bims-simsho Biomed News
on Systems immunology and sex hormones
Issue of 2025–11–30
38 papers selected by
Chun-Chi Chang, Lunds universitet
  1. Elevated tumor-associated androgen receptor activity correlates with poor immune infiltration and immunotherapy response across cancer types.
  2. Profiling NK cell receptor repertoire of women with idiopathic recurrent pregnancy loss.
  3. Vaginal epithelial estrogen receptor α coordinates glycogen deposition, microbial stability, and pH regulation in mice.
  4. Islet-intrinsic sex differences in inflammatory signaling contribute to autoimmune diabetes susceptibility.
  5. The role of sex steroids in the human gut microbiome.
  6. Ablation of microglial estrogen receptor alpha predisposes to diet-induced obesity in male mice.
  7. Estrogen Receptor May Play Important Role in Gender Differences of Early-Onset Colorectal Cancer.
  8. Microglial estrogen receptor 1 signal designates sexual dimorphism of AQP4 antibody-induced neuroinflammation and demyelination.
  9. Whole-genome profiling of age- and sex-associated DNA methylation signatures in human plasma cell-free DNA.
  10. Profiling muscle mass, function and molecular signalling in females aged 18-80 years and their associations with sex hormones.
  11. New Frontier in Cancer Immunotherapy: Sexual Dimorphism of Immune Response.
  12. Sex-Specific Differences in Gut Microbial Composition and Metabolism of Jiangshan Black Pigs.
  13. Male Monocyte-Like Cells are Prone to a Senescence-Induced Pro-inflammatory State.
  14. Ticking Differently: Elucidating Sexual Dimorphism in Human Aging through Metabolomics, Proteomics and Genomics.
  15. Acetylation reader BRD4-driven TXNIP transcription enhances NLRP3 inflammasome activation in PCOS.
  16. Sex-specific thermoregulatory effects of estrogen signaling in Reprimo lineage cells.
  17. Proteome-Based Plasma Biomarkers for Cognitive Dysfunction in an Androgen Deprivation Model.
  18. Gut microbiota-derived metabolites modulate Treg/Th17 balance: novel therapeutic targets in autoimmune diseases.
  19. In Vitro Fertilization Accelerates Female Reproductive Aging Through Early Ovarian Failure.
  20. Sex-Specific Subcutaneous Adipose Tissue Transcriptome in Obesity: Insights From Monozygotic Twin Pairs Discordant for BMI.
  21. Cervicovaginal microbiome alters transcriptomic and chromatin accessibility signatures across cervicovaginal epithelial barriers.
  22. Mechanisms of sex differences in acute and long COVID sequelae in mice.
  23. Immune-inflammation markers are related to hormone levels in polycystic ovary syndrome: a case-control study : Immune-inflammatory markers in PCOS.
  24. Gut-Immune Interplay: Decoding the Microbiome's Impact on Immunity and Diseases.
  25. Multimodal Integration of Genomic Data Reveals Regulatory Mechanisms at the Polycystic Ovary Syndrome (PCOS)-Associated 12q13.2 Locus.
  26. Gonadocorticoids Have Different Effects on the Expression of Toll-like Receptors When Infected with Various HIV-1 Subtypes.
  27. Androgen deprivation induces distinct muscle-specific transcriptional changes to genes regulating glucose, lipid, and amino acid metabolism.
  28. Exploring Proteomic Differences in PBMCs for Sex-Specific Insights into Alzheimer's Disease.
  29. Lactobacillus iners dominates the vaginal microbiota of healthy Italian women of reproductive age.
  30. Toll-like Receptor 4 Contributes to PCOS-like Metabolic and Reproductive Pathogenesis.
  31. Integrated gut microbiome and metabolomics analysis reveals microbial-metabolic cross-talk in allergic rhinitis.
  32. Sex-specific genetic regulation of proteomics in cerebrospinal fluid uncovers genetic causes for sex differences in neurodegeneration.
  33. The sicker sex is plastic: Thermal plasticity determines sex biases in pathogen transmission.
  34. Sex-biased immune rewiring may underlie reduced risk for cardiac allograft vasculopathy in females following heart transplantation.
  35. pDCs amplify tissue-resident memory CD8+ T cell responses during viral reinfection.
  36. Mapping the landscape of cell type-dependent genetic regulation of DNA methylation across human tissues.
  37. Long noncoding RNAs and microRNAs in Endometriosis.
  38. Microbial influx during early postnatal life fortifies the ocular surface and guards against allergic eye disease in mice.
  1. Cancer Res Commun. 2025 Nov 26.
    Elevated tumor-associated androgen receptor activity correlates with poor immune infiltration and immunotherapy response across cancer types.
    Ya-Mei Hu, Faming Zhao, Julie N Graff, Canping Chen, Yi Zhang, Jayne M Stommel, Jinho Lee, Gabriel M Zangirolani, Joshua Rose, George V Thomas, Hui Wu, Adel Kardosh, Gordon B Mills, Joshi J Alumkal, Amy E Moran, Zheng Xia.
      The role of androgen receptor (AR) signaling in modulating antitumor immune responses has received increasing attention in recent years; however, its broader impact across diverse cancer types and between sexes remains largely unexplored. Here, we investigated how AR activity correlates with tumor-infiltrating leukocytes, patient prognosis, and immunotherapy response across cancers and sexes. We inferred AR activity using a network-based approach across bulk RNA-seq (TCGA), single-cell RNA-seq (prostate cancer meta-atlas), and immunotherapy cohorts. Pathway analysis and Cox regression assessed mechanisms and survival. Immune infiltration and signatures were evaluated via TIMER and ssGSEA. Key findings were validated using Digital Spatial Profiling and immunohistochemistry. Our pan-cancer analysis of 33 TCGA cancer types revealed broad variability in AR activity, highest in prostate adenocarcinoma. Genes significantly correlated with AR activity show negative associations and are enriched in immune activation pathways. Notably, AR activity inversely correlated with leukocyte abundance and IFN-γ pathway activity across tumors and sexes-unlike estrogen or progesterone receptors. Longitudinal biopsy analysis in metastatic prostate cancer showed AR inhibition enhanced immune cell and IFN-γ signatures. Single-cell analysis confirmed that tumor-intrinsic AR activity inversely correlates with immune infiltration in prostate cancer. Furthermore, low AR activity is significantly associated with favorable immunotherapy responses in hormone-independent cohorts. Spatial proteomics showed a negative correlation between AR and CD45 protein in sarcoma and ovarian cancers. These findings suggest AR activity as a pan-cancer predictive biomarker of immunotherapy response and support that AR blockade in immunotherapy-refractory tumors represents a promising treatment strategy, regardless of tumor type or patient sex.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0409
  2. J Reprod Immunol. 2025 Nov 19. pii: S0165-0378(25)00381-X. [Epub ahead of print]173 104803
    Profiling NK cell receptor repertoire of women with idiopathic recurrent pregnancy loss.
    Aysel Gurbanova, Dorien Feyaerts, Marilen Benner, Tess Meuleman, Marie-Louise van der Hoorn, Irma Joosten, Lotte Wieten, Marien I de Jonge, Renate G van der Molen.
      Natural killer (NK) cells have been extensively studied to understand the pathophysiology of idiopathic recurrent pregnancy loss (iRPL), however a clear association between NK cell frequency and iRPL has yet to be established. Most studies have focused on peripheral NK (pNK) cells, which may not accurately reflect the uterine immune environment. This study aimed to investigate the receptor repertoire of uterine NK (uNK) cells derived from menstrual blood in women with iRPL (n = 20) and compare it to controls with uncomplicated pregnancies (n = 16). The uNK cell receptor analysis revealed a significant reduction in the expression intensities of 2B4 and NKp44 on several uNK cell clusters in women with iRPL. In addition, stratification by cytomegalovirus (CMV) seropositivity revealed that CMV-positive women had significantly higher NKp44 expression on uNK cells and frequencies of NKG2A+KIRs+LILRB1+NKG2C- uNK cells (10.3 % vs. 4.2 %, p = 0.025) compared to CMV-negative women. Surprisingly, this population was lowest in women with primary iRPL compared to secondary iRPL and control subjects (2.6 % vs. 8.6 %, 12.8 %, p = 0.005). These findings highlight differences in uNK cell receptor repertoire of women with iRPL and indicate that live birth history and CMV seropositivity influence uNK cells.
    Keywords:  CMV; Idiopathic recurrent pregnancy loss; Live birth; Menstrual blood; NK cell receptors; Natural killer (NK) cells; Primary iRPL; Secondary iRPL
    DOI:  https://doi.org/10.1016/j.jri.2025.104803
  3. bioRxiv. 2025 Oct 30. pii: 2025.10.29.685365. [Epub ahead of print]
    Vaginal epithelial estrogen receptor α coordinates glycogen deposition, microbial stability, and pH regulation in mice.
    Srinivasan Mahalingam, Erin M Carulli, Jiude Mao, Kalli K Stephens, Jeffery A Erickson, Wipawee Winuthayanon.
      Estrogen plays a central role in regulating the vaginal environment, but the specific contribution of epithelial estrogen receptor α (ESR1) to microbial and biochemical homeostasis has not been fully defined. In our previous work, we showed that epithelial ESR1 is indispensable for estrogen-induced epithelial proliferation, cornification, and MUC1 expression. Here, using mice with conditional deletion of Esr1 in vaginal epithelial cells, called epithelial Esr1 d/d , we extend these findings to demonstrate that epithelial ESR1 also regulates glycogen deposition, luminal pH, and microbial stability. Compared to control littermates, epithelial Esr1 d/d mice reduced glycogen abundance, elevated vaginal pH, and a compositional shift in the vaginal microbiome, marked by enrichment of Comamonadaceae and loss of Lactobacillus species, without significant differences in alpha diversity. These changes parallel features of postmenopausal dysbiosis in women. Together, our findings identify epithelial ESR1 as a master regulator of multiple pathways that sustain vaginal homeostasis, integrating epithelial metabolism, barrier function, and host-microbe interactions. This work provides a mechanistic framework to understand postmenopausal vaginal dysbiosis and suggests epithelial estrogen signaling as a potential therapeutic target for genitourinary syndrome of menopause.
