chang, Lunds universitet

Can Sex-based Variations in the Immune Responses to AAV Gene Therapy Affect Safety and Efficacy? A Review of Current Understanding.
Meta-analysis examining fetal sex-specific placental DNA methylation intensities and estimated cell composition post in vitro fertilization.
Impact of sex hormones on postoperative outcomes in plastic surgery: a narrative review.
Estrogen Modulation of B Cell Immunity: Implications for HIV Control and Therapeutic Strategies.
Regulatory Mechanism and Drug Therapy of NLRP3 Inflammasome in Recurrent Pregnancy Loss: Research Status and Prospect.
Deciphering cross-cohort metabolic signatures of immune responses and their implications for disease pathogenesis.
Drug targets in prostate cancer: an appetite for KLK2-mediated destruction.
Molecular Insights into Elevated Autoantibodies in Polycystic Ovary Syndrome: Mechanisms and Clinical Implications.
Sex hormones and 14 autoimmune diseases: The causal relationship from a bidirectional 2-sample Mendelian randomization study.
Metabolites as regulators of autoimmune diseases.
Acute myeloid leukaemia cells express high levels of androgen receptor but do not depend on androgen signaling for survival.
Effect of Estrogen on Sirt1 Signaling in Human Macrophages.
Biological Sex and Cardiovascular Disease Prevention in Systemic Arterial Hypertension.
Progress of estrogen receptor and spliceosome in endometrial carcinoma.
A Pilot Study of the Role of Salivary Biomarkers in the Diagnosis of PCOS in Adolescents Across Different Body Weight Categories.
Investigation of the Endometrial Microbiome in Recurrent Pregnancy Loss Individuals: Microbial Imbalance and Network Fragility.
Mechanisms of c-Fos regulation of mTOR signaling via ERα/β in abnormal lipid metabolism of granulosa cells in PCOS.
Disrupting the interaction between androgen receptor and its coregulator WDR77 delays the growth of treatment-resistant prostate cancer.
Genital microbiota in infertile couples.
Targeting IL-6 receptor mediated metabolic pathways to control Th17 cell differentiation and inflammatory responses.
Sex-specific alterations in placental mitochondria, oxidative damage and apoptosis in mice of advanced maternal age.
Evaluating endometrial response to human chorionic gonadotropin: alterations in epigenetic regulation and extracellular vesicle cargo of endometrial stromal cells.
Metabolism-driven posttranslational modifications and immune regulation: Emerging targets for immunotherapy.

AAPS J. 2025 Sep 10. 27(6): 141

Can Sex-based Variations in the Immune Responses to AAV Gene Therapy Affect Safety and Efficacy? A Review of Current Understanding.

Leila Abdelhamid, Ronit Mazor.

  As the field of gene therapy advances and as the importance of sex as a biological variable in shaping viral immune responses is recognized, the impact of sex on adeno-associated virus (AAV) vectors mediated gene therapies remain largely unexplored. Here we review current understanding of the immune response against AAV gene therapy as well as the knowledge of sex differences observed in viral responses. We discuss sex differences in innate immune mechanisms such as Toll-like receptor recognition and complement activation, as well as the functional responses of key immune cells such as dendritic cells, macrophages, and T/B cells that are involved in AAV immunogenicity. Variations in pre-existing immunity, including differences in antibody levels and neutralizing activity among sexes, are also described. Additionally, we investigate evidence in the literature of sex differences in AAV transduction in animal and suggest a potential link between the immune responses and higher transductions in males.

Keywords:  AAV Immunogenicity; Adaptive immune response; Innate immune sensing; Pre-existing anti-AAV antibodies; Sex differences

DOI:  https://doi.org/10.1208/s12248-025-01127-5
Mol Hum Reprod. 2025 Sep 09. pii: gaaf046. [Epub ahead of print]

Meta-analysis examining fetal sex-specific placental DNA methylation intensities and estimated cell composition post in vitro fertilization.

Melanie Lemaire, Wei Q Deng, Keaton W Smith, Samantha L Wilson.

  Infertility impacts up to 17.5% of reproductive-aged couples worldwide. To aid in conception, many couples turn to assisted reproductive technology, such as IVF. IVF can introduce both physical and environmental stressors that may alter DNA methylation regulation, an important and dynamic process during early fetal development. This meta-analysis aims to assess the differences in the placental DNA methylome between spontaneous and IVF pregnancies. Potential datasets were identified by searching NCBI Gene Expression Omnibus (GEO) using keywords related to in vitro fertilization in human participant studies published before November 2023. In our combined fetal sex population (N = 575) from three eligible GEO datasets, 127 autosomal CpGs were significant (False Discovery Rate (FDR)<0.05) between IVF (n = 96) and spontaneous (n = 479) placentae, with 47 CpGs considered differentially methylated (FDR < 0.05 and |Δβ|>0.05). Stratification by fetal sex revealed no significant autosomal CpGs in fetal female placentae (N = 281), however in the fetal male placentae (N = 294), we identified nine autosomal CpGs that reached statistical significance between IVF (n = 56) and spontaneous (n = 238) placentae, with three CpGs considered differentially methylated. Fetal male placentae had lower proportions of trophoblasts (p < 0.0001) and stromal cells (p = 0.007) and higher proportions of syncytiotrophoblasts (p = 0.0001), compared to fetal female placentae regardless of conception type. IVF placentae had higher proportions of stromal cells (p = 0.01) and lower proportions of syncytiotrophoblasts (p = 0.01) compared to spontaneous placentae regardless of sex. Controlling for cell type proportions in linear models reduced test statistic inflation and identified new significant CpGs that may previously have been masked by cell type heterogeneity. The results of this meta-analysis are critical to further understand the impact of IVF on tissue epigenetics which may help with understanding the connections between IVF and negative pregnancy outcomes. Additionally, our study suggests that sex specific differences in placental DNA methylation and cell composition should be considered as factors for future placental DNA methylation analyses.

