bims-simsho 2025-10-19 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–10–19
24 papers selected by
Chun-Chi Chang, Lunds universitet

Trained immunity: induction of an inflammatory memory in disease.
Cell line-specific estrogen responses uncover functional sex differences in murine macrophages.
Sex Hormones and Metabolic Dysfunction-Associated Steatotic Liver Disease.
Dynamic Reprogramming of Immune-Related Signaling During Progression to Enzalutamide Resistance in Prostate Cancer.
Distribution of prolactin and its correlation with insulin resistance in women with polycystic ovary syndrome.
Novel hormone therapies for advanced prostate cancer: Understanding and countering drug resistance.
NDR1 enhances USP9X-mediated AR deubiquitination and promotes enzalutamide resistance in castration-resistant prostate cancer.
The role of CTLA-4, epiregulin and PD-1 in women with polycystic ovarian syndrome.
Journey through the gut-inflammation axis in polycystic ovary syndrome: the microbiota's role in shaping inflammatory pathways.
The Role of the Microbiome in Endometriosis.
Resident memory T cells call the shots in tissue immunity.
Ginsenoside Rh2 targets SIRT1-mediated deacetylation to modulate ERα/AR balance and overcome endocrine therapy resistance in prostate cancer using 3D organoid models.
Sex hormone-specific regulation of ferroptosis in vascular cells in atherosclerosis: molecular mechanisms and targeted strategies.
POLYCYSTIC OVARY SYNDROME: LONG-TERM EFFECTS ON FERTILITY AND UTERINE LESIONS.
Selective androgen receptor modulators: a critical appraisal.
Sex-Chromosome-Dependent Ageing in Female Heterogametic Methylomes.
Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles.
Mechanisms of maternal antibody interference with rotavirus vaccination.
Sex-specific dysregulation of exosomal non-coding RNAs drives multiple myeloma progression.
Age and sex influence diurnal memory oscillations, circadian rhythmicity, and Per1 expression.
Maternal Thymus Adaptations and Hormone Regulation During Pregnancy.
The role of m6A methylation in female reproductive physiology and pathology.
FCRL3 is an immunoregulatory receptor that restrains the activation of human memory T lymphocytes.
Serum VEGF Potential as a Biomarker for Diagnosis of Female Unexplained Infertility: Does Atopy Matter?

Cell Res. 2025 Oct 14.

Trained immunity: induction of an inflammatory memory in disease.

Titus Schlüter, Yuri van Elsas, Bram Priem, Athanasios Ziogas, Mihai G Netea.

The innate immune system adapts its behavior based on previous insults, mounting an enhanced response upon re-exposure. Hematopoietic progenitors in the bone marrow and peripheral innate immune cells can undergo epigenetic and metabolic reprogramming, establishing an innate immune memory known as trained immunity. The concept of trained immunity recently gained relevance in our understanding of how innate immunity is regulated in various diseases. This review explores the role of trained immunity in infections, autoimmune disease, cardiovascular disease, cancer, and neurodegenerative disease. We discuss how trained immunity can provide heterologous protection against infections, as it has been induced for decades by the Bacillus Calmette Guérin vaccine, how it can help counteract immunosuppression, and how it can be inappropriately induced leading to chronic inflammation. By understanding how trained immunity is involved in processes leading to health and disease, novel therapeutic strategies can be developed.

DOI: https://doi.org/10.1038/s41422-025-01171-y
Biol Sex Differ. 2025 Oct 14. 16(1): 75

Cell line-specific estrogen responses uncover functional sex differences in murine macrophages.

Alison M Veintimilla, Zoe Turner, Nana Owusu-Boaitey, Varun Deshpande, Margaret McCarthy, Erika Moore.

   BACKGROUND: RAW 264.7 (male-derived) and J774A.1 (female-derived) cell lines are widely used in immunology research and are considered preferred models for studying signaling pathways, yet their responses to gonadal hormones remain poorly understood. Gonadal hormones, particularly estrogen, shape immune cell function and contribute to sex differences in disease outcomes, with macrophages playing a central role through their expression of intracellular estrogen receptors (ERs). Herein, we investigated ER expression and functional responses to 17β-estradiol (E2) in male-derived RAW 264.7 and female-derived J774A.1 macrophages, in 2D culture. Additionally, we looked at sex-matched and mismatched media conditions in a 3D hydrogel system. Our results reveal distinct phenotypic and functional differences between the cell lines, emphasizing the need for sex-aware approaches in immunological research and model design.
METHODS: RAW 264.7 and J774A.1 macrophages were cultured in basal media for 24 hours, then treated with varying concentrations of 17β-estradiol (5, 25, 100 nM), as well as hormone-free and control media. Post-treatment analyses included viability, estrogen receptor expression, phenotype skewing, matrix metalloprotease 9 (MMP9) activity, and phagocytosis. These macrophages were also used to condition sex-specific media environments and were encapsulated in a hydrogel network containing adhesive and cleavable sites. Encapsulated cells were then exposed to sex-matched or sex-mismatched conditioned media, and proliferation and MMP9 activity were assessed.
RESULTS: Our results revealed distinct differences in estrogen receptor gene and protein expression, as well as in core macrophage functions such as proliferation, inflammation, matrix remodeling, and phenotype skewing. Additionally, the sex-derivation of the surrounding molecular environment affected macrophage behavior in a 3D hydrogel system. Female-derived macrophages were more sensitive in terms of proliferation to sex-mismatched environments, while male-derived macrophages exhibited altered enzyme activity when exposed to female-conditioned media.
CONCLUSIONS: These findings underscore the importance of accounting for both the origin of immune cells as well as the hormonal and environmental context in which they are studied. Without these considerations, experimental models risk missing critical biological differences that shape immune responses and disease outcomes.