    Significance Statement: The vaginal environment is essential for reproductive and gynecologic health, yet the mechanisms by which estrogen shapes this niche remain incompletely understood. We show that epithelial estrogen receptor α (ESR1) regulates glycogen deposition, luminal pH, and microbial composition in the murine vagina. Loss of epithelial ESR1 reduced glycogen and increased luminal pH without altering overall microbial diversity, but shifted community structure toward enrichment of Comamonadaceae , a family associated with neutral to mildly alkaline environments. These findings identify epithelial ESR1 as a key regulator of the metabolic and physicochemical conditions that maintain vaginal microbial balance and provide a mechanistic framework for understanding postmenopausal dysbiosis.
    DOI:  https://doi.org/10.1101/2025.10.29.685365
  4. bioRxiv. 2025 Oct 07. pii: 2025.10.06.680429. [Epub ahead of print]
    Islet-intrinsic sex differences in inflammatory signaling contribute to autoimmune diabetes susceptibility.
    Kierstin L Webster, Armando A Puente, Jacob R Enriquez, Soumyadeep Sarkar, Ernesto S Nakayasu, Bobbie-Jo M Webb-Robertson, Lisa M Bramer, Kayla Figatner, Sarida Pratuangtham, Wenting Wu, Carmella Evans-Molina, Hubert M Tse, Saptarshi Roy, Jon D Piganelli, Stephen R Hammes, Sarah A Tersey, Raghavendra G Mirmira.
      Whereas most autoimmune diseases exhibit female predominance, type 1 diabetes (T1D) occurs more frequently in males after puberty, suggesting a role for sex hormones in disease modification. Because islet β cells actively shape local immune responses, we hypothesized that sex-specific islet responses to inflammation contribute to this disparity. Using transcriptomic and proteomic analyses of human islets from male and female donors, we found that male islets exhibit a more aggressive response to proinflammatory cytokines, characterized by greater induction of interferon signaling and suppression of developmental signaling compared to female islets. Treatment of human islets and mouse β cells with the sex hormone 17β-estradiol (E2) suppressed inflammatory signaling and markers of β-cell maturity while enhancing developmental gene programs. Complementary studies in non-obese diabetic (NOD) mice showed that E2 treatment reduces diabetes incidence and limits progression to severe insulitis. Islet single-cell RNA sequencing revealed that E2 treatment of NOD mice suppresses interferon signaling, chemokine production, and antigen presentation in β cells, while reducing activation and cytotoxicity pathways in immune cells. In co-culture studies in vitro, E2 pretreatment of mouse islets reduces subsequent activation of T cells, and in an aggressive adoptive transfer model in vivo, E2 pretreatment of the recipient mice was found to attenuate hyperglycemia. These findings support a model in which E2-mediated β-cell reprogramming reduces β-cell immunogenicity and promotes local immune tolerance, offering mechanistic insight into sex-biased T1D susceptibility.
    DOI:  https://doi.org/10.1101/2025.10.06.680429
  5. Curr Opin Pediatr. 2025 Nov 20.
    The role of sex steroids in the human gut microbiome.
    Gianvincenzo Zuccotti, Valeria Calcaterra.
       PURPOSE OF REVIEW: Sex steroid hormones and the gut microbiome are increasingly recognized as bidirectionally interacting regulators of growth, metabolism, and endocrine maturation. While most research has focused on adults, accumulating evidence indicates that these interactions are established early in life and influence pubertal timing, metabolic homeostasis, and neuroendocrine development. This review synthesizes current human evidence on microbiome-sex steroid relationships across childhood and adolescence, highlighting mechanistic insights and clinical implications for pediatric endocrinology.
    RECENT FINDINGS: Gut microbes modulate steroid hormone metabolism through enzymatic deconjugation and enterohepatic circulation, while pubertal hormonal shifts reciprocally influence microbial diversity and function. Early-life dysbiosis linked to antibiotics, diet, or obesity may alter hypothalamic-pituitary-gonadal activity. Microbial metabolites such as short-chain fatty acids, bile acids, and tryptophan derivatives regulate immune, metabolic, and neuroendocrine pathways, affecting growth and insulin sensitivity. Disruptions of this microbiome-hormone axis are implicated in pubertal timing disorders, metabolic dysfunction, polycystic ovary syndrome (PCOS), and inflammatory intestinal diseases, whereas fiber-rich diets and probiotics may help restore balance.
    SUMMARY: The microbiome-sex steroid axis constitutes a fundamental component of pediatric endocrine development. Understanding this bidirectional relationship provides a framework for microbiome-informed strategies aimed at preventing and managing pubertal, metabolic, and neuroendocrine disorders during childhood and adolescence.
    Keywords:  endocrine regulation; estrobolome; gut microbiome; personalized medicine; sex steroids
    DOI:  https://doi.org/10.1097/MOP.0000000000001527
  6. bioRxiv. 2025 Nov 05. pii: 2025.11.03.685977. [Epub ahead of print]
    Ablation of microglial estrogen receptor alpha predisposes to diet-induced obesity in male mice.
    Inmaculada Velasco, Jeremy M Frey, Vladislav Baglaev, Tristan Jafari, Thomas Huang, Sophia Schwie, Olivia D Santiago, Rachael D Fasnacht, Joshua P Thaler, Mauricio D Dorfman.
      Estrogen receptor alpha (ERα) signaling has metabolic and anti-inflammatory properties in addition to its impact on reproductive function. In male but not female mice, inflammatory activation of microglia, the resident macrophages of the brain, has been implicated in the pathogenesis of diet-induced obesity (DIO), raising the possibility that differences in microglial estrogen signaling may account for the sexual dimorphism. In this study, we assessed metabolic and CNS histopathological properties in a mouse model with inducible microglia-specific ablation of ERα (MG-ERαKO). Male MG-ERαKO mice developed increased weight gain and insulin resistance relative to controls during high-fat diet (HFD) feeding. Indirect calorimetry analysis revealed that reduced energy expenditure was the main driver of the obese phenotype. In contrast, female MG-ERαKO mice fed HFD developed mild insulin resistance with no change in body weight gain compared to controls. Immunohistochemical analyses of the microglial activation marker IBA1 in the mediobasal hypothalamus (MBH) revealed that female MG-ERαKO mice had increased number of microglia without showing morphological signs of activation. In contrast, MBH microglial number was unchanged in MG-ERαKO male mice, but the cells adopted more activated morphological profiles. Finally, HFD-fed MG-ERαKO male mice had increased POMC neuron-microglia interactions but fewer overall hypothalamic POMC neurons, suggesting microglia may disrupt POMC neuron integrity to promote DIO. Together, these findings indicate that sex-specific actions of estrogen in microglia limit the metabolic complications of HFD feeding.
    DOI:  https://doi.org/10.1101/2025.11.03.685977
  7. Clin Colorectal Cancer. 2025 Nov 01. pii: S1533-0028(25)00087-8. [Epub ahead of print]
    Estrogen Receptor May Play Important Role in Gender Differences of Early-Onset Colorectal Cancer.
    Qian-Nan Wang, Xiao Zhang, Lan-Lan Feng, Na Ning, Fu-Qin Zhang, Jia-Min Liang, Wei Zhang, Li Gong.
       BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC) is increasing year by year. However, it is still unclear and controversial whether there is a significant gender difference. Our aims to investigate the clinicopathological characteristics of EOCRC, especially gender differences, and their correlation with the expression of estrogen receptor (ER), so as to provide a scientific basis for optimizing the early screening and treatment strategy of EOCRC.
    METHODS: All surgical specimens of CRC were collected from January 2015 to July 2024. Then, the clinicopathological characteristics were analyzed between EOCRC and late-onset CRC (LOCRC). Simultaneously, the expression of ER was investigated in EOCRC by RT-PCR and immunohistochemical staining.
    RESULTS: A total of 3041 CRC cases were analyzed in this study, which included 485 EOCRC and 2556 LOCRC cases. Specifically, EOCRC had significant differences in gender (P = .0356), deficient mismatch repair (dMMR) status (P = .0029), and lymph node metastases (P = .0425) compared with LOCRC. Simultaneously, in EOCRC, males were more susceptible to colon cancer (P = .0009) and dMMR status (P = .0365) compared with females. Moreover, the variation of dMMR status was related to the absence of genetic history of disease (P = .0034). Totally, the expression of ER mRNA was higher in female CRC than that in male one (P = .0009), which was also in EOCRC (P = .0092). In addition, its expression was higher in LOCRC (P = .0056) and female LOCRC with dMMR (dLOF) (P = .0341) than that in EOCRC and female EOCRC with dMMR (dEOF). Further analysis showed that the expression of ER mRNA was significantly higher in male LOCRC (LOM) (P = .0305), LOCRC with dMMR (dLO) (P = .0030), male LOCRC with dMMR (dLOM) (P = .0275), and sporadic LOM (dLOM-s) (P = .0274) than that in their corresponding male EOCRC (EOM), EOCRC with dMMR (dEO), male EOCRC with dMMR (dEOM), and sporadic dEOM (dEOM-s) in turn, but there was no significant difference in proficient MMR (pMMR) (P = .6046).
    CONCLUSIONS: There were significant differences in the clinicopathological features and sex hormone expression in EOCRC with different genders, suggesting that gender may be an independent factor in clinical classification of EOCRC.
    Keywords:  Androgen receptor; Early-age onset; Female; Male; Microsatellite instability
    DOI:  https://doi.org/10.1016/j.clcc.2025.10.008
  8. Cell Rep. 2025 Nov 26. pii: S2211-1247(25)01408-1. [Epub ahead of print]44(12): 116636
    Microglial estrogen receptor 1 signal designates sexual dimorphism of AQP4 antibody-induced neuroinflammation and demyelination.
    Zhijie Zhou, Zhangyuzi Deng, Yingying Huang, Jian Chen, Jing Yang, Ying Cao.