Keywords:  ART; DNA methylation; IVF; cell composition; placenta; sex differences

DOI:  https://doi.org/10.1093/molehr/gaaf046
Front Surg. 2025 ;12 1587708

Impact of sex hormones on postoperative outcomes in plastic surgery: a narrative review.

Xiong Lv, Chun Xiang, Yan Zheng, Xuling Lv, Wanxuan Zhou, Jiajun Zhu.

   Background: Since 1929, when scientists first identified estrogen in urine and coined the term "sex hormones," these vital steroid hormones have been recognized for their critical role in tissue repair and wound healing. This is particularly evident in the postoperative recovery of plastic surgery patients. While the effects of sex hormones differ between males and females, their mechanisms in wound healing, angiogenesis, and collagen regulation have drawn significant attention.
Methods: This narrative review synthesizes key literature from four databases including PubMed (up to 2024) focusing on the effects of sex hormones on healing after plastic surgery.Key terms such as "sex hormones," "tissue repair," and "postoperative recovery" were used. The analysis highlights the differential roles of estrogen and testosterone in skin healing, angiogenesis, and inflammatory responses. Additionally, it explores the effects of sex, age, and hormone replacement therapy (HRT) in transgender patients on surgical outcomes.The main target audience of this article is professional surgeons and endocrinologists, medical students and scientific researchers.
Results: Existing evidence suggests that estrogen enhances wound healing by upregulating vascular endothelial growth factor (VEGF), stimulating angiogenesis, and playing a pivotal role in collagen regulation. Testosterone may influence fibroblast proliferation and angiogenesis, although its effects vary by sex and age. Postmenopausal women exhibit diminished healing capacity due to decreased estrogen levels, whereas transgender patients undergoing HRT show improved postoperative recovery.
Conclusion: Sex hormones significantly influence postoperative recovery in plastic surgery. The distinct mechanisms of estrogen and testosterone in wound healing provide valuable insights for personalized medical approaches, optimizing surgical outcomes across diverse patient populations.

Keywords:  estrogen; plastic surgery; skin healing; testosterone; transgender patients

DOI:  https://doi.org/10.3389/fsurg.2025.1587708
Compr Physiol. 2025 Oct;15(5): e70050

Estrogen Modulation of B Cell Immunity: Implications for HIV Control and Therapeutic Strategies.

John Kasibante, Todd T Brown, Jordan E Lake, Mohamed Abdel-Mohsen.

  Biological sex profoundly impacts HIV acquisition, disease progression, and persistence. Beyond genetic differences, sex hormones such as estrogen play multifaceted roles in shaping immune responses to HIV. However, the precise effects of estrogen and other sex hormones on the various components of the immune system, and their implications for HIV progression and persistence, remain poorly understood. Addressing these gaps is essential for developing strategies to improve the management of chronic HIV, especially in post-menopausal cisgender women and transgender women. B cells are crucial for HIV control, primarily through the production of anti-HIV antibodies. Emerging evidence suggests that estrogen exerts significant, yet underappreciated, effects on B cell function. However, the interactions between estrogen and B cells during HIV remain poorly characterized. This review explores current insights into the estrogen-B cell axis, emphasizing its role in modulating immune responses critical to HIV. Specifically, it examines estrogen's effects on B cell activation, antibody production, and antibody functionality, all of which can influence HIV control and disease progression. We also highlight key research gaps, including the impact of differential estrogen levels on immune-mediated HIV control and the potential of estrogen modulators to enhance B cell-driven immunity during HIV.

Keywords:  B cells; HIV; antibody; antibody‐producing cells; estrogen; glycosylation; sex hormones

DOI:  https://doi.org/10.1002/cph4.70050
J Inflamm Res. 2025 ;18 12279-12294

Regulatory Mechanism and Drug Therapy of NLRP3 Inflammasome in Recurrent Pregnancy Loss: Research Status and Prospect.

Yonghan Cui, Yuqi Yang, Yuru Li, Yuwei Zhang, Dingren Niu, Xiaoling Feng.

  Recurrent pregnancy loss (RPL) is a distressing reproductive system disease with complex underlying causes and difficult treatment, making it a common fertility challenge for women of childbearing age. In recent years, the role of inflammasomes in RPL has gradually been recognized. NOD-like receptor family pyrin domain-containing 3 (NLRP3) is a key component of the innate immune system and a central regulator of inflammatory signaling. Accumulating evidence links NLRP3 inflammasome activation to female reproduction. During pregnancy, the assembly and activation of the NLRP3 inflammasome generate pro-inflammatory cytokines and pyroptosis-associated factors that engage in extensive cross-talk with other inflammatory pathways, thereby contributing to RPL through diverse mechanisms, including inflammatory cascades, endometrial receptivity, immune cell differentiation and polarization, pyroptotic cell death, autophagy, and intestinal barrier permeability. A detailed understanding of these intricate interactions may unveil novel therapeutic targets and strategies to mitigate the physiological and psychological burden of RPL on affected couples. However, currently there are still limited RPL therapeutic drugs targeting NLRP3. Developing drugs that precisely target and regulate NLRP3 is expected to promote the development of RPL therapy research. This comprehensive review investigates the complex relationship between NLRP3 inflammasome and RPL, highlighting the central role of inflammation in disease progression. It also summarizes potential drugs targeting NLRP3 inflammasome for the treatment of RPL, providing theoretical basis for potential clinical therapeutic targets.

Keywords:  autophagy; endometrial receptivity; immunity; inflammation; intestinal barrier; pyroptosis

DOI:  https://doi.org/10.2147/JIR.S549048
Mol Syst Biol. 2025 Sep 10.

Deciphering cross-cohort metabolic signatures of immune responses and their implications for disease pathogenesis.

Jianbo Fu, Nienke van Unen, Andrei Sarlea, Nhan Nguyen, Martin Jaeger, Javier Botey Bataller, Valerie A C M Koeken, L Charlotte de Bree, Vera P Mourits, Simone J C F M Moorlag, Godfrey Temba, Vesla I Kullaya, Quirijn de Mast, Leo A B Joosten, Cheng-Jian Xu, Mihai G Netea, Yang Li.