Keywords:  Estrogen; Gonadal hormones; Macrophage function

DOI:  https://doi.org/10.1186/s13293-025-00760-1
Int J Mol Sci. 2025 Oct 01. pii: 9594. [Epub ahead of print]26(19):

Sex Hormones and Metabolic Dysfunction-Associated Steatotic Liver Disease.

Ralf Weiskirchen, Amedeo Lonardo.

  Positioned at the intersection of sex medicine and endocrinology, metabolic dysfunction-associated steatotic liver disease (MASLD) is often managed by specialists who may not be fully familiar with the complex roles of sex hormones in its pathogenesis and clinical course. To address this gap, we review the molecular actions of testosterone, estradiol, and progesterone on liver functions, as well as the role of sex-hormone binding globulin (SHBG) in MASLD histogenesis, highlighting disparities by sex as well as reproductive status. We also discuss how sex hormones influence fatty acid metabolism, gut dysbiosis, mitochondrial activity, gluco-lipidic homeostasis, lipotoxicity, inflammation, and MASLD-related liver tumorigenesis. Furthermore, we examine observational studies on associations between endogenous and exogenous sex hormones and SHBG with MASLD, with attention to hypogonadism in either sex or polycystic ovary syndrome. We summarize the role of sex hormones in modulating MASLD risk across life stages such as menopause, breastfeeding, and lactation. Lastly, we review the hepatic effects of hormone replacement therapy (HRT) on MASLD in both sexes, prospects, and safety of HRT and contraceptives among individuals with chronic liver disease. In conclusion, sex hormones play significant roles in MASLD pathobiology, underscoring the importance of sex-specific approaches in clinical practice and research.

Keywords:  HCC; MALO; cirrhosis; fibrosis; sex differences; steatohepatitis; steatosis

DOI:  https://doi.org/10.3390/ijms26199594
Cancers (Basel). 2025 Sep 30. pii: 3187. [Epub ahead of print]17(19):

Dynamic Reprogramming of Immune-Related Signaling During Progression to Enzalutamide Resistance in Prostate Cancer.

Pengfei Xu, Huan Qu, Joy C Yang, Fan Wei, Junwei Zhao, Menghuan Tang, Leyi Wang, Christopher Nip, Henson Li, Allen C Gao, Kit Lam, Marc Dall'Era, Yuanpei Li, Chengfei Liu.

   BACKGROUND: Treatment with androgen receptor (AR) signaling inhibitors, such as enzalutamide, can induce neural lineage plasticity in prostate cancer, potentially progressing to t-NEPC. However, the molecular mechanisms underlying this enzalutamide-driven plasticity, particularly the contribution of immune signaling pathways, remain poorly understood.
METHODS: We analyzed transcriptomic profiles of patient samples and prostate cancer cell lines to investigate changes in immune signaling pathways. Interferon gamma (IFNγ), interferon alpha (IFNα), and interleukin 6 (IL6)-Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling were assessed in enzalutamide-sensitive and -resistant prostate cancer cells. Functional assays were conducted to examine cell responsiveness to cytokine stimulation and susceptibility to STAT1 inhibition using fludarabine.
RESULTS: Immune-related pathways, including IFNγ, IFNα, IL6-JAK-STAT3, and inflammatory responses, were significantly suppressed in NEPC patient samples compared to those with castration-resistant prostate cancer (CRPC). Enzalutamide-resistant and NEPC cells exhibited markedly impaired IFNγ and IL6 signaling. In contrast, early-stage enzalutamide treatment paradoxically enhanced IFNγ and IL6 responsiveness. Transcriptomic profiling revealed coordinated upregulation of E2F target genes and activation of IFNα/IFNγ and JAK/STAT signaling pathways during early treatment. Importantly, these early-stage cells remained highly sensitive to IFNγ and IL6 stimulation and showed increased susceptibility to STAT1 inhibition by fludarabine, a sensitivity that was lost in resistant cells.
CONCLUSIONS: Early enzalutamide treatment enhances immune responsiveness, while the development of resistance is associated with suppressed immune signaling and increased lineage plasticity. These results suggest a therapeutic window where combining enzalutamide with STAT inhibitors may delay or prevent lineage plasticity and resistance.

Keywords:  JAK/STAT; enzalutamide resistance; immune-related signaling; lineage plasticity; prostate cancer

DOI:  https://doi.org/10.3390/cancers17193187
Front Endocrinol (Lausanne). 2025 ;16 1674795

Distribution of prolactin and its correlation with insulin resistance in women with polycystic ovary syndrome.

Stefan Ghobrial, Robert Krysiak, Tal Goldstein, Antonella Patsch, Chiara Paternostro, Florian Heinzl, Rodrig Marculescu, Johannes Ott.

   Introduction: Polycystic ovary syndrome (PCOS) is often associated with insulin resistance (IR). The role of prolactin (PRL) in this context remains unclear, particularly across different PCOS phenotypes. The aim of this study was to investigate the distribution of PRL, as well as its correlation with basal IR in women with PCOS.
Methods: 200 women with PCOS, evenly distributed across phenotypes A-D and matched for age and body mass index (BMI) were retrospectively analyzed. PRL, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), sexual hormone binding globulin (SHBG), testosterone, and BMI were assessed. Correlation analysis and unsupervised clustering (based on PRL and HOMA-IR) were performed.
Results: PRL levels were similar across phenotypes, but phenotype D had a significantly lower prevalence of HOMA-IR ≥ 2.5 (p = 0.032). PRL was inversely correlated with HOMA-IR in all groups (p < 0.05). Cluster analysis identified three distinct subgroups, independent of phenotype, differing significantly in both PRL and HOMA-IR.
Conclusion: PRL is inversely associated with IR in PCOS, regardless of phenotype. Cluster analysis reveals metabolic subtypes not captured by current phenotype-based classification, suggesting potential for improved risk stratification.