      Neuromyelitis optica spectrum disorder, often linked to autoimmune antibodies against aquaporin-4 (AQP4), is a demyelinating disease exhibiting a profound sex bias in female patients. However, the pathophysiological mechanism underlying this clinical manifestation remains to be better understood. In this study, we observe a higher extent of neuroinflammation and demyelination in female mice than in males with the AQP4 antibody-induced disease model. Of importance is that sex hormone depletion in ovariectomized female mice is sufficient to mitigate the disease severity, while estradiol replacement in castrated male mice exacerbates these neuropathological features. We then demonstrate that microglia predominantly express estrogen receptor 1 (Esr1) and that specific deletion of Esr1 inhibits microglia-mediated neuroinflammation and reduces demyelination. Moreover, the administration of fulvestrant, a clinically approved estrogen receptor antagonist, can effectively ameliorate the mouse disease model. These results have elucidated a critical, proinflammatory role of the microglial Esr1 signal in AQP4 antibody-induced neuroinflammation and demyelination with clinical implications.
    Keywords:  CP: immunology; CP: neuroscience:; estrogen receptor 1; fulvestrant; microglia; neuromyelitis optica spectrum disorder; sexual dimorphism
    DOI:  https://doi.org/10.1016/j.celrep.2025.116636
  9. Commun Med (Lond). 2025 Nov 28. 5(1): 503
    Whole-genome profiling of age- and sex-associated DNA methylation signatures in human plasma cell-free DNA.
    Wei Chen, Jinjin Xu, Guodan Zeng, Rijing Ou, Changlin Yang, Chuang Xu, Yeqin Wang, Xinxin Wang, Qiuyan Li, Chenhui Zhao, Wenwen Zhou, Yu Lin, Wending Pang, Haiqiang Zhang, Jianhua Yin, Yan Zhang, Xin Jin.
       BACKGROUND: Age and sex significantly impact DNA methylation patterns, however, existing datasets typically include only a subset of methylation sites in the human genome, hindering our thorough understanding.
    METHODS: We recruited 98 generally healthy adults aged from 22 to 77 and investigated the effects of age and sex on plasma cell-free DNA (cfDNA) methylation through whole-genome bisulfite sequencing (WGBS) and association analysis.
    RESULTS: Here we show 3,047 age-associated and 1,053 sex-associated CpGs on autosomes, corresponding to 1,587 and 324 genes, respectively. To the best of our knowledge, many of these CpGs are newly discovered to be age- and sex-related at the DNA methylation level. The discovered sex-differential cfDNA methylation patterns on the X chromosome are related to XCI status. Besides, a cfDNA epigenetic clock comprising 125 CpGs is developed, demonstrating relatively high accuracy in predicting chronological age. Tissue-of-origin analysis reveals that cfDNA derived from monocytes/macrophages, granulocytes, and hepatocytes is associated with age and sex. Several individuals with abnormal cfDNA proportions of some specific cell types are found to have individual health problems.
    CONCLUSIONS: Our discovered CpGs and genes help to explain age-related and sex-biased diseases such as psychiatric disorders, diabetes, and autoimmune diseases, and we demonstrate the potential of cfDNA methylation signatures as very promising biomarkers for health monitoring for the general population.
    DOI:  https://doi.org/10.1038/s43856-025-01220-y
  10. J Physiol. 2025 Nov 23.
    Profiling muscle mass, function and molecular signalling in females aged 18-80 years and their associations with sex hormones.
    Annabel J Critchlow, Danielle Hiam, Steven J O'Bryan, Ross M Williams, Megan Soria, Viktor Engman, Karel Van Belleghem, Ross P Wohlgemuth, Andrew Garnham, Christopher S Fry, David Scott, Séverine Lamon.
      Whether and how ovarian hormone fluctuations mediate the skeletal muscle response to ageing in females remains to be elucidated. We examined a tightly controlled, cross-sectional cohort of 96 females 18-80 years of age to map the functional and molecular trajectory of muscle ageing and determine its relationship with female sex hormones. Across every decade, we quantified body composition (using dual-energy X-ray absorptiometry), muscle morphology (using peripheral quantitative computed tomography), and voluntary and evoked muscle function. Circulating sex hormone concentrations were measured with GC-MS and immunoassays. Morphology and gene expression of vastus lateralis muscle samples were assessed with immunohistochemical staining and RNA sequencing, respectively. Age was negatively associated with muscle mass, strength and muscle fibre size, and positively associated with hybrid type I/IIa fibre prevalence and fibrosis. We found 37 unique patterns of gene expression across individual decades of age. Immune signalling, cellular adhesion and extracellular matrix organization pathways were the most upregulated with age, whilst mitochondrial function pathways were the most downregulated. Independently of age, circulating oestradiol and progesterone, but not testosterone, concentrations were positively associated with lean mass and negatively associated with hybrid muscle fibres across the lifespan. Oestrogen receptor binding sites were significantly enriched in upregulated genes in pre- versus post-menopausal muscle, suggesting a reduction in the translation of oestrogen target genes after menopause. Altogether, sex hormone fluctuations across the female lifespan may contribute to age-related muscle wasting, although longitudinal and interventional studies are needed to determine the causal nature of the relationship. KEY POINTS: Females live longer than males but experience worse disability in the later decades of life, highlighting the need to study female-specific patterns of ageing. This study mapped female body composition, muscle morphology, function and gene expression across every decade from 18 to 80 years of age in tightly controlled conditions and examined the relationships with circulating sex hormones. Unique patterns of muscle gene expression across ageing showed an overall increase in immune signalling and a decrease in mitochondrial respiration pathways, but limited associations with circulating sex hormones. Independently of age, circulating oestradiol and progesterone, but not testosterone, were associated with muscle mass and morphology across the lifespan, after adjusting for influential lifestyle factors (protein intake and physical activity). Fluctuations in female sex hormones across the lifespan should be considered when developing therapies to mitigate age-related muscle wasting and improve the female health span.
    Keywords:  ageing; female; gene expression; sex hormones; skeletal muscle
    DOI:  https://doi.org/10.1113/JP289765
  11. Metabolites. 2025 Oct 23. pii: 686. [Epub ahead of print]15(11):
    New Frontier in Cancer Immunotherapy: Sexual Dimorphism of Immune Response.
    Nadeem Bilani, Nicole Charbel, Joe Rizkallah, Sam Sater, Firas Kreidieh.
      Sexual dimorphism influences immune responses, cancer progression, and therapeutic outcomes, yet its metabolic underpinnings remain underexplored. Metabolomics enables the comprehensive profiling of biochemical pathways that shape sex-based differences in immune function and immunotherapy efficacy. Meta-analytic data indicate that men achieve a larger overall survival benefit from immune checkpoint inhibitors than women (pooled hazard ratio 0.72, 95% CI 0.65-0.79 vs. 0.86, 95% CI 0.79-0.93), while women may experience higher major pathologic response rates in neoadjuvant settings. At the biomarker level, elevated kynurenine-to-tryptophan ratios-reflecting indoleamine 2,3-dioxygenase activity-and distinct lipidomic signatures associate with reduced immunotherapy efficacy and may vary by sex. Sex-specific differences in microbiome-derived metabolites, including short-chain fatty acids, further modulate systemic immunity and treatment response. Ongoing clinical investigations combine hormone modulation with immune checkpoint blockade and increasingly integrate metabolomic profiling to identify predictors of benefit and toxicity. This review will synthesize meta-analytic and mechanistic evidence on sex differences in immunotherapy outcomes, highlight metabolomic biomarkers linked to response, and summarize ongoing clinical trials that incorporate metabolomics to guide sex-aware precision oncology. Understanding sex-specific metabolic pathways can refine patient stratification and optimize immunotherapeutic strategies.
    Keywords:  cancer immunotherapy; immune checkpoint inhibitors; immunometabolism; metabolic biomarkers; metabolomics; precision medicine; sex hormones; sex-based differences; sexual dimorphism; tumor microenvironment
    DOI:  https://doi.org/10.3390/metabo15110686
  12. Microorganisms. 2025 Nov 07. pii: 2551. [Epub ahead of print]13(11):
    Sex-Specific Differences in Gut Microbial Composition and Metabolism of Jiangshan Black Pigs.
    Yanan Zhang, Xian Wu, Dan Song, Panlin Wang, Haifeng Wang, Xiangchen Li.
      The gut microbiota plays a vital role in regulating the host's physiological functions, including metabolism and immunity. The microbial composition and metabolism are modulated by multiple factors; host sex is an important yet under-explored determinant. To investigate the sex-dependent differences in the gut microbiota within the small and large intestine, sixteen somatic mature Jiangshan black pigs (eight males and eight females) were analyzed. The ileal and colonic microbial community and metabolites were profiled using 16S rRNA gene high-throughput sequencing and gas chromatography. Distinct sex-related discrepancies were observed in both the microbial composition and metabolism of the ileum and colon. In the ileum, compared with the male group, the female group exhibited higher abundances of Unclassified Chloroplast and Pseudomonas but a lower abundance of Romboutsia (adjusted p < 0.05). Functional prediction indicated enrichment in amino acid metabolism pathway in females, with more copy numbers of genes encoding key enzymes for propionate (mmdA) generation and elevated valerate levels (p < 0.05). In the colon, compared with the male group, the female group showed higher abundances of Streptococcus, Phascolarctobacterium, and Prevotella spp. and lower abundances of Eubacterium coprostano-ligenes group, Blautia, Christensenellaceae R-7 group, and Ruminococcus (adjusted p < 0.05). Additionally, the female group had more copies of genes mmdA and LcdA (associated with lactate production), along with higher concentrations of propionate and lactate (p < 0.05). Correlation analysis between microbial metabolites and sex-biased bacteria further revealed that the SCFA concentration positively correlated with Prevotella spp. and negatively correlated with Romboutsia, Christensenellaceae R-7 group, and Blautia. Collectively, these findings highlight the pronounced sex-dependent discrepancies in the microbial composition and metabolism within the small and large intestines of Jiangshan black pigs, providing new insights for precisely modulating the microbiota community and metabolism in pigs according to sex.