  The complex interplay between circulating metabolites and immune responses, which is pivotal to disease pathophysiology, remains poorly understood and understudied in systematic research. Here, we performed a comprehensive analysis of the immune response and circulating metabolome in two Western European cohorts (534 and 324 healthy individuals) and one from sub-Saharan Africa (323 healthy donors). At the metabolic level, our analysis revealed sex-specific differences in the correlation between phosphatidylcholine and cytokine responses following ex vivo stimulation. Notably, sphingomyelin exhibited a significant negative correlation with monocyte-derived cytokine production in response to Staphylococcus aureus stimulation, a finding that was validated through functional experiments. Subsequently, using Mendelian randomization analysis, we established a link between sphingomyelin and COVID-19 severity, providing compelling evidence for its modulatory role in immune responses during human infection. Collectively, our results represent a unique resource ( https://lab-li.ciim-hannover.de/apps/imetabomap/ ) for exploring metabolic signatures associated with immune function in different populations, highlighting sphingomyelin metabolism as a potential target in treating inflammatory and infectious diseases.

Keywords:  Immune Response; Mendelian Randomization; Metabolomics; Multi-cohort; Multi-omics

DOI:  https://doi.org/10.1038/s44320-025-00146-w
Clin Cancer Res. 2025 Sep 09.

Drug targets in prostate cancer: an appetite for KLK2-mediated destruction.

Steven Blinka, Evan Y Yu.

Human Kallikrein 2 (KLK2) is a prostate cancer tissue specific protein that is regulated by androgen receptor (AR) signaling. KLK2 was not previously recognized as a therapeutic target as it is secreted. It has now been demonstrated that KLK2 is expressed on the cell surface and targetable by various methodologies.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-2546
Int J Mol Sci. 2025 Aug 23. pii: 8192. [Epub ahead of print]26(17):

Molecular Insights into Elevated Autoantibodies in Polycystic Ovary Syndrome: Mechanisms and Clinical Implications.

Jakub Kwiatkowski, Nicole Akpang, Zofia Ziemkiewicz, Lucja Zaborowska, Artur Ludwin.

  Polycystic ovary syndrome (PCOS) is a prevalent endocrinological condition among women of reproductive age, characterized by several well-known symptoms, including hyperandrogenism, anovulation, irregular menstrual cycles, and insulin resistance. In addition, women suffering from PCOS are also at an increased risk of developing several autoimmune diseases, including thyroid disorders, type 1 diabetes, and rheumatoid arthritis. Furthermore, an elevated prevalence of diverse autoantibodies is observed in women diagnosed with PCOS. These include antibodies specific to autoimmune diseases, e.g., anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (anti-TG), and antinuclear antibodies (ANAs), as well as those that are non-specific, such as anti-malondialdehyde-modified human serum albumin (anti-HSA-MDA) or anti-α-crystallin. It appears that several mechanisms may be responsible for this phenomenon. PCOS has been observed to co-occur with autoimmune diseases, potentially attributable to shared genetic susceptibility or the presence of hormonal disorders resulting from autoimmune diseases. Moreover, PCOS is a chronic low-grade inflammatory disease that may contribute to immune dysfunction and subsequent overproduction of autoantibodies. A further intriguing aspect may be the yet-unknown role of autoantibodies in the pathogenesis of PCOS, considering PCOS as a disease with an autoimmune etiology.

Keywords:  PCOS; autoantibodies; autoimmune diseases; autoimmunity; inflammation; polycystic ovary syndrome

DOI:  https://doi.org/10.3390/ijms26178192
Medicine (Baltimore). 2025 Sep 05. 104(36): e44160

Sex hormones and 14 autoimmune diseases: The causal relationship from a bidirectional 2-sample Mendelian randomization study.

Renzhe Tang, Xiaoqing You, Botao Yuan, Ziqiang Ling, Yu Li.

  Numerous observational studies have suggested links between sex hormones and various autoimmune diseases (ADs). However, the causality of these associations remains uncertain. This study employs Mendelian randomization (MR) analysis to investigate the causal relationship between sex hormones and ADs risk. We conducted bidirectional MR using publicly available genome-wide association study summary statistics to explore the association between 4 sex hormones (total testosterone, bioavailable testosterone, estradiol, dehydroepiandrosterone sulfate), and sex-hormone-binding globulin with the risk of 14 common ADs. Causality was evaluated using the inverse variance weighted, MR Egger, weighted median, and Wald ratio methods. Sensitivity analyses included Cochran Q test, the MR Egger intercept test, and the leave-one-out approach. Higher genetically predicted levels of total testosterone were associated with a decreased risk of ankylosing spondylitis, type 1 diabetes, and primary biliary cholangitis. Higher levels of bioavailable testosterone were associated with a decreased risk of primary biliary cirrhosis and Sicca syndrome. Higher levels of estradiol were associated with increased risks of celiac disease. Higher levels of dehydroepiandrosterone sulfate were associated with increased risks of vitiligo. Higher levels of sex-hormone-binding globulin were associated with increased risks of rheumatoid arthritis and multiple sclerosis, but were associated with a decreased risk of type 1 diabetes. In the reverse MR analyses, 9 ADs showed causal relationships with sex hormones. The consistency of results across various methods and their validation through further sensitivity analyses confirm the robustness of the findings. This study demonstrates a causal association between sex hormones and the risk of a variety of ADs. These findings offer significant insights into the pathogenesis of ADs and suggest new avenues for future research and therapeutic strategies. Specifically, they highlight the potential of modulating sex hormone levels in the prevention and treatment of these disorders.

Keywords:  Mendelian randomization; SNPs; autoimmune diseases; causality; sex hormones

DOI:  https://doi.org/10.1097/MD.0000000000044160
Front Immunol. 2025 ;16 1637436

Metabolites as regulators of autoimmune diseases.

Maria Tada, Michihito Kono.