Keywords:  HOMA-IR; hyperprolactinemia; insulin resistance; polycystic ovary syndrome; prolactin

DOI:  https://doi.org/10.3389/fendo.2025.1674795
J Pharm Anal. 2025 Sep;15(9): 101232

Novel hormone therapies for advanced prostate cancer: Understanding and countering drug resistance.

Zhipeng Wang, Jie Wang, Dengxiong Li, Ruicheng Wu, Jianlin Huang, Luxia Ye, Zhouting Tuo, Qingxin Yu, Fanglin Shao, Dilinaer Wusiman, William C Cho, Siang Boon Koh, Wei Xiong, Dechao Feng.

  Prostate cancer is the most prevalent malignant tumor among men, ranking first in incidence and second in mortality globally. Novel hormone therapies (NHT) targeting the androgen receptor (AR) pathway have become the standard of care for metastatic prostate cancer. This review offers a comprehensive overview of NHT, including abiraterone, enzalutamide, apalutamide, darolutamide, and rezvilutamide, which have demonstrated efficacy in delaying disease progression and improving patient survival and quality of life. Nevertheless, resistance to NHT remains a critical challenge. The mechanisms underlying resistance are complex, involving AR gene amplification, mutations, splice variants, increased intratumoral androgens, and AR-independent pathways such as the glucocorticoid receptor, neuroendocrine differentiation, DNA repair defects, autophagy, immune evasion, and activation of alternative signaling pathways. This review discusses these resistance mechanisms and examines strategies to counteract them, including sequential treatment with novel AR-targeted drugs, chemotherapy, poly ADP-ribose polymerase inhibitors, radionuclide therapy, bipolar androgen therapy, and approaches targeting specific resistance pathways. Future research should prioritize elucidating the molecular basis of NHT resistance, optimizing existing therapeutic strategies, and developing more effective combination regimens. Additionally, advanced sequencing technologies and resistance research models should be leveraged to identify novel therapeutic targets and improve drug delivery efficiencies. These advancements hold the potential to overcome NHT resistance and significantly enhance the management and prognosis of patients with advanced prostate cancer.

Keywords:  Advanced prostate cancer; Androgen receptor; Drug resistance; Novel hormone therapies

DOI:  https://doi.org/10.1016/j.jpha.2025.101232
Int J Biol Sci. 2025 ;21(13): 5628-5644

NDR1 enhances USP9X-mediated AR deubiquitination and promotes enzalutamide resistance in castration-resistant prostate cancer.

Zeyuan Zheng, Jinxin Li, Yifan Du, Liyan Li, Qingqing Wu, Bin Liu, Haodong Wu, Zeyi Zhang, Zuodong Xuan, Yue Zhao, Huimin Sun, Chen Shao.

  Castration-resistant prostate cancer (CRPC) enzalutamide resistance is a significant issue in the current treatment of prostate cancer (PCa). Previously, nuclear Dbf2-related 1 (NDR1) was found to influence metastasis in PCa patients; however, the role of NDR1 in enzalutamide resistance in CRPC remains unclear. In this study, we found that after CRPC cells developed resistance to enzalutamide, NDR1 expression levels were elevated and that NDR1 expression could reduce the sensitivity of CRPC cells to enzalutamide. Furthermore, in androgen receptor (AR) positive PCa cell lines, the use of enzalutamide induced an increase in NDR1 expression levels. Further mechanistic exploration revealed that NDR1 positively regulates AR protein expression levels by promoting the deubiquitination of AR by USP9X, thereby increasing AR stability, which leads to cellular resistance to enzalutamide. Finally, we confirmed that pharmacological suppression of NDR1 by 17AAG significantly inhibited the growth of enzalutamide-resistant CRPC tumors in both in vitro and in vivo models. In summary, this study revealed that NDR1 enhances the deubiquitination of AR mediated by USP9X, improving its stability and activity and thereby maintaining the continuous activation of the androgen signaling pathway in CRPC, leading to resistance to enzalutamide treatment. These findings suggest that cotargeting NDR1 and AR may represent a novel therapeutic strategy for AR-positive CRPC.

Keywords:  AR; Castration-resistant prostate cancer; Enzalutamide resistance; NDR1; USP9X

DOI:  https://doi.org/10.7150/ijbs.114686
Egypt J Immunol. 2025 Oct;32(4): 62-68

The role of CTLA-4, epiregulin and PD-1 in women with polycystic ovarian syndrome.

Sura F Alsaffar, Hiba M Khaleel.

Polycystic ovarian syndrome (PCOS) is a hormonal, reproductive, metabolic disorder, affect female at reproductive age. PCOS is associated with hormonal and immunological defect, and chronic low-grade inflammation, that affect some proteins expression, like cytotoxic T Lymphocyte Associate protein 4 (CTLA-4), programmed death-1 (PD-1), epiregulin (EREG) in association with T-cell activation. These immunological parameters may indicate autoimmune diseases and PCOS. CTLA-4 and PD-1 are immune checkpoints that regulate the immunity during the chronic inflammation, by suppressing T-cells activation, natural killer cell, B-cell production. Epiregulin, a member of the epidermal growth factor (EGF) family, is released in response to luteinizing hormone(LH) released from granulosa cells in ovaries. There is an indirect link between PCOS and epiregulin in chronic low-grade inflammation. The purpose of this study was to indicate the role of CTLA-4, epiregulin, and PD-1 in women with polycystic ovarian syndrome, also the estimation of some related hormones level in PCOS, like prolactin, testosterone anti-Mullerian hormone (AMH). This study included 65 patients with PCOS and 56 normal controls (healthy women). Their average ages were from 20 to 45 years. The study subjects were from the private women's infertility clinics at the Medical City Hospital, Baghdad. The study lasted from November 2024 to January 2025. Metformin, vitamin D, and oral contraceptives were prescribed by consultant to patients. The blood samples were collected and CTLA-4, PD-1, EREG were measured by enzyme-linked immunosorbent assay (ELISA) technique. The results showed a significant decrease in CTLA-4 in patients (46.04 ±4.51) than in controls (70.46 ±9.41), (p≤0.01). Also, there was no difference in PD-1 level in patients (250.37 ±23.37), and controls (247.81 ±29.80), (p>0.05). EREG showed a significant increase in patients (1099.12 ±138.51), compared to controls (835.02 ±48.62), (p≤0.05). In addition, prolactin hormones recorded a significant increase in patients (154.86 ±27.22) compared to controls (13.91 ±1.50), (p≤0.05). While for the testosterone hormone there was a significant decrease in patients (16.36 ±2.58), as compared to controls (28.73 ±1.75), (p≤0.05). The AMH showed no difference between patients (5.79 ±0.40), and controls (4.18 ±0.44), (p>0.05). In conclusion, based on the current findings, the decrease in CTLA-4, and the increase in EREG in the patient's group was associated with low-grade inflammation like PCOS.