    Keywords:  Jiangshan black pig; gut microbiota; microbial function; microbial metabolism; sex discrepancy
    DOI:  https://doi.org/10.3390/microorganisms13112551
  13. Aging Dis. 2025 Nov 21.
    Male Monocyte-Like Cells are Prone to a Senescence-Induced Pro-inflammatory State.
    Luan Hernando Samit, Julia Temp, Irene Algarra Flores, Olesya Vakhrusheva, Yury Ladilov, Maria Luisa Barcena.
      Chronic systemic inflammation in the elderly is a hallmark of aging and a major contributor to age-related diseases. It both results from and promotes the accumulation of senescent immune cells. While the sex difference in the aging process has been widely studied, the impact of cellular sex on immune cell senescence remains unclear and was the focus of this present study. Senescence was induced in human male (THP-1) and female (HL-60) monocyte-like cells by treatment with D-galactose for 48 h. The expression of metabolic sensors (Sirt1 and pAMPK), mitochondrial biogenesis and respiration, reactive oxygen species formation, as well as pro-inflammatory markers was investigated alongside senescence markers. Treatment with D-galactose resulted in significant reduction of the nuclear proteins HMGB1 and lamin B1, and an upregulation of senescence-associated secretory phenotype factors including IL-6, VEGF, TGF-β, and MMP-9, in male and female cells. The expression of the metabolic sensors Sirt1 and pAMPK was reduced, whereas mitochondrial ROS production and mitochondrial gene expression were elevated in both male and female cells to a similar extent. In contrast, D-Galactose-induced senescence was accompanied by a significant elevation of pro-inflammatory markers (NF-κB, TNF-α, IL-1β, HLA-DR, and MCP-1) primarily in male monocytes, whereas primary monocytes did not display sex differences. This study suggests that male immune cells are more prone to developing a pro-inflammatory state under senescent stimuli. These findings highlight the potential significance of sex-specific anti-inflammatory therapies.
    DOI:  https://doi.org/10.14336/AD.2025.0871
  14. medRxiv. 2025 Oct 31. pii: 2025.10.30.25339071. [Epub ahead of print]
    Ticking Differently: Elucidating Sexual Dimorphism in Human Aging through Metabolomics, Proteomics and Genomics.
    Sihao Xiao, Pallavi Kaushik, Gaoyu Du, Bowen Liu, Salman B Hosawi, Benoit Hastoy, M Austin Argentieri, Laura M Winchester, Alejo J Nevado-Holgado, Rima Kaddurah-Daouk, Najaf Amin, Cornelia van Duijn.
      That males and females age differently has been overlooked while developing aging clocks. Here, we developed a sex-specific metabolic aging clock in 390,941 individuals from the UK Biobank and integrated it with genetic, proteomic and epidemiological data to identify mechanisms accelerating/decelerating metabolic aging in males and females. Our findings reveal dysregulation of cholesterol metabolism, immune system, hemostasis, and cell growth, survival and apoptosis as common mechanisms accelerating metabolic aging in males and females, and upregulation of oxidative stress detoxification, cellular resilience and tissue integrity as common mechanisms decelerating metabolic aging. In females, a further dysregulation of carbohydrate/glucose metabolism, circadian rhythm and hormone metabolism accelerating metabolic aging is observed, while dysregulation of energy metabolism, cancer and longevity pathway is specifically observed in males. Among reproductive factors, late puberty and higher parity manifest as protective factors, decelerating metabolic aging in both sexes, and additionally childbirth at older age decelerating metabolic aging in women. Accelerated metabolic age strongly predicted morbidity and mortality in both sexes, except that the magnitude of association was several folds higher in males, and obesity explained most of the disease associations in females, suggesting that obesity influences metabolic aging and subsequent health outcomes differently in males and females. Consistent with the upregulation of molecular mechanisms involved in cancer in males, accelerated metabolic aging predicted several common cancers in males but not females. Our study provides novel insights into the biological mechanisms underlying aging and disease susceptibility in males and females, underscoring the importance of considering sex differences in healthcare strategies and public health policies.
    DOI:  https://doi.org/10.1101/2025.10.30.25339071
  15. Cell Mol Life Sci. 2025 Nov 26. 82(1): 427
    Acetylation reader BRD4-driven TXNIP transcription enhances NLRP3 inflammasome activation in PCOS.
    Yajing Weng, Yi Zhang, Wei Dong, Zhengquan Zhu, Zou Xiang, Guijun Yan, Hongwei Wang, Yanting Wen, Min Liu, Daojuan Wang, Yong Wang.
      Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by the developmental arrest and dysfunction of ovarian granulosa cells (GCs), serving as a major cause of infertility among women of reproductive age. Persistent activation of thioredoxin-interacting protein (TXNIP) due to aberrant histone acetylation modifications of transcription is a potential trigger; however, its precise upstream regulatory mechanism remains poorly understood. In this study, we found that TXNIP was aberrantly upregulated in both the dehydroepiandrosterone (DHEA)-induced PCOS-like rat model and the dihydrotestosterone (DHT)-induced primary GCs PCOS-like model in vitro. The TXNIP/NLRP3 inhibitor ruscogenin and the small interfering RNA (siRNA) targeting TXNIP remarkably inhibited NLRP3 inflammasome activation, subsequently reversing aberrant reproductive and metabolic phenotypes in PCOS-like models. Further bioinformatic analysis revealed that the promoter region of TXNIP contains binding motifs of bromodomain-containing protein 4 (BRD4) and androgen receptor (AR). BRD4 and AR exhibited inducible binding to the histone H3 acetylation-enriched TXNIP promoter, whereas intervention with the BRD4-selective inhibitor JQ1 and the AR-selective inhibitor attenuated this binding, leading to subsequent downregulation of TXNIP transcription that ultimately resulted in NLRP3 inflammasome suppression. Our data indicate that BRD4 upregulation and the resultant TXNIP transcriptional activation are crucial regulatory pathways for NLRP3 inflammasome activation, resulting in associated reproductive and metabolic abnormalities in ovarian GCs from PCOS.
    Keywords:  Androgen receptor; Bromodomain-containing protein 4; NLRP3 inflammasome; Polycystic ovary syndrome; Thioredoxin-interacting protein
    DOI:  https://doi.org/10.1007/s00018-025-05925-0
  16. Endocrinology. 2025 Nov 28. pii: bqaf177. [Epub ahead of print]
    Sex-specific thermoregulatory effects of estrogen signaling in Reprimo lineage cells.
    Jae W Park, Laura R Cortes, Norma P Sandoval, Adriana R Vree, Alejandra G Baron, Kelly Vranich, Higor J Fideles, Rosalizbeth M Martinez, Elizabeth A Dilday, Mia R Hansen, Weronika Budek, Julissa I Lopez, Laura G Kammel, J Edward van Veen, Stephanie M Correa.
      Estrogens have considerable impact on energy homeostasis and metabolic health. In mice, signaling through estrogen receptor alpha (ERα) alters energy intake and expenditure, effects that may be mediated by specific regions or cellular sub-populations of the hypothalamus. This study investigates the function of ERα signaling in the lineage that expresses Rprm (Reprimo), a gene we previously linked to thermoregulation in females. Here, we engineered a novel ReprimoCre mouse to selectively knock out ERα in Rprm lineage cells (Reprimo-specific ERα KO; RERKO). We report modest changes in core temperature, higher brown adipose tissue (BAT) mass, elevated BAT temperature during the light phase, and lower tail temperature during the light phase in females relative to controls. RERKO females also exhibited a subtle difference in locomotion and no differences in feeding or body mass. These phenotypes suggest sex-specific effects on the patterns of body temperature instead of overall increases or decreases in heat generation or dissipation. Labeling of the Rprm lineage was detected in the brain, but not in BAT or white adipose, suggesting that temperature changes may be mediated by the nervous system. To test for centrally mediated effects on temperature, we ablated Rprm expressing cells in the mediobasal hypothalamus. Although this approach eliminates the cells entirely instead of selectively eliminating ERα in Rprm expressing cells, we observed a phenotype similar to RERKO mice, with effects on core temperature and BAT mass. Together, these results indicate that estrogen signaling in the Rprm lineage is important for thermoregulation in female, but not male, mice.
    Keywords:   Reprimo ; Estrogen receptor alpha; energy expenditure; hypothalamus; metabolism; thermogenesis
    DOI:  https://doi.org/10.1210/endocr/bqaf177
  17. Mol Neurobiol. 2025 Nov 28. 63(1): 201
    Proteome-Based Plasma Biomarkers for Cognitive Dysfunction in an Androgen Deprivation Model.
    Vaibhav Singh, Shiv Verma, Eswar Shankar, Diya Swain, Belinda B Willard, Herta H Chao, Chiang-Shan R Li, Zhenghong Lee, Gregory T MacLennan, Lee E Ponsky, Sanjay Gupta.
      Cognitive dysfunction frequently arises from androgen deprivation therapy (ADT), a primary treatment for men with prostate cancer. ADT affects key cognitive functions like memory, learning, reasoning, and decision-making. Extant studies lack a systematic evaluation of biomarkers related to ADT's cognitive impact. To address this, we used nano-liquid chromatography tandem mass spectrometry (nLC-MS/MS) to identify biomarkers in specific brain regions of a mouse model. Sixteen-week-old BALB/c mice received enzalutamide, a nonsteroidal antiandrogen, at 50 mg/kg/day via oral gavage 5 days a week for 8 weeks to simulate the ADT protocol. Control mice received a comparable volume of the vehicle. Enzalutamide treatment resulted in modest weight gain along with behavioral changes, including attention deficits and reduced social activity. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) showed altered glucose metabolism in the brain and peripheral tissues of treated mice. Histological analysis of brain sections revealed preserved neuron structure in control mice, whereas enzalutamide-treated mice showed decreased neuron density, signs of neuron damage, and astrocyte swelling. Proteomic analysis of the cortex, cerebellum, and hippocampus after euthanasia identified 29 proteins with altered expression linked to cognitive dysfunction in ADT-treated mice. Further validation showed significantly increased levels of Pum2, Mcur1, Slc39a14, Fbxo7, Myo10, Arl6ip1, Slc8a3, Mt1, and Mt3 in the blood plasma of treated mice compared to controls. These results suggest that blood could be a valuable source of biomarkers for ADT-induced cognitive dysfunction. Further studies are needed to assess their clinical applicability in monitoring cognitive decline in prostate cancer patients on ADT and in neurotypical aging.