  Immune cell metabolism is essential for regulating immune responses, including activation, differentiation, and function. Through glycolysis and oxidative phosphorylation (OXPHOS), metabolism supplies energy and key intermediates for cell growth and proliferation. Importantly, some metabolites generated during these processes act as signaling molecules that influence immune activity. Autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) involve multiple immune cell types, and recent research in immunometabolism has revealed that disrupted metabolic pathways in these cells contribute to disease progression. Effector T cells, for instance, undergo metabolic reprogramming, particularly increased glycolysis, to meet the demands of proliferation and function during autoimmune responses. Targeting metabolic enzymes has shown therapeutic potential. In addition, metabolites themselves, termed immunometabolites, can directly modulate immune responses. These include both intracellularly generated and secreted molecules. Itaconate is a key immunometabolite and is derived from the TCA cycle by aconitate decarboxylase 1 (ACOD1) in activated macrophages. It inhibits the NLRP3 inflammasome and pro-inflammatory cytokines, such as IL-1β and IL-6. Beyond macrophages, itaconate alters metabolism and epigenetics in T cells by reducing 2-hydroxyglutarate and the S-adenosyl-L-methionine (SAM)/S-adenosyl-L-homocysteine (SAH) ratio, thereby suppressing Th17 differentiation and enhancing Foxp3 expression in Tregs. Itaconate ameliorates disease in experimental autoimmune encephalomyelitis, RA, SLE, and others. It also exhibits antimicrobial effects by blocking bacterial isocitrate lyase and viral replication. Despite increasing interest, reviews focusing specifically on immunometabolites remain limited. This review highlights emerging insights into metabolites involved in glycolysis, the TCA cycle, glutaminolysis, one-carbon metabolism, and lipid metabolism that influence autoimmune pathophysiology.

Keywords:  cellular metabolism; glutaminolysis; glycolysis; itaconate; metabolite

DOI:  https://doi.org/10.3389/fimmu.2025.1637436
Leukemia. 2025 Sep 11.

Acute myeloid leukaemia cells express high levels of androgen receptor but do not depend on androgen signaling for survival.

Farideh Miraki-Moud, Linda Ariza-McNaughton, Thinzar KoKo, Jad Othman, Randal Stronge, Johann de Bono, Nigel Russell, Ian Thomas, Amanda Gilkes, Alan Burnett, Leandro Rodrigues Santiago, Fay Cafferty, Leo Taussig, Allan Thornhill, Simon O'Connor, Dominique Bonnet, David C Taussig.

Male sex is associated with worse outcome in acute myeloid leukemia (AML) in many studies. We analyzed the survival of 4281 patients treated with intensive chemotherapy in the AML17 and AML19 trials based on sex. Men had a significantly lower remission rate than women. Men had a higher incidence of adverse cytogenetic features and a lower incidence of the relatively favorable NPM1 mutation. However, male sex was an independent risk factor for survival in multi-variate analysis. We hypothesized that androgen signaling in men could worsen outcomes by protecting AML cells from chemotherapy. We demonstrated high levels of androgen receptor (AR) expression in AML across cytogenetic risk groups. We showed the AR expression was induced by IL-6 signaling in vitro and correlates with poor overall survival. Androgens had no effect on survival of primary AML cells in vitro, nor did they impact gene expression. Androgens did not protect AML cells against chemotherapy either in vitro or in vivo. Similar results were observed with estrogen signaling through estrogen receptor in vitro in AML cells. In conclusion, targeting the androgen pathway may not be a promising clinical strategy and sex hormone signaling in AML cells does not explain the poorer outcomes of men.

DOI: https://doi.org/10.1038/s41375-025-02752-x
Int J Mol Sci. 2025 Sep 05. pii: 8670. [Epub ahead of print]26(17):

Effect of Estrogen on Sirt1 Signaling in Human Macrophages.

Maria Luisa Barcena, Anne Breiter, Julia Temp, Yury Ladilov, Vera Regitz-Zagrosek.

  Cardiovascular diseases are the leading cause of human death worldwide. The role of the female hormone estrogen (E2) in this context is subject of debate. E2 might counteract inflammation by acting on macrophages; however, the underlying cellular mechanisms remain poorly understood. In the current study, we used primary human macrophages to investigate the effects of E2 on the NAD+-dependent deacetylase Sirt1, protein acetylation, and pro-inflammatory phenotype. Male and female primary monocytes from healthy adult individuals were polarized into pro-inflammatory M1 macrophages via treatment with LPS and IFN-γ followed by treatment with E2 for 24 h. While E2 treatment had no effect on the Sirt1 protein expression, it significantly increased the acetylation state of nuclear proteins p53 and Ku70. In addition, E2 increased NFκB-p65 expression exclusively in male M1 macrophages, while TNF-α was reduced in female M1 macrophages following E2 treatment. In male monocyte-like cells, E2 significantly reduced nuclear Sirt1 expression and increased Ku70 acetylation. The current study demonstrated that E2 treatment of human M1 macrophages leads to downregulation of nuclear Sirt1 and hyperacetylation of corresponding nuclear proteins. These molecular changes are associated with an enhancement of the pro-inflammatory phenotype in male primary macrophages, while an attenuation of inflammation was observed in female cells.

Keywords:  Sirt1; acetylation; macrophage-like cells; nucleus isolation; sex differences

DOI:  https://doi.org/10.3390/ijms26178670
Arterioscler Thromb Vasc Biol. 2025 Sep 11.

Biological Sex and Cardiovascular Disease Prevention in Systemic Arterial Hypertension.

Eva Gerdts, Susana Novella, Yvan Devaux, Paolo Magni, Hans Peter Marti, Miron Sopić, Georgios Kararigas.