DOI: https://doi.org/10.55133/eji.320408
Mol Cell Biochem. 2025 Oct 16.

Journey through the gut-inflammation axis in polycystic ovary syndrome: the microbiota's role in shaping inflammatory pathways.

Ujjawal Sharma, Anidrisha Sahu, Neelam Thakur, Ranjay Kumar Choudhary, Himanshu Shekhar, Shafiul Haque, Hardeep Singh Tuli, Aygul Toktasynovna Aubakirova, Bunty Sharma.

  Polycystic ovary syndrome (PCOS) is a prevalent endocrine disease in women in their reproductive phase of life. It could be characterized by irregularity in menstrual cycles, abnormal levels of androgen, and multiple cyst formations in the ovaries. It involves a complex and multifaceted pathophysiology including endocrine and metabolic irregularity, genetic and epigenetic abnormality, inflammation, and gut microbiota dysbiosis. PCOS interferes with the fertility of the patient directly due to irregular ovulation caused by hormonal imbalances. Further, this condition is also associated with increased risk for other health conditions such as type2 diabetes and cardiovascular disease, as well as psychological conditions such as anxiety and depression. Among various other factors, metabolic profiles and gut health also play a crucial role in PCOS pathogenesis. Various recent studies have reported an association of gut microbiota dysbiosis with PCOS. gut microbiota: The microbial population residing in the host organism influences our health status, and their diversity and balance are crucial to maintaining the healthy status of the body. There is growing evidence of the involvement of gut microbe dysbiosis in different diseases, including PCOS. Further inflammation is another key hallmark of PCOS. The inflammatory status of the host body depends on various factors; gut microbe dysbiosis is one such factor that can modulate the inflammatory status and thus contribute to various health conditions such as PCOS. In the present article, we have thoroughly reviewed the current status of research on the involvement of gut microbiota dysbiosis in PCOS pathogenesis and the inflammatory mechanism by which it leads to PCOS, including MCP-1/IL-2 mediated cytokine signaling, LPS-induced leaky gut inflammation, JNK/NF-KB and IKK pathways, tight junction disruption, and oxidative stress. Further, we have also discussed the factors affecting gut microbe dysbiosis and the current status of therapeutic interventions targeting gut dysbiosis in PCOS. These insights emphasize the clinical potential of targeting gut dysbiosis and associated inflammatory pathways to improve the metabolic, reproductive, and psychological outcomes in women with PCOS.

Keywords:  Dysbiosis; Gut Microbiota; Inflammation; PCOS; Polycystic Ovary Syndrome

DOI:  https://doi.org/10.1007/s11010-025-05409-6
Reprod Sci. 2025 Oct 13.

The Role of the Microbiome in Endometriosis.

Sabri Saeed Sanabani.

  Endometriosis is a chronic gynecological disease characterized by the presence of endometrial-like tissue outside the uterus, leading to pain and infertility. Recent research has highlighted the important role of the microbiome in various health conditions, including endometriosis. The aim of this review is to examine the central role of the microbiome in the development and treatment of endometriosis. Key findings include the influence of the gut microbiota on estrogen metabolism, whereby certain bacteria can increase estrogen levels and systemic inflammation and exacerbate endometriosis. Changes in the vaginal and endometrial microbiota are also associated with the disease, as they influence inflammatory and estrogen-dependent metabolic pathways. Dysbiosis in various microbiomes can affect inflammatory pathways, with a shift in the vaginal microbiota to the upper reproductive tract affecting endometriosis without symptoms. Probiotic interventions show promise in restoring a healthy microbiota and improving outcomes, with clinical trials demonstrating the efficacy of lactobacilli-based medications for pain relief. In addition, diet and lifestyle changes can directly impact the gastrointestinal microbiome, reducing inflammation and potentially influencing endometriosis. Future research should focus on establishing comprehensive microbiome profiles, mechanistic studies and longitudinal studies to discover new therapeutic targets and improve clinical outcomes for women with endometriosis.

Keywords:  Dysbiosis; Endometriosis; Estrogen metabolism; Microbiome; Probiotic interventions

DOI:  https://doi.org/10.1007/s43032-025-01985-6
Immunity. 2025 Oct 14. pii: S1074-7613(25)00428-5. [Epub ahead of print]58(10): 2364-2366

Resident memory T cells call the shots in tissue immunity.

Sigrun Stulz, Georg Gasteiger.

Vaccines that induce immunity in tissues are urgently needed. In this issue of Immunity, Joag et al. demonstrate that systemic vaccination of primates induces tissue-resident CD8+ T cells in numerous organs that can activate antiviral responses by stromal, parenchymal, and immune cells.

DOI: https://doi.org/10.1016/j.immuni.2025.09.017
Cell Biol Toxicol. 2025 Oct 15. 41(1): 139

Ginsenoside Rh2 targets SIRT1-mediated deacetylation to modulate ERα/AR balance and overcome endocrine therapy resistance in prostate cancer using 3D organoid models.