    Keywords:  Androgen deprivation therapy; Androgen receptor; Cognitive dysfunction; Enzalutamide; Proteomics
    DOI:  https://doi.org/10.1007/s12035-025-05548-3
  18. Front Immunol. 2025 ;16 1710733
    Gut microbiota-derived metabolites modulate Treg/Th17 balance: novel therapeutic targets in autoimmune diseases.
    Guolin Li, Yu Xiong, Zhimin Li, Qin Yu, Shiran Li, Jingxian Xie, Siyu Zeng, Dongke Yu, Yong Yang, Jiangping Yu.
      Dysregulation of the homeostasis between regulatory T cell (Treg) and T helper 17 cell (Th17) is increasingly recognized as a pivotal mechanism in the pathogenesis of autoimmune diseases. Emerging evidence indicates that gut microbiota-derived metabolites, including short-chain fatty acids, secondary bile acids, and aromatic metabolites, modulate Treg/Th17 balance by shaping immune cell differentiation and function, thereby revealing novel therapeutic opportunities. This Review synthesizes recent clinical and preclinical findings on the influence of microbial communities and their metabolites on Treg/Th17 dynamics and examines the underlying mechanisms in representative autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, Graves' disease, autoimmune hepatitis, and myasthenia gravis. We critically evaluate current microbiome-targeted interventions and discuss their translational potential, highlighting both promises and challenges. Finally, we outline priorities for future research, focusing on multi-omic integration, the development of individualized therapeutic strategies, and rigorous clinical evaluation, to facilitate the development of safe and effective microbiota-based therapies for autoimmune diseases.
    Keywords:  Treg/Th17 balance; autoimmune diseases; gut microbiota; immune regulation; microbial metabolites; therapeutic targets
    DOI:  https://doi.org/10.3389/fimmu.2025.1710733
  19. bioRxiv. 2025 Oct 14. pii: 2025.10.13.682153. [Epub ahead of print]
    In Vitro Fertilization Accelerates Female Reproductive Aging Through Early Ovarian Failure.
    Eric A Rhon-Calderon, Cassidy N Hemphill, Alexandra J Savage, Ana Domingo-Muelas, Zhengfeng Liu, Christopher J Krapp, Laren Riesche, Nicolas D Plachta, Richard M Schultz, Marisa S Bartolomei.
      Reproductive aging is characterized by the progressive decline of reproductive function, with broad implications for overall health and longevity. Environmental factors, including assisted reproductive technologies (ART), can accelerate reproductive aging by promoting premature ovarian failure in females. In vitro fertilization (IVF), though widely used and generally considered safe, is associated with lasting effects on offspring health. Using a mouse model that closely approximates human IVF, we demonstrate that IVF accelerates reproductive aging in female offspring by inducing premature ovarian failure. IVF-conceived females exhibit altered ovarian function, disrupted endocrine profiles, and transcriptomic and epigenetic changes consistent with premature reproductive decline. These findings reveal long-term consequences of IVF on female reproductive health and highlight the need to understand how early-life interventions influence reproductive longevity.
    DOI:  https://doi.org/10.1101/2025.10.13.682153
  20. Obesity (Silver Spring). 2025 Nov 23.
    Sex-Specific Subcutaneous Adipose Tissue Transcriptome in Obesity: Insights From Monozygotic Twin Pairs Discordant for BMI.
    Hanna Haltia, Maheswary Muniandy, Sini Heinonen, Sina Saari, Marcus Alvarez, Antti Hakkarainen, Jesper Lundbom, Juho Kuula, Per-Henrik Groop, Jaakko Kaprio, Päivi Pajukanta, Kirsi H Pietiläinen, Birgitta W van der Kolk.
       OBJECTIVE: We investigated the impact of sex on the subcutaneous adipose tissue (AT) transcriptome and its obesity-related adaptations.
    METHODS: We studied rare BMI-discordant monozygotic twin pairs (ΔBMI > 2.5 kg/m2; 21 female, 16 male pairs) to assess how sex affects AT and whole-body metabolism. AT RNA sequencing was analyzed using linear mixed modeling and pathway enrichment for: (1) sex differences in individual twins, adjusted for BMI, (2) sex-stratified effects of acquired obesity (ΔBMI between co-twins separately in females and males), (3) sex-specific effects of obesity (differences in the ΔBMI effect between sexes).
    RESULTS: (1) AT transcriptional profiles differed between sexes, associating with insulin sensitivity. (2) Sex-stratified obesity effects within pairs were stronger in females, with upregulated inflammation and downregulated mitochondrial oxidative phosphorylation; males showed increased inflammation and decreased histone modification. (3) The response to obesity was sex-specific: lower expression of genes in unsaturated fatty acid metabolism in obesity was seen in females only. Sex-specific obesity AT gene expression was associated with metabolic health, with a negative association between unsaturated fatty acid metabolism and insulin sensitivity in males only.
    CONCLUSIONS: Biological sex influences the AT transcriptome and its response to obesity, highlighting distinct molecular mechanisms that may contribute to sex-specific metabolic health.
    Keywords:  adipose tissue; monozygotic twins; obesity; sex differences; transcriptome
    DOI:  https://doi.org/10.1002/oby.70078
  21. Microbiome. 2025 Nov 25. 13(1): 238
    Cervicovaginal microbiome alters transcriptomic and chromatin accessibility signatures across cervicovaginal epithelial barriers.
    Lauren Anton, Ana G Cristancho, Briana Ferguson, Jacques Ravel, Michal A Elovitz.
       BACKGROUND: The cervicovaginal microbiome plays a critical role in women's health with microbial communities dominated by Lactobacillus species considered optimal. In contrast, the depletion of lactobacilli and the presence of a diverse array of strict and facultative anaerobes, such as Gardnerella vaginalis, have been linked with adverse reproductive outcomes. Despite these associations, the molecular mechanisms by which host-microbial interactions modulate cervical and vaginal epithelial function remains poorly understood.
    RESULTS: In this study, we used RNA sequencing to characterize the transcriptional response of cervicovaginal epithelial cells exposed to the culture supernatants of common vaginal bacteria. Our findings revealed that G. vaginalis culture supernatants upregulate genes associated with an activated innate immune response and increased cell death. Conversely, Lactobacillus crispatus culture supernatants induced transcriptional changes indicative of epigenomic modeling in ectocervical epithelial cells. Epigenomic modification by L. crispatus was confirmed by ATAC-sequencing, which demonstrated reduced chromatin accessibility.
    CONCLUSIONS: These results provide new insights into host-microbe interactions within the lower reproductive tract and suggest that modulating the cervicovaginal microbiome could offer innovative therapeutic strategies to improve reproductive health. Video Abstract.
    Keywords:   Gardnerella vaginalis ; Lactobacillus crispatus ; ATAC-seq; Anti-microbial peptides; Cervix; Chromatin; Epithelial cells; RNA-seq; Women’s health
    DOI:  https://doi.org/10.1186/s40168-025-02223-6
  22. bioRxiv. 2025 Oct 14. pii: 2025.10.13.682101. [Epub ahead of print]
    Mechanisms of sex differences in acute and long COVID sequelae in mice.
    Jennifer A Liu, Sabal Chaulagain, Patrick S Creisher, Weizhi Zhong, Tianle Zhang, Maraake Taddese, Karly Shi, Han-Sol Park, Haley Hcnir, Arthur P Arnold, Ralph S Baric, Natasha B Barahona, Elizabeth B Engler-Chiurazzi, Kevin J Zwezdaryk, Chloe L Thio, Ashwin Balagopal, Jack R Harkema, Elizabeth A Thompson, Andrew Pekosz, Andrea L Cox, Sabra L Klein.
      While males are more likely to suffer severe outcomes during acute COVID-19, a greater proportion of females develop post-acute sequalae of COVID-19 (PASC) despite similar rates of infection. To identify mechanisms of PASC, mice were infected with SARS-CoV-2 and viral, inflammatory, and behavioral outcomes were evaluated through 84 days post infection. Sex differences were not observed in virus replication or persistence of viral RNA in pulmonary or extrapulmonary tissues in acute or PASC phases. Following recovery from infection, female mice exhibited persistent neurocognitive and behavioral impairments, along with greater frequencies of inflammatory myeloid subsets, neuroinflammation, and dysregulated T cell subsets, including Tregs. Sex differences in inflammation and cognitive phenotypes during PASC were mediated by the presence of two X chromosomes. XX animals independent of chromosome Y presented with neuroinflammation and PASC along with infection-induced upregulation of the X-linked genes Xist and Tlr7 that regulate inflammation and chronic disease outcomes.
    DOI:  https://doi.org/10.1101/2025.10.13.682101
  23. BMC Endocr Disord. 2025 Nov 26. 25(1): 274
    Immune-inflammation markers are related to hormone levels in polycystic ovary syndrome: a case-control study : Immune-inflammatory markers in PCOS.
    Isil Cakir, Nuri Çakir.
       BACKGROUND: We aimed to evaluate the relationships between the pan immune-inflammation value (PIV), the systemic immune-inflammation index (SII), and hormonal levels in patients with polycystic ovary syndrome (PCOS).
    METHODS: 160 patients with PCOS and 142 healthy participants took part in the study. Demographic characteristics, lymphocytes, monocytes, neutrophils, white blood cells (WBC), platelets, fasting glucose levels, hormonal parameters as insulin, dehydroepiandrosterone sulfate (DHEASO4), prolactin, free and total testosterone, estradiol, luteinizing hormone (LH), 17-OH-progesterone, follicle-stimulating hormone (FSH), and 11-deoxycorticosterone were examined. Hematological indices, SII and PIV, were calculated. Receiver operating characteristic (ROC) analysis showed the diagnostic potential of the research parameters.