  Biological sex influences the life course development of blood pressure, systemic arterial hypertension, and hypertension-associated complications through neural, hormonal, renal, and epigenetic mechanisms. Sex hormones influence blood pressure regulation through interaction with several main regulatory systems, including the autonomic nervous system, the renin-angiotensin-aldosterone system, endothelin, and renal mechanisms. The modulation of vascular function by sex hormones varies over the lifespan. A more progressive decline in vascular endothelial function and an increase in vascular remodeling and arterial stiffness with aging are found in female individuals. Epigenetic mechanisms, including DNA methylation, histone modifications, and noncoding microRNAs, may be implicated in systemic arterial hypertension development and complications. Overall, current knowledge highlights the importance of including biological sex as a critical factor in understanding systemic arterial hypertension pathophysiology and advancing cardiovascular prevention.

Keywords:  blood pressure; cardiovascular diseases; epigenomics; gonadal steroid hormones; sex

DOI:  https://doi.org/10.1161/ATVBAHA.125.322092
Front Endocrinol (Lausanne). 2025 ;16 1586191

Progress of estrogen receptor and spliceosome in endometrial carcinoma.

Ziqi Hong, Ting Mo, Peiquan Zhou, Jian Chen, Xin Li.

  Endometrial cancer (EC) is one of the most common gynecological cancers in developed countries. Like EC, most female reproductive tract malignancies are thought to be hormonally driven, with estrogen signaling acting as an oncogenic signal. The actions of estrogen are mediated through the classical nuclear estrogen receptors α (ER-α) and β (ER-β) as well as transmembrane G protein-coupled estrogen receptors (GPR30 and GPER). Ligand-bound estrogen receptor (ER) and GPER trigger multiple downstream signaling pathways that regulate the cell cycle, differentiation, migration, and apoptosis in various tissues, including the endometrium. Additionally, growing evidence suggests that selective splicing events at the receptor result in multiple ERα proteins with different molecular weights and functional structural domains. Examples include ER-α66, ER-α46, and ER-α36. In addition, various post-translational modifications (PTMs) further affect ER-α cellular localization and ligand affinity, resulting in a change in the cellular function. These splice isoforms and PTMs are differentially expressed in a tissue-specific manner. They mediate some aspects of ER-α signaling and may even antagonize full-length ER-α. Therefore, both ER-α and its splice isoforms may play a role in the development of EC. In this review, we examine the influential roles of ER-α and ER-β, as well as the GPER estrogen signaling pathway, in EC. Our goal is to provide theoretical support for further research on the molecular mechanisms between ER and EC and to generate new ideas for the early diagnosis of EC and the development of new drugs.

Keywords:  endometrial cancer; estrogen; estrogen receptor; isoform; molecular mechanism

DOI:  https://doi.org/10.3389/fendo.2025.1586191
J Clin Med. 2025 Aug 31. pii: 6159. [Epub ahead of print]14(17):

A Pilot Study of the Role of Salivary Biomarkers in the Diagnosis of PCOS in Adolescents Across Different Body Weight Categories.

Justyna Opydo-Szymaczek, Natalia Wendland, Dorota Formanowicz, Anna Blacha, Grażyna Jarząbek-Bielecka, Paulina Radomyska, Dominika Kruszyńska, Małgorzata Mizgier.

  Background/Objectives: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting reproductive, metabolic, and inflammatory processes in women of reproductive age. This study explored the diagnostic potential of salivary cytokines, uric acid, and testosterone in distinguishing PCOS patients from healthy controls, as well as to examine their associations with hormonal and metabolic profiles within the PCOS group. Methods: Forty-one adolescent girls with PCOS and thirty healthy controls participated in the study. The PCOS group included both normal-weight and overweight individuals, allowing evaluation of salivary biomarkers across different nutritional statuses. Salivary levels of TNF-α, IL-6, IL-1β, testosterone, and uric acid were measured and compared between the groups. A receiver operating characteristic (ROC) analysis was performed to assess the diagnostic value of each biomarker. Results: Salivary TNF-α, IL-6, and IL-1β showed high diagnostic accuracy (AUC = 0.921, 0.891, and 0.870, respectively), supporting their potential as non-invasive biomarkers. The diagnostic accuracy of salivary cytokines and testosterone remained high even in normal-weight participants, suggesting that low-grade inflammation and hormonal disturbances in PCOS are not limited to excess body weight. Salivary testosterone was strongly associated with hyperandrogenism, while uric acid correlated with the cortisol/DHEA-S ratio, indicating possible links to metabolic stress. Conclusions: In conclusion, salivary assays may offer a valuable, non-invasive tool for the early diagnosis of PCOS in adolescents, including normal-weight girls. This approach could facilitate the timely detection of inflammatory and hormonal imbalances, supporting earlier interventions and more personalized care.

Keywords:  IL-1β; IL-6; TNF-α; adolescents; hyperandrogenism; polycystic ovary syndrome; salivary assays; testosterone; uric acid

DOI:  https://doi.org/10.3390/jcm14176159
Int J Womens Health. 2025 ;17 2853-2868

Investigation of the Endometrial Microbiome in Recurrent Pregnancy Loss Individuals: Microbial Imbalance and Network Fragility.

Bolun Zhang, Shaochong Lin, Sidong Wang, Weiyu Chen, Yushu Chen, Dandan Cao, Qingzhi Liu, Yuanqing Yao.

   Purpose: Emerging evidence suggests that an abnormal endometrial microbiota may be a potential factor contributing to recurrent pregnancy loss (RPL). This study aimed to characterize the endometrial microbiota in patients with RPL and to explore its association with miscarriage.
Patients and Methods: Based on specific inclusion and exclusion criteria, EndoMetrial Microbiome Assay (EMMA) data from women attending clinics were collected and categorized into RPL and control groups according to their miscarriage history. Species diversity analysis, differential microbiota analysis, and machine learning methods were employed to identify key microbial genera associated with RPL. Microbial network analysis was then performed to further characterize the endometrial microbiome in patients with RPL.
Results: No significant differences in α-diversity were observed between the RPL and control groups across multiple indices (all P > 0.05); however, β-diversity differed significantly (Euclidean distance, P = 0.039). Regarding species composition, the control group showed a significantly higher abundance of Lactobacillus, whereas the RPL group had increased levels of pathogenic bacteria, including Gardnerella, Staphylococcus, and Streptococcus. Machine learning identified three key genera associated with RPL: Streptococcus, Chryseobacterium, and Fusobacterium. Microbial network analysis further revealed the fragility of the endometrial microbial community in patients with RPL.
Conclusion: These findings offer novel insights into the mechanisms of endometrial microenvironmental changes in patients with RPL and highlight potential microbial biomarkers and therapeutic targets for future clinical applications.