Xinan Chen, Wei Luo, Yueying Ren, Zezhong Mou, Chenyang Xu, Jimeng Hu, Mengbo Hu, Haowen Jiang.

  Resistance to endocrine therapy remains a major challenge in treating prostate cancer (PCa), highlighting the need for alternative therapeutic approaches. In this study, we investigated the potential of Ginsenoside Rh2 to counteract such resistance by influencing the SIRT1-dependent deacetylation pathway, thereby modulating the equilibrium between estrogen receptor α (ERα) and androgen receptor (AR). We proposed that Rh2 may suppress therapy-resistant PCa progression by adjusting ERα/AR transcriptional dynamics. Through network pharmacology analysis, key anti-PCa targets of Rh2 were identified, with Cytoscape enrichment indicating a pivotal role in AR signaling modulation. Functional validation was performed using 3D tumor organoids and human PCa cell lines (C4-2B and LNCaP) treated with Rh2 to assess cellular behaviors and receptor deacetylation status. Additionally, xenograft mouse models were employed to evaluate Rh2's in vivo effects, based on tumor burden, serum PSA levels, and tissue histopathology. Rh2 treatment led to significant, dose- and time-dependent inhibition of PCa cell proliferation and metastatic traits, accompanied by restored ERα/AR balance through activation of SIRT1. In animal studies, Rh2 notably reduced tumor size, decreased PSA expression, and improved systemic health indicators. Collectively, our results suggest that Rh2 re-sensitizes PCa to endocrine therapy by targeting the SIRT1 pathway, positioning it as a promising phytochemical candidate for managing resistant PCa. This work provides mechanistic insights supporting Rh2's potential for clinical translation.

Keywords:  3D Organoid Model; ERα/AR Balance; Endocrine Resistance; Ginsenoside Rh2; Prostate Cancer; SIRT1 Deacetylation

DOI:  https://doi.org/10.1007/s10565-025-10091-x
Front Physiol. 2025 ;16 1680625

Sex hormone-specific regulation of ferroptosis in vascular cells in atherosclerosis: molecular mechanisms and targeted strategies.

Keying Yu, Jitong Li, Tenghui Tian, Rui Shi, Yue Deng, Liping Chang.

  Atherosclerosis (AS), the leading cause of cardiovascular morbidity and mortality worldwide, exhibits significant sex differences in its incidence and pathological progression, yet the underlying molecular mechanisms remain fully elucidated. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has recently been identified as a key pathological event contributing to the progression of AS. The basis of physiological sex dimorphism is composed of both circulating sex hormone levels and cell-intrinsic sex differences, which may play a critical role in determining the sex-specific characteristics of AS by modulating the ferroptosis signaling network. This review aims to systematically elaborate and substantiate the "sex hormone-ferroptosis regulatory axis" as a pivotal theoretical framework in the context of AS-related sex differences. We integrate existing evidence suggesting that estrogen can synergistically inhibit ferroptosis in vascular cells, particularly endothelial cells and macrophages, through multiple pathways. These include: (1) activating the central antioxidant system driven by Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2); (2) regulating mitochondrial homeostasis and function; and (3) directly modulating key iron metabolism proteins, such as upregulating the iron efflux protein Ferroportin-1 (FPN1). These mechanisms collectively contribute to the cardiovascular protective effects observed in premenopausal women. Conversely, available evidence suggests that androgens may promote ferroptosis in vascular cells by enhancing oxidative stress, potentially increasing cellular iron uptake (e.g., through potential upregulation of Transferrin Receptor 1, TFR1), and modulating lipid metabolism to increase the availability of peroxidizable substrates. This could be a significant contributor to the earlier onset and higher incidence of AS in men. Based on this framework, this review further explores potential sex-specific therapeutic strategies targeting this regulatory axis. This review provides a novel molecular perspective for understanding the sex differences in AS and provides a theoretical basis for the development of a new paradigm in sex-stratified precision cardiovascular medicine.

Keywords:  androgen; atherosclerosis; estrogen; ferroptosis; precision medicine; sex differences; sex hormones; vascular cells

DOI:  https://doi.org/10.3389/fphys.2025.1680625
Mol Cell Endocrinol. 2025 Oct 14. pii: S0303-7207(25)00232-1. [Epub ahead of print] 112681

POLYCYSTIC OVARY SYNDROME: LONG-TERM EFFECTS ON FERTILITY AND UTERINE LESIONS.

Gisela Soledad Bracho, María Virginia Acosta, Inri Iñiguez, Gabriela Anahí Altamirano, Laura Kass, Verónica Lis Bosquiazzo.

  Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. In this study, we aimed to investigate the long-term effects of PCOS. We assessed fertility at 3 months of age and uterine histomorphology along with endocrine status at 6 and 24 months of age in an experimental model. PCOS was induced in female Wistar rats from 21 to 40 days of age by subcutaneous injection of dehydroepiandrosterone (6 mg/100g bw). After treatment, rats were separated into groups and euthanized on gestational day 18 (GD18), 6 months and 24 months of age. Fertility test was performed on GD18 and no changes were observed in the PCOS rats. At 6 months of age, PCOS rats showed uterine lesions associated with a higher serum 17-β estradiol (E2)/progesterone (P4) ratio. At 24 months of age, PCOS rats had a higher incidence of luminal hyperplasia and a greater number of glands with metaplasia and conglomerates of glands. This was associated with increased serum E2/P4 ratio, uterine steroidogenic enzymes (steroid sulfatase, 5α-reductase type I) and estrogen receptor alpha expression. In addition, an increased infiltration of eosinophils in the uterus was observed, suggesting an estrogenic effect. These results show that PCOS induced early in life alters the uterine endocrine status in the long term, suggesting increased uterine exposure and sensitivity to estrogens. Taken together, these findings may explain the increased incidence/multiplicity of uterine lesions observed in the PCOS group.