    RESULTS: The median WBC, SII and PIV values (7.63, 605.5, 312.69, respectively) were significantly higher in patients (p = 0.023; p < 0.001; p = 0.002; respectively). The median free testosterone, 17-OH progesterone, and LH values were also significantly higher in PCOS group (p = 0.009, p = 0.017, p = 0.012, respectively). Statistically significant and positive correlations were found between SII and insulin, SII and DHEA-SO4, PIV and insulin, and PIV and DHEA-SO4 levels (p = 0.006, p = 0.003, p = 0.037, p = 0.042, respectively). A statistically significant and positive correlation was also observed between PIV and free testosterone levels (p = 0.008). We found that a baseline serum SII > 520.0 and PIV > 262.4 were associated with PCOS with 65% specificity and 61% sensitivity for the SII (area under the curve [AUC], 0.669; 95% CI 0.584-0.755; p < 0.001) and 58% specificity and 60% sensitivity for the PIV ([AUC], 0.642; 95% CI 0.555-0.729; p = 0.002).
    CONCLUSIONS: Monitoring SII and PIV may assist clinicians in evaluating inflammation and treatment needs in patients with PCOS.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Hormone levels; Pan immune-inflammation value; Platelets; Polycystic ovary syndrome; Systemic immune inflammation index
    DOI:  https://doi.org/10.1186/s12902-025-02094-w
  24. J Pharm Bioallied Sci. 2025 Jul-Sep;17(3):17(3): 108-116
    Gut-Immune Interplay: Decoding the Microbiome's Impact on Immunity and Diseases.
    Amal I Khazi, Amber Ahmad.
      The gut microbiome is a critical regulator of local and systemic immunity with downstream consequences on immune functions and health of the host. Coevolution with the host bolsters the development and performance of the immune system, particularly during early life, and also plays roles in immune responses in adulthood. Alterations in the gut microbiome, whether as a result of antibiotics, diet, or environmental manipulation, can also drive inappropriate immune responses and predisposition to infections and inflammatory and autoimmune diseases. Since the microbiome impacts systemic immunity, microbial products stemming from the gut can alter immunity in far-flung tissues. Recent studies have emphasized the therapeutic promise of probiotics due to their ability to modulate gut microbiota and improve immune system activity and symptoms as well as prognosis of different diseases. Aging is one of the key risk factors for several age-related conditions, where the immune system and gut microbiome are major culprits, further explaining the importance of microbiome health across the life course. This emerging approach of microbiome modulation is opening up new pathways for combating infectious diseases, including both antibiotic-resistant infections and viral disease. This review highlights the interdependent nature of the gut microbiome and immune health, with significant ramifications for disease prevention and treatment.
    Keywords:  Gut microbiome; immune modulation; immune system; infections; probiotics; systemic immunity
    DOI:  https://doi.org/10.4103/jpbs.jpbs_1377_25
  25. Int J Mol Sci. 2025 Nov 19. pii: 11184. [Epub ahead of print]26(22):
    Multimodal Integration of Genomic Data Reveals Regulatory Mechanisms at the Polycystic Ovary Syndrome (PCOS)-Associated 12q13.2 Locus.
    R Alan Harris, Jan M McAllister, Jerome F Strauss.
      Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting reproductive-aged women. Previous studies have identified genomic associations at chromosome 12q13.2, but the functional mechanisms underlying these associations remain unclear. We integrated three complementary datasets: (1) WES-identified single nucleotide variants (SNVs) from PCOS and normal theca cells with association testing for forskolin-stimulated androgen production, (2) STARR-seq enhancer activity data with eQTL colocalization analysis, and (3) scRNA-seq expression data comparing forskolin-stimulated PCOS and normal theca cells. We previously identified haplotypes involving 10 SNVs at 12q13.2 containing RPS26/RAB5B/SUOX that are significantly associated with forskolin-stimulated androgen production. The identified haplotypes were further shown to associate with PCOS in a whole genome sequencing (WGS) cohort. Other studies have recently found the enhancer variant rs1081975 demonstrated perfect colocalization (PP = 1.0) with RPS26/RAB5B/SUOX eQTLs. Our scRNA-seq analysis revealed differential expression patterns for key genes. RAB5B showed a forskolin response upregulation in normal cells but an impaired response in PCOS. SUOX exhibited opposite forskolin responses between normal and PCOS cells. PA2G4, an androgen corepressor in the locus, was upregulated in normal untreated cells. ERBB3, an epidermal growth factor receptor in the locus, was downregulated in normal forskolin treated cells. The integration of multimodal genomic data provides functional validation of PCOS-associated variants at 12q13.2, revealing coordinated dysregulation of vesicular trafficking (RAB5B), androgen receptor regulation (PA2G4), and metabolic processes (SUOX) in PCOS theca cells.
    Keywords:  STARR-seq; androgens; eQTL; human ovarian theca cells; multimodal; polycystic ovary syndrome; single-cell RNA sequencing; whole exome sequencing
    DOI:  https://doi.org/10.3390/ijms262211184
  26. Viruses. 2025 Nov 18. pii: 1512. [Epub ahead of print]17(11):
    Gonadocorticoids Have Different Effects on the Expression of Toll-like Receptors When Infected with Various HIV-1 Subtypes.
    Marina Nosik, Konstantin Ryzhov, Elena Berezhnaya, Elizaveta Bystritskaya, Olga Lobach, Irina Kiseleva, Elizaveta Kostyuchenko, Anna Kuzina, Ekaterina Meremianina, Dmitry Kireev, Oxana Svitich.
      Recent studies suggest that immune response to pathogens may vary depending on changes in hormone levels. Toll-like receptors (TLRs) are the key components of the innate immune system and play a crucial role in HIV infection. Given the significant genetic diversity of HIV-1, this study examined the effect of female sex hormones on the several TLR2, TLR4, and TLR9 expression in human peripheral blood mononuclear cells (PBLs) isolated from different female donors and infected with different variants of HIV-1 subtypes A6 and B. Thus, high doses of hormones upregulated the TLR2 and TLR9 expression in PBLs infected only with v1.A6, which also correlated with an increased viral load: by 3.8 times (p = 0.0033) when cells were treated with estradiol and by 4.4 times (p = 0.006) when treated with progesterone. Hormones did not modulate TLRs expression in the cells infected with subtype B, with the exception of one donor. In PBLs from this donor infected with the v1.B variant, hormones upregulated TLRs expression, which also correlated with the increased viral load (1.3-fold increase (p = 0.0036)). Hence, it was shown that gonadal steroids can play an important role in HIV-1 replication and immune response to a pathogen. Moreover, it was shown that different isolates of the same subtype may have distinct biological properties. The detected diversity in the TLRs expression in infected PBLs from different donors indicates that host genetics may also play an important role in HIV susceptibility.
    Keywords:  HIV-1 sub-subtype A6; HIV-1 subtype B; TLR2; TLR4; TLR9; estradiol; progesterone
    DOI:  https://doi.org/10.3390/v17111512
  27. Mol Cell Endocrinol. 2025 Nov 20. pii: S0303-7207(25)00255-2. [Epub ahead of print]612 112704
    Androgen deprivation induces distinct muscle-specific transcriptional changes to genes regulating glucose, lipid, and amino acid metabolism.
    Wayne A Ayers-Creech, Jennifer L Steiner, Grant R Laskin, Bradley S Gordon.
       BACKGROUND: Androgens such as testosterone regulate whole-body metabolic homeostasis. Low androgen levels lead to undesirable shifts in metabolism including lower glucose oxidation, greater lipid reliance, and altered amino acid metabolism. Skeletal muscle is a primary site regulating fuel substrate metabolism, but whether all muscles contribute to the undesirable metabolic shifts in response to low androgen levels is unclear.
    METHODS AND RESULTS: Male mice underwent sham or castration surgery and muscles were harvested 7, 14-, 21-, 28-, or 49-days post-surgery. The content of genes related to glucose, lipid, and amino acid metabolism were assessed in the tibialis anterior (TA) and gastrocnemius muscles. The content of genes related to glucose metabolism were altered in a manner consistent with lower rates of oxidation in both the TA and gastrocnemius following castration although the magnitudes of change were generally more pronounced in the TA. Genes related to lipid oxidation were altered in a manner consistent with higher oxidation rates only in the TA following castration. Genes related to amino acid catabolism were paradoxically unaltered or even lower in both muscles in response to castration.
    CONCLUSION: These findings indicate that the TA undergoes more pronounced transcriptional changes related to glucose and lipid metabolism compared to the gastrocnemius, likely contributing more to whole-body metabolic shifts during androgen deprivation.
    Keywords:  Hypogonadism; Muscle atrophy; Testosterone
    DOI:  https://doi.org/10.1016/j.mce.2025.112704
  28. bioRxiv. 2025 Nov 01. pii: 2025.10.31.685960. [Epub ahead of print]
    Exploring Proteomic Differences in PBMCs for Sex-Specific Insights into Alzheimer's Disease.
    Takako Ishida-Takaku, Colin K Combs.
      Peripheral blood mononuclear cells (PBMCs) offer a minimally invasive window into systemic biology and immune dysregulation in Alzheimer's disease (AD). We performed quantitative proteomic profiling of PBMCs from male and female AD patients and controls to assess sex differences. AD was associated with proteomic remodeling, with complement activation, coagulation, and neuronal signaling enriched in males, whereas females showed increased steroid hormone secretion, lipid metabolism, and acute-phase response with reduced translation and DNA maintenance. Despite distinct patterns, both sexes exhibited immune and hemostatic activation, underscoring shared systemic mechanisms and the need for sex-specific biomarkers and therapeutic strategies in AD.
    DOI:  https://doi.org/10.1101/2025.10.31.685960
  29. mSystems. 2025 Nov 25. e0098325
    Lactobacillus iners dominates the vaginal microbiota of healthy Italian women of reproductive age.