Keywords:  endometrial microbiota; machine learning; microbial biomarkers; recurrent pregnancy loss

DOI:  https://doi.org/10.2147/IJWH.S534065
Front Endocrinol (Lausanne). 2025 ;16 1587595

Mechanisms of c-Fos regulation of mTOR signaling via ERα/β in abnormal lipid metabolism of granulosa cells in PCOS.

Xinyi Chen, Xiaoxue Shen, Shanyue Guan, Yan Liu, Ning Song, Wenyan Song, Haixia Jin.

   Objective: This study investigates the role of the c-Fos/estrogen receptors (ERs)/mTOR pathway in lipid metabolism in human follicular granulosa cells of individuals with polycystic ovary syndrome (PCOS). Specifically, we aim to determine whether c-Fos targets estrogen receptors (ERα and ERβ) to mediate the mTOR pathway, influencing lipid metabolism, and to identify the key molecular mechanisms involved.
Methods: A PCOS mouse model was established using dehydroepiandrosterone (DHEA), and ovarian tissues were collected from both PCOS and control mice. RT-qPCR and Western blotting were used to measure the expression levels of c-Fos, ERα, ERβ, and mTOR. Follicular fluids were obtained from patients with PCOS and male factor infertility on the day of ovulation. Adenovirus-mediated upregulation of c-Fos was performed in human follicular granulosa cells from male infertility patients, followed by analysis of mRNA and protein levels of c-Fos, ERα, ERβ, and mTOR. Additionally, granulosa cells' triglyceride (TG) and total cholesterol (TC) levels were assessed. Granulosa cells were cocultured with various concentrations of 17β-estradiol to investigate the effects of estrogen on the pathway.
Results: In ovarian tissues of PCOS mice, mRNA and protein levels of c-Fos were significantly elevated compared to controls, while ERα and ERβ expression was notably reduced. No significant changes were observed in the p-mTOR/mTOR protein ratio. In PCOS patients, c-Fos and p-mTOR/mTOR protein levels were higher than in male factor infertility patients, while ERα levels were lower, with no significant difference in ERβ expression between the two groups. Upregulation of c-Fos in human granulosa cells led to a significant reduction in ERα and ERβ levels, while p-mTOR/mTOR protein levels increased. TG content was elevated in the c-Fos-upregulated group compared to controls, but no significant changes were observed in TC levels. Co-culture of granulosa cells with increasing concentrations of 17β-estradiol resulted in significantly higher ERα and ERβ expression, decreased p-mTOR/mTOR levels, and a reduction in TG content, while TC levels remained unchanged.
Conclusions: These findings suggest that c-Fos may target ERα and ERβ to mediate the mTOR signaling pathway, thereby influencing lipid metabolism in granulosa cells. This novel mechanism provides insights into potential therapeutic strategies for managing PCOS-related metabolic dysfunction.

Keywords:  c-Fos; estrogen receptor; lipid metabolism; mTOR; polycystic ovary syndrome; triglycerides

DOI:  https://doi.org/10.3389/fendo.2025.1587595
Cell Rep. 2025 Sep 09. pii: S2211-1247(25)01006-X. [Epub ahead of print]44(9): 116235

Disrupting the interaction between androgen receptor and its coregulator WDR77 delays the growth of treatment-resistant prostate cancer.

Ujjwal R Dahiya, Sangeeta Kumari, Nidhi Singh, Chitra Rawat, Eduardo Cortes, Yara Ghanem, Eva Corey, Scott M Dehm, Belinda Willard, Mohammed Alshalalfa, Elai Davicioni, Jesse McKenney, Christopher Weight, Samuel C Haywood, Song Liu, Tao Liu, Hannelore V Heemers.

  Continued reliance on the androgen receptor (AR) after androgen deprivation therapy (ADT) fails causes 35,000 American prostate cancer (CaP) deaths annually. Targeting the AR's transcriptional activity could overcome this acquired resistance, but has been challenging. We demonstrate the therapeutic potential of disrupting interactions between the AR and its coregulator WDR77. WDR77 stimulated CaP growth, and its overexpression was associated with worse patient survival. AR and WDR77 cistromes overlapped considerably, and AR- and WDR77-bound genes correlated with aggressive CaP features. Direct WDR77-AR interaction occurred, which, when disrupted, prevented AR-WDR77 complex formation, reduced AR DNA-binding and AR-dependent gene expression, and decreased cell proliferation to the same extent as ADT. Such interference inhibited cell growth by ADT-resistant AR action and after ADT-resistance without impacting AR-negative CaP or benign cells. Blocking AR-WDR77 cooperation also delayed the growth of organoids from patient-derived xenografts and fresh CaP specimens. Disrupting coregulator control over AR action may thus improve survival from ADT-resistant CaP.

Keywords:  CP: Cancer; CP: Molecular biology; MEP50; androgen deprivation therapy; androgens; antiandrogens; castration; hormonal therapy; hormones; methylosome; transcription; treatment resistance

DOI:  https://doi.org/10.1016/j.celrep.2025.116235
Reprod Biomed Online. 2025 May 21. pii: S1472-6483(25)00263-9. [Epub ahead of print]51(5): 105056

Genital microbiota in infertile couples.

David Baud, Adriana Peric, Angela Vidal, Jürgen M Weiss, Philipp Engel, Sudip Das, Milos Stojanov.