Keywords:  PCOS; fertility; steroid hormones; tissular steroid metabolism; uterus

DOI:  https://doi.org/10.1016/j.mce.2025.112681
Front Endocrinol (Lausanne). 2025 ;16 1634799

Selective androgen receptor modulators: a critical appraisal.

Peter Bond, Diederik L Smit, Tijs Verdegaal, Willem de Ronde.

  The concept of selective androgen receptor modulators (SARMs) was introduced in 1999 in analogy to selective estrogen receptor modulators (SERMs). The primary goal was to separate the unwanted androgenic or virilizing effects from the anabolic or myotrophic effects. This separation would result from tissue-selective effects. In this paper, we critically appraise the evidence behind SARMs' purported tissue selectivity with emphasis on historical androgen research, which, in essence, tried to achieve the same goal by modifying the steroid nucleus. While SARMs demonstrate favorable 'anabolic-androgenic ratios' in preclinical studies, much of this apparent selectivity may stem from a lack of steroidal metabolism - such as 5α-reduction and 3α/β-reduction - when compared with steroidal androgens that are susceptible to these metabolic pathways. Emerging evidence suggests that differential recruitment of coregulators and differences in activation of nongenomic signaling pathways may contribute to tissue-selective effects, but it remains unclear whether this translates to clinically meaningful tissue selectivity. Clinical trials reveal some efficacy of SARMs in terms of improvements in body composition or anti-tumor activity in advanced breast cancer, yet these results might equally well have been achieved with conventional androgens as head-to-head trials are lacking. Furthermore, the absence of estrogenic activity poses a clinical challenge, especially regarding bone health and sexual function in men. Overall, while SARMs present an attractive therapeutic concept, robust evidence supporting their superiority over traditional androgens remains incomplete, warranting cautious interpretation and further comparative research.

Keywords:  SARMs; androgen pharmacology; androgen receptor; androgens; selective androgen receptor modulators

DOI:  https://doi.org/10.3389/fendo.2025.1634799
Mol Ecol. 2025 Oct 13. e70147

Sex-Chromosome-Dependent Ageing in Female Heterogametic Methylomes.

Marianthi Tangili, Joanna Sudyka, Fabricio Furni, Per J Palsbøll, Simon Verhulst.

  Recent research in humans and both model and non-model animals has shown that DNA methylation (DNAm), an epigenetic modification, is one of the mechanisms underlying the ageing process. DNAm-based indices predict mortality and provide valuable insights into biological ageing mechanisms. Although sex-dependent differences in lifespan are ubiquitous and sex chromosomes are thought to play an important role in sex-specific ageing, they have been largely ignored in epigenetic ageing studies. We characterised the genome-wide distribution of age-related CpG (Cytosine-phosphate-Guanine) sites from longitudinal samples in two avian species (zebra finch and jackdaw), including for the first time the avian sex chromosomes (Z and the female-specific, haploid W). In both species, we find a small fraction of the CpG sites to show age-related changes in DNAm with the majority of them being located on the haploid, female-specific W chromosome, where DNAm levels predominantly decrease with age. Age-related CpG sites were over-represented on the zebra finch but under-represented on the jackdaw Z chromosome. Our results highlight distinct age-related changes in sex chromosome DNAm compared to the rest of the genome in two avian species, suggesting this previously understudied feature of sex chromosomes may be instrumental in sex-dependent ageing. Moreover, studying the DNAm of sex chromosomes might be particularly useful in ageing research, facilitating the identification of shared (sex-dependent) age-related pathways and processes between phylogenetically diverse organisms.

Keywords:  DNA methylation; avian sex chromosomes; female heterogametic; sex‐dependent ageing

DOI:  https://doi.org/10.1111/mec.70147
Sci Transl Med. 2025 Oct 15. 17(820): eadq3401

Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles.

Yuichiro Itoh, Noriko Itoh, Sophia Wendin, Nadya Higgins, Rhonda R Voskuhl.

Women are more susceptible to multiple sclerosis (MS) than men, with a reported incidence ratio of ~3:1. Kdm6a is an X-chromosomal gene that escapes X inactivation, leading to higher expression of the histone demethylase KDM6A in females compared with males. Here, we focused on the role of Kdm6a in microglia in MS because this cell type plays a key role in the neuropathology of MS. Kdm6a was selectively deleted from microglia in experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. Deletion of Kdm6a in microglia ameliorated pathology, reduced the expression of disease-associated markers, increased the expression of resting microglial markers, and reversed other translatome changes in spinal cord tissues of female EAE mice. Deletion of Kdm6a in microglia had only very minor effects on EAE in male mice. The diabetes medicine metformin, which also blocks KDM6A's histone demethylase activity, ameliorated EAE in females, but not males, and normalized translatome profiles in microglia. CUT&RUN and sequencing analysis of microglial nuclei identified genes bound by KDM6A. When combined with translatomic analysis, this revealed correspondence between KDM6A protein binding and gene expression changes. Transcriptomic analysis of human microglia confirmed the higher expression of KDM6A in women compared with men and revealed that more microglial genes were dysregulated in women than in men with MS. Our results suggest that KDM6A might contribute to sex differences in susceptibility to MS.

DOI: https://doi.org/10.1126/scitranslmed.adq3401
EMBO J. 2025 Oct 14.

Mechanisms of maternal antibody interference with rotavirus vaccination.

Tawny L Chandler, Sarah Woodyear, Valerie Chen, Tom M Lonergan, Natalie Baker, Katherine Harcourt, Simon Clare, Faraz Ahmed, Sarah L Caddy.