    E Vinerbi, F Chillotti, A Maschio, S Lenarduzzi, S Camarda, F Crobu, D V Zhernakova, V Lo Faro, G Beltrame Vriz, S Incollu, J Spreckels, N Kuzub, A Kadric, R Gacesa, A Zhernakova, F De Seta, D Mazzà, F Busonero, M L Ferrando, G Girotto, S Sanna.
      Large sex hormonal fluctuations are thought to influence vaginal microbiota, but little is known about the impact of small, physiological variations. Here, we tracked changes in vaginal microbiota during four key menstrual cycle phases in 61 healthy, naturally menstruating Italian women from the Women4Health cohort. The microbiota, characterized using a high-depth 16S rRNA amplicon sequencing approach covering four hypervariable regions, was primarily composed of Lactobacillus species, with Lactobacillus iners being the most abundant (average relative abundance: 40%) and the most prevalent (prevalence: 98%). Individual microbiota were generally stable, but beta diversity was higher during the follicular phase (P = 0.007). Only 11 women exhibited compositional shifts, mostly occurring between the follicular and ovulatory phases. Finally, using linear mixed models, we assessed the association between taxa relative abundance and five sex hormones along the menstrual cycle. Among these, 17-beta estradiol showed the largest number of significant associations, linking its increase to a decrease in the relative abundance of taxa that are more common after menopause. Our study highlights specific features of the Italian population and points to the resilience of the vaginal microbiota to physiological hormonal changes. Noteworthy, the observed high abundance of L. iners contrasts with previous studies in European populations, challenging its proposed pathogenic role and suggesting distinct microbiota profiles within Europe.IMPORTANCEThe vaginal microbiota plays an important role in women's health, yet we know little about how it responds to normal hormonal fluctuations. In this study, we followed 61 healthy Italian women over a natural menstrual cycle to explore microbiota changes across different hormonal phases. We found that Lactobacillus iners was the most common species, unlike previous findings in Northern Europe, suggesting population-specific patterns. The common hypothesis that L. iners is invariably linked with poor health is called into question by our findings. They emphasize the importance of considering population context and hormonal status when assessing vaginal health. The vaginal microbiota was generally stable, with only a few changes observed between the follicular and ovulatory phases. When evaluating the association between five sex hormones and taxa abundances, we found that 17-beta estradiol levels had the largest number of significant associations. These highlight an association between increased levels of 17-beta estradiol and increased relative abundance of rare bacterial taxa rather than dominant species like Lactobacillus. Our findings help define what constitutes a "healthy microbiota" in generally healthy Italian women of reproductive age and may inform future strategies for diagnosing or preventing women's health conditions.
    Keywords:  Italian women; Lactobacillus crispatus; Lactobacillus iners; menstrual cycle; sex hormones; vaginal microbiota; women's health
    DOI:  https://doi.org/10.1128/msystems.00983-25
  30. bioRxiv. 2025 Oct 17. pii: 2025.10.16.682907. [Epub ahead of print]
    Toll-like Receptor 4 Contributes to PCOS-like Metabolic and Reproductive Pathogenesis.
    Kiara Wiggins, Zena Del Mundo, Julio Ayala Angulo, Nandini Naidu, Angelina Saba, Christopher Garcia, Christy Nguyen, Naveena Ujagar, Jamie-Jean De La Torre, Gabriela De Robles, Angie Rivera, Davina Trinh, Roberto Tinoco, Alexander S Kauffman, Varykina G Thackray, Anshu Agrawal, Marcus Seldin, Gabriela Pacheco Sanchez, Dequina Nicholas.
      Polycystic ovary syndrome (PCOS) is a reproductive disorder with heterogeneous symptoms and severity. Despite extensive research documenting chronic immune dysfunction as a hallmark of PCOS, the specific molecular mechanisms driving immune activation and its connection to the syndrome's diverse symptoms remain poorly understood. Emerging evidence suggests that gut-derived bacterial endotoxins, particularly lipopolysaccharide (LPS), may breach the intestinal barriers in PCOS patients and trigger systemic inflammation through Toll-like receptor 4 (TLR4), a pattern recognition receptor of the innate immune system. This study investigated whether TLR4 serves as a critical mechanistic driver of PCOS pathogenesis by examining the effect of genetic TLR4 knockout (TLR4 -/- ) in a letrozole (LET)-induced mouse model of PCOS. Our results demonstrate that TLR4 deficiency reduces many PCOS-like symptoms, including elevated luteinizing hormone, anovulation, and metabolic dysfunction. TLR4 knockout also preserved estrous cycling and fertility, improved glucose tolerance, maintained gut barrier integrity, and reduced inflammatory markers in LET-treated females. These findings establish TLR4 as a key mediator orchestrating PCOS's multi-system pathology, positioning TLR4 as a critical convergence point rather than affecting individual symptoms in isolation. This novel work reveals that TLR4-mediated inflammation drives multiple PCOS pathologies, opening avenues for targeted anti-inflammatory treatments in women with this disorder.
    Significance Statement: Polycystic ovary syndrome (PCOS) affects up to 15% of reproductive-age women worldwide. This study reveals that TLR4, an innate immune receptor, is key to the pathophysiology of PCOS-like symptoms in female mice. When TLR4 was genetically deleted, mice treated with letrozole to induce PCOS-like symptoms maintained normal weight, glucose regulation, estrous cycling, and fertility. The improvements coincided with preserved gut barrier breakdown and reduced inflammation. These findings identify TLR4 as a key mediator between gut health, immune activation, and PCOS pathophysiology, suggesting that targeting TLR4 could offer new therapeutic approaches for this common but poorly understood syndrome affecting millions of women.
    DOI:  https://doi.org/10.1101/2025.10.16.682907
  31. Front Microbiol. 2025 ;16 1652915
    Integrated gut microbiome and metabolomics analysis reveals microbial-metabolic cross-talk in allergic rhinitis.
    Guangchen Sun, Shouyan Zhao, Hehua Huang, Wenchao Guan, Xinzhuo Wang, Hong Zhang, Min Zhang, Denghan Hou, Chong Xu, Ruonan Chai.
       Background: Emerging evidence indicates a link between gut dysbiosis and allergic rhinitis (AR) pathogenesis. Nevertheless, the mechanistic role of gut microbiota in AR progression requires further characterization. To address this, we employed an integrated multi-omics strategy to delineate gut microbial composition and metabolic signatures in AR patients.
    Methods: Fecal specimens from 23 AR patients and 15 matched healthy controls (total n = 38) were subjected to 16S rRNA gene sequencing to assess bacterial community structure, alongside untargeted metabolomic profiling of microbial metabolites. Spearman's rank correlation analysis was applied to evaluate microbiota-metabolite interactions.
    Results: Allergic rhinitis patients exhibited altered gut microbial community structure (beta diversity, P < 0.05) with depletion of SCFA-producing genera such as Faecalibacterium and enrichment of pro-inflammatory taxa like Fusobacterium. Metabolomic profiling identified significant disturbances in pathways including pantothenate and CoA biosynthesis, glycolysis, and pyruvate metabolism. Key discriminatory metabolites included maltol and 4-coumaric acid. Integrative analysis revealed significant correlations between specific bacteria and metabolites, such as Faecalibacterium with D-phenyllactic acid (ρ = 0.515, q = 0.046).
    Conclusion: Our findings demonstrate that AR is associated with gut dysbiosis and metabolic dysfunction, highlighting the role of microbial-derived metabolites in immune regulation via the gut-nose axis. These insights support the potential for microbiota-targeted therapeutic strategies in AR management.
    Keywords:  16S rRNA gene sequencing; allergic rhinitis; gut microbiome; gut-nose axis; untargeted metabolomics
    DOI:  https://doi.org/10.3389/fmicb.2025.1652915
  32. medRxiv. 2025 Oct 31. pii: 2025.10.29.25339064. [Epub ahead of print]
    Sex-specific genetic regulation of proteomics in cerebrospinal fluid uncovers genetic causes for sex differences in neurodegeneration.
    Soomin Song, Anh N Do, Lihua Wang, Gyujin Heo, Jiseon Kwon, Daniel Western, Seung Jin Yang, Jigyasha Timsina, Menghan Liu, John Budde, Michael E Belloy, Eric McDade, Merce Boada, Adelina Orellana, Maria Victoria Fernandez, Agustin Ruiz, Pau Pastor, John C Morris, David Holtzman, Suzanne E Schindler, Han Chen, Carlos Cruchaga, Yun Ju Sung.
      Sex-specific genetic regulation of cerebrospinal fluid (CSF) protein levels may contribute to differential vulnerability to neurodegenerative diseases. To systematically identify sex differences in the genetic regulation of CSF proteome and their link to neurodegeneration, we performed sex-stratified pQTL analysis of 6,361 proteins in 1,713 males and 1,640 females, separately. We identified 1,729 pQTLs significant in either sex. They included 407 sex-specific pQTLs (genetic regulation in only one sex) and 159 sex-biased pQTLs (regulation in both sexes, but with different magnitudes of regulation between sexes). The HLA locus on chromosome 6 and the APOE locus on chromosome 19, two known pleiotropic regions, regulated several proteins in a sex-dependent way. Pathway enrichment revealed several biological processes that were shared and distinctive of sex. Using proteome-wide association study (PWAS) and colocalization, we identified 22 proteins associated and colocalized with AD risk loci. TMEM106B and ACE proteins were identified in only one sex. Four proteins were associated and colocalized with PD risk loci. These findings provide insights into dissecting the underlying mechanisms contributing to sex differences in neurodegeneration.
    DOI:  https://doi.org/10.1101/2025.10.29.25339064
  33. Ecology. 2025 Nov;106(11): e70259
    The sicker sex is plastic: Thermal plasticity determines sex biases in pathogen transmission.
    Nathan J Butterworth, Jared Lush, Kerri J Moore, Matthew D Hall.