   RESEARCH QUESTION: What is the composition of bacterial communities at various genital sites and are there potential interactions between partners' microbiota?
DESIGN: This observational study involved metagenomic analyses of samples collected from male and female partners of couples undergoing fertility treatment. Samples included vaginal and penile swabs, as well as follicular fluid and semen, which were analysed using next-generation sequencing.
RESULTS: The bacterial community profiles of different genital tract niches were distinct, niche-specific compositions, with female samples predominantly featuring Lactobacillus species and male samples displaying greater microbial diversity, including genital-specific and skin-associated taxa. Significant differences were observed between the sample types and intra-couple comparisons, which suggested potential microbiota interactions between partners. Differential abundance analyses further identified genera specifically enriched in female versus male samples, and correlations between partner samples point towards possible microbial transmission or shared influences on genital microbiota composition.
CONCLUSIONS: Despite advances in reproductive medicine, many infertility cases remain idiopathic, prompting exploration into how the genital microbiota (both in female and male reproductive tracts) might influence reproductive success. Our findings reveal that, although female samples were predominantly colonized by Lactobacillus species, particularly in the lower genital tract, male samples had greater microbial diversity (including bacteria linked to bacterial vaginosis), with only limited evidence of inter-partner microbiota transmission, underscoring the need for further longitudinal studies on the effect of sexual activity on microbial dynamics.

Keywords:  Bacteria; Colonization; Lactobacillus; Microbiota; Semen; Vagina

DOI:  https://doi.org/10.1016/j.rbmo.2025.105056
Front Immunol. 2025 ;16 1568514

Targeting IL-6 receptor mediated metabolic pathways to control Th17 cell differentiation and inflammatory responses.

Yazan Alwarawrah, Amanda G Nichols, Isha Patel, Andréa B Ball, Nancie J MacIver.

  Interleukin-6 (IL-6) is a multifunctional cytokine that plays important roles in inflammation. Several studies have shown that IL-6 regulates various aspects of T cell function, including the differentiation of CD4+ T cells into the pro-inflammatory Th17 subset. Given the tight link between T cell metabolism and function, and the role of IL-6 in regulating cellular metabolism across tissues, we investigated the role of IL-6 signaling in Th17 cell metabolism. Using T cell specific IL-6 receptor (IL-6R) conditional knockout mice and littermate controls, we found that IL-6R signaling regulates the proportions of CD4+ and CD8+ T cells and drives CD4+ T cell differentiation into Th17 cells. We also found that IL-6R signaling is required for Th17 cell glycolytic metabolism. In T cell-specific IL-6R knockout mice, Th17 cells had reduced glucose uptake and glycolysis, as well as decreased expression of key glycolytic enzymes, while showing increased basal oxygen consumption. However, we also found that IL-6R signaling enhanced oxidative capacity and mitochondrial coupling efficiency in Th17 T cells. Importantly, inhibition of lactate dehydrogenase using FX11 selectively impaired Th17 cell differentiation with minimal effects on Treg cells. These findings suggest that targeting metabolic pathways regulated by IL-6R signaling can selectively inhibit inflammatory Th17 responses, offering a potential strategy for controlling IL-6 mediated inflammation.

Keywords:  T cells; Th17; cellular metabolism; glycolysis; immunometabolism; inflammation; interleukin-6 (IL-6)

DOI:  https://doi.org/10.3389/fimmu.2025.1568514
Reproduction. 2025 Oct 01. pii: e250160. [Epub ahead of print]170(4):

Sex-specific alterations in placental mitochondria, oxidative damage and apoptosis in mice of advanced maternal age.

Jessica Dalton-O'Reilly, Alexander E P Heazell, Susan Greenwood, Mark Dilworth, Michelle Desforges.

   In brief: Advanced maternal age (AMA) is associated with adverse pregnancy outcomes, particularly those associated with placental dysfunction. This study showed that in a mouse model of AMA, male but not female fetuses had increased placental apoptosis and lipid peroxidation, as well as increased mitochondrial content, suggesting that the placentas of male fetuses in AMA mothers adapt to be able to deliver sufficient energy to the fetus.
Abstract: Although advanced maternal age (AMA) increases the risk of fetal growth restriction (FGR) and stillbirth, the mechanisms leading to the placental dysfunction observed in AMA are unknown. Mitochondrial function declines and oxidative stress increases with age. Furthermore, FGR, of which placental dysfunction is a major cause, is associated with alterations in respiratory function of placental mitochondria. Therefore, this study aimed to examine placental mitochondrial function, oxidative stress, and apoptosis in AMA mice using respirometry and immunohistochemistry. Relative to young mice (12-16 weeks), AMA mice (36-42 weeks) demonstrated reduced weight in both female and male fetuses, but placental alterations occurred in a sex-specific manner. In AMA, lipid peroxidation and apoptosis were increased in the placental junctional zone (Jz) and labyrinth zone (Lz) of male but not female fetuses. Placental mitochondrial content was significantly increased in the Lz and Jz of male fetuses and the Lz of female fetuses in AMA. When normalised to sample mitochondrial content, complex I + II-linked respiration, electron transfer capacity, and complex IV activity were significantly reduced in the Jz of male fetuses and Lz of female fetuses in AMA. However, when normalised to protein content, no differences were observed in placentas of female fetuses; in the Lz of male fetuses, complex I-linked respiration was increased and complex IV activity was reduced. Collectively, these findings suggest that the observed increase in mitochondrial content could be an adaptation by the placenta to maintain appropriate bioenergetic capacity and that oxidative damage may contribute to placental dysfunction in male fetuses in AMA pregnancies.

Keywords:  apoptosis; fetal growth restriction; mitochondria; oxidative stress; placenta; pregnancy

DOI:  https://doi.org/10.1530/REP-25-0160
Hum Reprod Open. 2025 ;2025(3): hoaf051

Evaluating endometrial response to human chorionic gonadotropin: alterations in epigenetic regulation and extracellular vesicle cargo of endometrial stromal cells.

Deimantė Žukauskaitė, Erika Girniūtė, Rūta Navakauskienė.