  Maternal antibodies are transferred transplacentally to fetuses and then through lactation to infants to protect them whilst their own immune system is still immature. However, these maternal antibodies also suppress neonatal B-cell responses, thereby impairing vaccine efficacy and leaving infants potentially vulnerable to life-threatening pathogens, such as rotaviruses. Currently available rotavirus vaccines are composed of live-attenuated viral strains administered to infants orally at 6-8 weeks old. Although high concentrations of maternal antibodies correlate with poor production of antibodies following vaccination (i.e., seroconversion), the immunological basis of this interference is unknown. To investigate the underlying mechanisms, we here developed a mouse model of neonatal oral rotavirus vaccination, in which vaccination only fails to induce seroconversion if maternal antibodies are present. Such antibodies are shown to block vaccine replication, while faster maternal antibody waning is observed in vaccinated compared to unvaccinated pups. FcγRIIB deletion does not overcome interference in pups, although pup IgG levels increase when maternal antibody titers are very low. Our findings show that maternal antibody-mediated vaccine clearance is a key mechanism of interference with oral rotavirus vaccines, with a minor role for FcγRIIB in neonatal IgG responses.

Keywords:  FcγRIIB; Maternal Antibody; Rotavirus; Vaccine

DOI:  https://doi.org/10.1038/s44318-025-00582-2
Blood Cancer J. 2025 Oct 16. 15(1): 162

Sex-specific dysregulation of exosomal non-coding RNAs drives multiple myeloma progression.

Samaneh Maleknia, Sanam Rezaei Benam, Greg Ahmann, Rafael Fonseca, Diane F Jelinek, Reza Shahbazi.

Multiple myeloma (MM) is characterized by the clonal proliferation of plasma cells in the bone marrow. Although the precise molecular mechanisms differentiating men and women in MM are not fully understood, uncovering these differences is crucial for improving personalized therapeutic approaches. Here, we show sex-specific dysregulation of exosomal non-coding RNAs (ncRNAs) in MM. We conducted an in-depth analysis of dysregulated ncRNAs in male and female patients, as well as MM cell lines, revealing distinct expression signatures across multiple clinical contexts, including newly diagnosed, relapse, progression, Hyperdiploid, non-Hyperdiploid, and treatment exposure. Our findings highlight the pivotal roles of lncRNAs and miRNAs in MM pathogenesis, detecting alterations in enriched pathways that influence key biological processes such as cellular proliferation, apoptosis, and gene regulation. We established a panel of ncRNAs with distinct sex-specific expression patterns, significant effects on mRNA regulation, and involvement in MM-associated biological pathways. Our results demonstrate that exosomes provide enhanced analytical resolution for detecting non-coding RNAs, enabling more sensitive and precise identification of transcriptomic alterations. These results suggest that sex-specific dysregulation of ncRNAs may contribute to differences in MM progression and therapy response. Ultimately, this study underscores the importance of exosomal ncRNA profiling in designing sex-tailored therapeutic strategies targeting dysregulated ncRNAs, paving the way for personalized medicine in MM.

DOI: https://doi.org/10.1038/s41408-025-01362-1
Biol Sex Differ. 2025 Oct 14. 16(1): 74

Age and sex influence diurnal memory oscillations, circadian rhythmicity, and Per1 expression.

Lauren Bellfy, Gretchen C Pifer, Megan J von Abo, Chad W Smies, Alicia R Bernhardt, Achintya Perumal, Madison J Jackson, Janine L Kwapis.

   BACKGROUND: The circadian system influences many different biological processes across the lifespan, including memory performance and daily activity patterns. The biological process of aging causes decreased control of the circadian system that is accompanied by a decline in memory performance, suggesting that these two processes may be linked. Indeed, our previous work has shown that in male mice, the clock gene Per1 functions within the dorsal hippocampus to exert diurnal control over memory and repression of Per1 in the old hippocampus contributes to age-related impairments in spatial memory. Although it is clear that Per1 may be a key molecular link between memory and the circadian rhythm, next to nothing is known about how sex impacts this role in the young or old brain. Here, we are interested in understanding how the factors of sex and age impact memory performance, circadian activity patterns, sleep behavior, and hippocampal Per1 expression.
METHODS: We used a combination of spatial memory (Object Location Memory (OLM)) and circadian activity monitoring to determine how male and female mice change across the lifespan. In addition, we used RT-qPCR to quantify the change in Per1 levels in response to learning in young and old, male and female mice.
RESULTS: Young female mice resist diurnal oscillations in memory, showing robust spatial memory across the diurnal cycle. In contrast, old female mice show an emergence of diurnal memory oscillations, with better memory during the day than at night (similar to what we observed previously in young male mice). In contrast, old male mice showed better memory performance during the night than the day, suggesting that their peak memory performance is drastically shifted compared to young males. We also measured activity patterns and sleep behavior across the diurnal cycle and found that sex was more of an influence than age in multiple analyses, but age did have an impact, with old male mice showing stronger circadian rhythm disruptions than any other cohort. Finally, we investigated whether the circadian clock gene Per1 plays a role in these sex- and age-dependent effects in diurnal memory performance. We found that, in general, learning-induced Per1 and memory performance peaked at similar times of day in each group, consistent with our hypothesis that Per1 exerts diurnal control over memory performance.
CONCLUSIONS: This work supports a role for Per1 in exerting diurnal control over memory and suggests that Per1 may be an appealing therapeutic target to improve memory and circadian dysfunction in old age.
HIGHLIGHTS: Diurnal oscillations in spatial memory are sex- and age-dependent in mice. Per1 learning-induced expression matches diurnal memory patterns. Circadian rhythm patterns are sex- and age-dependent in mice. Young females show good memory across the diurnal cycle. Diurnal memory oscillations reemerge in old female mice.

Keywords:  Aging; Circadian rhythm; Learning; Memory; Per1; Sex differences

DOI:  https://doi.org/10.1186/s13293-025-00756-x
Cells. 2025 Sep 30. pii: 1534. [Epub ahead of print]14(19):

Maternal Thymus Adaptations and Hormone Regulation During Pregnancy.

Ling Yang, Xinxin Wang, Leying Zhang.