      Sex differences are predicted to play an important role in the spread and evolution of pathogens. However, attempts to generalize the "sicker" sex have been challenged by intraspecific variability of sex biases across the infection process. Sex-specific plasticity provides a framework to resolve this by elucidating how infection is shaped at the sex-pathogen-environment interface. Using the Daphnia magna and Pasteuria ramosa system, we measure infection outcomes for males and females across three temperatures and seven pathogen densities to quantify how sex-specific plasticity shapes susceptibility, pathogen loads, and ultimately transmission. We find unique forms of plasticity at each stage of infection - including equivalent, sex-specific, and divergent plasticity. Integrating these into a single estimate of transmission reveals a clear pattern-male-biased transmission at cold temperatures, and female-biased transmission at warm temperatures. Sex-specific thermal plasticity can thus determine the "sicker" sex, with implications for pathogen spread and evolution in a warming world.
    Keywords:  disease; host–pathogen interactions; pathogen transmission; phenotypic plasticity; sexual dimorphism; sexual selection; sex‐specific plasticity; thermal ecology; virulence
    DOI:  https://doi.org/10.1002/ecy.70259
  34. J Heart Lung Transplant. 2025 Nov 24. pii: S1053-2498(25)02411-8. [Epub ahead of print]
    Sex-biased immune rewiring may underlie reduced risk for cardiac allograft vasculopathy in females following heart transplantation.
    Kyle Saysana, Nelson Chow, Shi Huang, Benjamin French, Raymond Dieter, Ayeshia Ali, Eric Farber-Eger, Quinn S Wells, Hasan K Siddiqi, David W Bearl, Kelly H Schlendorf, Kaushik Amancherla.
       BACKGROUND: Uncovering sex-based differences in immunologic outcomes following heart transplantation (HT) can inform risk stratification and precision immunosuppressive strategies. However, granular clinical-translational understanding of sex-specific molecular risk in the modern era is lacking. Here, we investigate the relationship between sex, acute rejection, and cardiac allograft vasculopathy (CAV) in adults and children following HT. We then decode cell-specific gene expression patterns in healthy individuals and HT recipients to identify discordant pathways that inform immunologic risk.
    METHODS: We studied 833 adult and pediatric HT recipients to delineate risk of donor-specific antibody (DSA) formation, acute rejection, and angiographic CAV between males and females. Next, using publicly available single-cell RNA-sequencing (scRNA-seq) data in circulating immune cells of healthy individuals (N = 981) and a HT-specific scRNA-seq dataset (N = 40), we conducted sex-stratified differential gene expression and functional enrichment analyses.
    RESULTS: Among 833 HT recipients (694 adults, 139 children; overall 32.8% female), no significant differences in acute rejection were identified between males and females. Adult females were less likely to develop angiographic CAV (HR 0.58, 95% CI 0.42-0.79). In healthy individuals, scRNA-seq recapitulated enrichment for broad autoimmune/inflammatory pathways in females. However, this was inverted following HT, with male recipients exhibiting upregulation translational/ribosomal machinery and cytokine sensing/signaling in a cell-specific fashion, along with enrichment for autoimmune disease pathways. CAV-associated gene sets were preferentially male-skewed in memory T cells.
    DISCUSSION: Despite similar rates of acute rejection, adult females were less likely to develop angiographic CAV. Differences between healthy and post-HT individuals identified molecular biases that may drive chronic low-grade inflammation, favoring CAV development in males. Additional studies are needed to validate these findings.
    Keywords:  Heart transplantation; immunophenotyping; scRNA-seq; sex differences; single-cell RNA-sequencing
    DOI:  https://doi.org/10.1016/j.healun.2025.11.022
  35. J Exp Med. 2026 Feb 02. pii: e20250099. [Epub ahead of print]223(2):
    pDCs amplify tissue-resident memory CD8+ T cell responses during viral reinfection.
    Elena Hernández-García, Miguel Galán, Sofía C Khouili, Elena Moya-Ruiz, Ana Redondo-Urzainqui, Francisco J Cueto, Saraí Martínez-Cano, Manuel Rodrigo-Tapias, Elena Tomasello, Santos Mañes, Marc Dalod, David Sancho, Salvador Iborra.
      Resident memory CD8+ T cells (Trms) are essential for protecting barrier nonlymphoid tissues (NLTs) against reinfection, yet the involvement of dendritic cells (DCs) in this process and the nature of Trm-DC interactions within these tissues remain poorly understood. Our study demonstrates that upon reactivation, memory CD8+ T cells located in the skin-independently of circulating memory counterparts-initiate the infiltration and maturation of plasmacytoid DCs (pDCs) in the tissue. This, in turn, promotes the maturation of conventional type 1 DCs (cDC1s) through type I IFN (IFN-I) signaling in a pDC-dependent manner. Depletion of pDCs or blocking IFN-I signaling disrupts this axis, severely impairing Trm-driven protection against secondary infections with vaccinia virus (VACV) in the skin. Notably, this pDC-dependent, IFN-I-mediated pathway is also essential for Trm-mediated protection against secondary respiratory infections with influenza A virus (IAV). Our findings uncover a crucial collaboration between Trm, pDCs, and cDC1s, offering new insights for enhancing vaccines.
    DOI:  https://doi.org/10.1084/jem.20250099
  36. Res Sq. 2025 Nov 07. pii: rs.3.rs-7895550. [Epub ahead of print]
    Mapping the landscape of cell type-dependent genetic regulation of DNA methylation across human tissues.
    James Li, Niyati Jain, Jason Kiat, Lin Tong, Meritxell Oliva, Kathryn Demanelis, Jasmine Farzana, Muhammad Kibriya, Habibul Ahsan, Lin Chen, Andrew Teschendorff, Brandon Pierce.
      DNA methylation (DNAm) is an epigenetic modification involved in gene regulation. DNAm quantitative trait loci (mQTLs) have been identified in many tissues, but bulk-tissue studies obscure cell type-specific effects. Here, we present the first multi-tissue landscape of cell type-dependent regulation of DNAm in humans by mapping cell type-interaction mQTLs (imQTLs) across seven tissue types (breast, colon, lung, ovary, prostate, kidney, and whole blood), identifying 3,150 imQTLs. Inter-individual variability in cell type proportion, rather than mean proportion, was most associated with imQTL discovery. The cell type with the most imQTLs tended to have interaction effects directionally consistent with mQTL marginal effects from bulk-tissue. imQTLs exhibited biologically relevant effect sharing across related cell types. Compared to cell-agnostic mQTLs, imQTLs exhibited stronger enrichment in regulatory elements and higher colocalization with eQTLs and GWAS loci. Our cell type deconvolution-based approach provides a scalable alternative to single-cell DNAm profiling for uncovering the cellular contexts of genetic regulation of DNAm.
    DOI:  https://doi.org/10.21203/rs.3.rs-7895550/v1
  37. Biomedicines. 2025 Nov 13. pii: 2777. [Epub ahead of print]13(11):
    Long noncoding RNAs and microRNAs in Endometriosis.
    Edi Muhaxhiri, Maruša Debeljak, Katarina Trebušak Podkrajšek, Helena Ban Frangež.
      Endometriosis represents a prevalent gynaecological disorder, impacting around 10% of the female population and affecting as many as 50% of women who are facing challenges with infertility. The pathogenesis of the disease encompasses intricate processes such as the formation of adhesions, degradation of the extracellular matrix, angiogenesis, increased cell proliferation, impaired apoptosis, and dysregulation of the immune response. Although endometriosis is common, its precise etiology remains unidentified, despite various hypotheses being suggested. Recent findings underscore the significance of non-coding RNAs, specifically long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), which have been identified as important regulators in the development of endometriosis. This literature review integrates findings from various transcriptomic and molecular studies to distinguish between lncRNAs and miRNAs that are associated with direct pathogenic roles and those that simply represent altered gene expression profiles in endometriosis. Particular long non-coding RNAs, such as H19, MALAT1, and LINC01116, are associated with chromatin remodeling, functioning as competitive endogenous RNAs, and influencing critical signaling pathways. Concurrently, specific microRNAs, including the miR-200 family, miR-145, and let-7b, seem to govern processes like epithelial-to-mesenchymal transition, angiogenesis, and cell adhesion. The findings highlight the significant potential of non-coding RNAs to serve as biomarkers for diagnostic purposes and as innovative therapeutic targets. Subsequent research endeavours ought to focus on corroborating these findings and elucidating the specific pathogenic roles of these non-coding RNAs in the context of endometriosis.
    Keywords:  biomarkers; endometriosis; lncRNA; long noncoding RNAs; miRNA; microRNA
    DOI:  https://doi.org/10.3390/biomedicines13112777
  38. Commun Biol. 2025 Nov 26. 8(1): 1694
    Microbial influx during early postnatal life fortifies the ocular surface and guards against allergic eye disease in mice.
    Yanbo Liu, Hang Sun, Shulin Song, Xiezhou He, Han Wu, Shangkun Ou, Hui He, Rongrong Zong, Yongxiong Chen, Guo Fu, Yiqiang Wang, Huping Wu, Andrew J Quantock, Zuguo Liu, Wei Li.
      Host-microbiome interplay during development governs the homeostasis of various bodily surfaces, however, postnatal colonization of the microbiome and its impact on the homeostasis of ocular surface is still unclear. Here, the changes of the conjunctival microbiome in C57BL/6 J mice were tracked in 1-week-old neonates through to 8-week-old adult mice. This disclosed that changes in the conjunctival microbiome correlate with age, especially at the 2-week and 3-week time points, which, respectively, are accompanied by eyelid-opening and weaning. Antigen presenting cells were also recruited to the conjunctival epithelium after eyelid-opening, whilst an inhibition of microbial colonization at 2-to-3 weeks of age led to a disruption of mucosal homeostasis and aggravated the development of allergic eye disease. This study improves our understanding of the development of the conjunctival microbiome in mice, and provides an indication that early microbial colonization is required for the establishment of mucosal ocular surface homeostasis, the perturbation of which leads to increased susceptibility to allergic eye disease.
    DOI:  https://doi.org/10.1038/s42003-025-09095-4
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