   STUDY QUESTION: What is the effect of hCG on the epigenetic profile and the expression of other molecular factors in endometrial stromal cells (ESCs)?
SUMMARY ANSWER: Our findings suggest that hCG treatment alters the molecular environment of decidualized ESCs, potentially influencing implantation and immune regulation through epigenetic modifications and changes in the levels of secreted proteins and micro-ribonucleic acids (miRNAs).
WHAT IS KNOWN ALREADY: Embryo implantation depends not only on the quality of the embryo but also on the receptivity of the endometrium, the specialized lining of the uterus that undergoes dynamic changes to support pregnancy. Effective communication between the maternal and fetal compartments, facilitated by molecular signals and cellular interactions, is essential for successful implantation.
STUDY DESIGN SIZE DURATION: Cross-sectional study of patient-derived ESCs comparing untreated cells with cells treated with hCG and/or decidualization induction. The number of samples depends on the method and varies from 2 to 8. Results were analyzed after 6-, 24-, 48-, and 72-h time-points.
PARTICIPANTS/MATERIALS SETTING METHODS: ESCs were isolated from patients undergoing assisted reproductive technologies. In the study, we analyzed changes in the epigenetic profile and other molecular factors of ESCs during decidualization and in in vitro response to the embryo-secreted factor, hCG. ESCs were induced for decidualization for 3 days (medroxyprogesterone acetate+cAMP), or treated with hCG for 24 h, or given combined treatment: 2 days of decidualization followed by 24 h of hCG. Furthermore, we compared decidualized ESCs with decidualized ESCs that were also treated with hCG. We examined various cellular properties, including morphology, metabolic activity, and cell viability of ESCs after induction of decidualization and hCG treatment. Additionally, we assessed changes in the expression of genes associated with decidualization, inflammatory response, apoptosis regulation, and epigenetic factors using RT-qPCR. The levels of histone modifications and the factors regulating these modifications were explored by performing western blot assays. Additionally, we performed a chromatin immunoprecipitation assay to extract gene regions enriched with the epigenetic modification H3K27Ac. Finally, we analyzed the protein and miRNA level changes in ESC extracellular vesicles (ESC-EVs) after the indicated treatments, using mass spectrometry and small RNA sequencing.
MAIN RESULTS AND THE ROLE OF CHANCE: Our study found that hCG treatment increased prolactin gene (PRL) expression (P < 0.05), while the expression of IL6 and BAK1 was inhibited in ESCs (P < 0.05). We also revealed that hCG affects epigenetic regulation, leading to changes in the expression of EED, HDAC1, and TET1/2/3 (P < 0.05). Specifically, hCG treatment resulted in increased levels of H3K27Ac in gene regions associated with decidualization, such as FOXO1 (P < 0.05), and implantation genes like HOXA10 and HAND2 (P = 0.06). After decidualization, we observed increased protein levels in ESC-EVs that are associated with embryo implantation (P = 0.0038) and pregnancy (P = 0.0012). These included proteins such as FIBL-1, IGFBP-1/7, MMP-2, STC-1/2, and PAPP-A (P < 0.05). Additionally, hCG treatment in decidualized ESCs elevated the levels of proteins involved in immune system regulation, including PR-3 (P = 0.0131). Moreover, we revealed changes in miRNA levels within EVs secreted by ESCs following hCG treatment and decidualization, which are associated with embryo development in the uterus (P = 0.03). Notable miRNAs include hsa-miR-340-3p, hsa-miR-663a, hsa-miR-766-5p, hsa-miR-3138, and hsa-miR-3180-5p (P < 0.05).
LARGE SCALE DATA: N/A.
LIMITATIONS REASONS FOR CAUTION: This study utilizes a comprehensive analysis to explore potential epigenetic and molecular targets essential for endometrial function. The research is based on in vitro experiments using ESCs derived from ex vivo samples. Future studies involving a broader range of cell types and larger sample sizes could help to further validate and expand upon these results.
WIDER IMPLICATIONS OF THE FINDINGS: We found that hCG enhances the decidualization process in a dose-dependent manner and affects implantation and immune regulation through epigenetic changes, as well as variations in the levels of secreted proteins and miRNAs. Our study suggests that the application of hCG in assisted reproduction technologies may offer potential benefits for patients. However, carefully considering the appropriate dosage is important to ensure optimal outcomes.
STUDY FUNDING/COMPETING INTERESTS: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors have no conflicts of interest to declare.

Keywords:  endometrium; epigenetics; extracellular vesicles; hCG; histone modification; miRNA

DOI:  https://doi.org/10.1093/hropen/hoaf051
Sci Adv. 2025 Sep 12. 11(37): eadx6489

Metabolism-driven posttranslational modifications and immune regulation: Emerging targets for immunotherapy.

Gujie Wu, Xiaofei Fan, Lin Cheng, Zongwei Chen, Yanjun Yi, Jiaqi Liang, Xiaolong Huang, Na Yang, Jiacheng Yin, Weigang Guo, Yiwei Huang, Shanye Yin.

The interplay between cellular metabolism and immune regulation is central to immune function and disease progression, revealing notable therapeutic opportunities. Upon activation, immune cells undergo metabolic reprogramming to meet heightened demands for energy and biosynthesis, reshaping regulatory networks across epigenomic, transcriptomic, and proteomic layers. Metabolite-derived posttranslational modifications (PTMs) serve as pivotal mechanisms integrating metabolic intermediates with immune signaling pathways. Beyond classical acetylation, diverse nonacetyl PTMs-including lactylation, succinylation, malonylation, palmitoylation, and myristoylation-modify histone and nonhistone proteins, regulating gene expression, protein stability, subcellular localization, enzymatic activity, and protein-protein interactions. Advances in mass spectrometry and bioinformatics now enable precise characterization of these PTMs, uncovering their broad roles in immune regulation. This review summarizes current progress in immunometabolism and explores future directions such as mechanistic studies, combination strategies, and clinical applications. Metabolite-driven PTMs critically connect metabolism to immune regulation, suggesting promising therapeutic approaches for cancer, autoimmune disorders, and inflammatory diseases.

DOI: https://doi.org/10.1126/sciadv.adx6489