  The thymus is necessary for the development of T lymphocytes and central tolerance, and adaptations in the maternal thymus are required during pregnancy. In the present paper, maternal thymic cellular anatomy, T-cell development in the thymus, and related progress are reviewed. In addition, the recent progress in maternal thymic adaptations during pregnancy is discussed, including adaptations in thymic cellular anatomy, T-cell development, and immune-related cytokines. Finally, the latest information about hormones that regulate thymic immunology during pregnancy is summarized. In summary, there are many factors, including a lot of hormones, which are involved in maternal thymic immunological adaptations during pregnancy, and may be used to prevent pregnancy-related thymic diseases and preterm birth.

Keywords:  hormones; immunology; pregnancy; thymus

DOI:  https://doi.org/10.3390/cells14191534
Genes Dis. 2026 Jan;13(1): 101755

The role of m6A methylation in female reproductive physiology and pathology.

Jie Ding, Yalun He, Yangshuo Li, Shuai Sun, Wen Cheng, Jiami Huang, Chaoqin Yu.

  N6-methyladenosine (m6A) is a critical regulator of female reproductive physiology, yet existing reviews have focused predominantly on oocytes. The objective of this review is to systematically evaluate the regulatory effects of m6A throughout the pregnancy process. This review covers aspects such as oocyte maturation, granulosa cell dynamics, endometrial receptivity, immune homeostasis, and systemic adaptations, aiming to demonstrate the comprehensive regulatory capacity of m6A in female reproduction. Dysregulated m6A modifications in infertility-associated pathologies, including endometriosis, polycystic ovary syndrome, and recurrent miscarriage, are analyzed to identify mechanistic links between an epitranscriptomic imbalance and reproductive dysfunction. The key findings indicate that m6A is involved in the entire reproductive process and precisely coordinates stage-specific molecular programs within it, whereas aberrant methylation patterns disrupt gene networks essential for fertility. Notably, m6A-modifying enzymes exhibit strong potential as diagnostic biomarkers for female reproductive disorders. The synthesis of the current evidence establishes m6A dysregulation as a convergent pathogenic mechanism in diverse infertility etiologies, suggesting that the therapeutic modulation of m6A pathways could address unmet clinical needs in reproductive medicine.

Keywords:  Endometrial receptivity; Female infertility; Granulosa cell; Immune environment; Oocyte; m6A methylation

DOI:  https://doi.org/10.1016/j.gendis.2025.101755
J Exp Med. 2026 Jan 05. pii: e20242474. [Epub ahead of print]223(1):

FCRL3 is an immunoregulatory receptor that restrains the activation of human memory T lymphocytes.

Niccolò Bianchi, Elena Foli, Mehrpouya Mostanfar, Roberta Marzi, Mara Cetty Spinella, Sara Polletti, Matteo Pecoraro, Antonino Cassotta, Roshan Thakur, David Jarrossay, Federica Sallusto, Gioacchino Natoli, Silvia Monticelli.

Genetic variants in the FCRL3 gene are linked to autoimmune disorders. However, the functional properties of FCRL3-expressing T lymphocytes, and the regulation and functional impact of FCRL3 expression remain understudied. Here, we performed a multiomic and functional analysis of human T lymphocytes expressing FCRL3. FCRL3 expression correlated with reduced capacity of T cells to undergo activation and was accompanied by functional specialization toward a cytotoxic phenotype, resembling cytotoxic CD4+ T lymphocytes and CD8+ effector memory TEMRA cells. FCRL3 expression was induced upon repetitive TCR engagement, and sufficed to attenuate T cell responses, indicating a role as a negative regulator of the activation of differentiated T cell subsets with high cytotoxic capacity. Mechanistically, the cytoplasmic domain of FCRL3 engaged inhibitory molecules, suggesting a direct role in limiting activating signals. Overall, our study establishes FCRL3 as a functional immunoregulatory receptor that restrains the activation of highly specialized human memory T cells.

DOI: https://doi.org/10.1084/jem.20242474
Int J Mol Sci. 2025 Sep 28. pii: 9499. [Epub ahead of print]26(19):

Serum VEGF Potential as a Biomarker for Diagnosis of Female Unexplained Infertility: Does Atopy Matter?

Gabija Didžiokaitė, Austėja Grudytė, Aida Kuznecovaitė, Margarita Žvirblė, Žilvinas Survila, Vita Pašukonienė, Violeta Kvedarienė.

  Unexplained infertility (UI) remains a diagnostic challenge affecting a significant proportion of women of reproductive age. Vascular endothelial growth factor (VEGF), a key mediator of angiogenesis and inflammation, has been implicated in reproductive and immune processes. This prospective observational study evaluated serum VEGF levels and allergen sensitization (via ALEX2 macroarray) in 70 women-51 with UI and 19 fertile controls-to assess VEGF's potential as a biomarker in UI. Median VEGF concentrations were higher in women with UI compared to fertile controls (128.6 pg/mL vs. 82.5 pg/mL), though not statistically significantly. However, sensitized women showed significantly elevated VEGF levels compared to non-sensitized peers (115.9 pg/mL vs. 85.7 pg/mL, p = 0.028), and a stepwise increase in VEGF was observed with rising allergy severity (p = 0.045). Sensitization to pet allergens, particularly cat allergen Fel d 1, was associated with the highest VEGF levels. A literature review confirmed wide variability in VEGF concentrations and the lack of standardized norms. While VEGF alone may not serve as a definitive biomarker for infertility, elevated levels may reflect an underlying inflammatory state. Our findings suggest VEGF testing could support broader clinical evaluation in women with UI, especially in the presence of allergic sensitization.

Keywords:  ALEX2 macroarray; allergic sensitization; atopy; biomarker; female reproductive health; unexplained infertility; vascular endothelial growth factor (VEGF)

DOI:  https://doi.org/10.3390/ijms26199499