bims-simsho Biomed News
on Systems immunology and sex hormones
Issue of 2026–03–01
53 papers selected by
Chun-Chi Chang, Lunds universitet
  1. Sex hormone-psoriasis interactions: from sex-specific clinical features to immunoregulatory mechanisms.
  2. Hormonal regulation of androgen, estrogen receptor-α, and progesterone receptor expression in the adult male rabbit brain.
  3. Androgen Metabolism in Prostate Cancer: Recent Advances.
  4. Exploring Sex-Based Mechanisms of Inflammation and Neurodegeneration in Multiple Sclerosis.
  5. Estradiol enhances influenza vaccine responses through B cell metabolic reprogramming in female mice.
  6. Transcriptional and epigenetic reprogramming, lineage plasticity and therapy resistance in prostate cancer.
  7. Intratumoral Androgens and Genetic Variants Driving Therapy Resistance in Prostate Cancer.
  8. Differential sex-dependent responses of circulating steroid hormones and cortical gene expression in a preclinical traumatic brain injury model.
  9. Effect of estrogen and testosterone on cardiac electrophysiology and atrial fibrillation.
  10. Neutrophil extracellular traps in gynecological disease: pathogenic mechanisms and therapeutic opportunities.
  11. Sexually Dimorphic Response to Dietary Restriction-induced Longevity and Muscle Rejuvenation in Nothobranchius furzeri.
  12. Impact of Sex on Plasma Biomarkers in ob/ob Mice.
  13. Escape from X inactivation drives sex differences in gene expression.
  14. Sex-specific hypothalamic PVN transcriptomic signatures of blood pressure autonomic regulation and neuroinflammation in hypertension.
  15. Androgen Signaling Represses Homeobox C9, an Inhibitor of Androgen Receptor, in Prostate Cancer Cells.
  16. The Gut-Prostate Axis: Decoding the Interplay of Environmental Factors, Microbial Metabolites, and Hormonal Regulation in Prostate Cancer Pathogenesis.
  17. Selective Androgen Receptor Modulators in Women: What Do We Know, and What Is Still Missing.
  18. BMI-stratified phenotypes of polycystic ovary syndrome: advances in gut microbiota research and personalized management strategies.
  19. Double Knockdown of the Androgen Receptor Target Genes DKK1 and SFRP1 Does Not Potentiate the Hair Growth-Promoting Effect of SFRP1 Silencing in Healthy Human Hair Follicles Ex Vivo.
  20. Are we truly accounting for sex differences in experimental neuroscience?
  21. Regional and Sex-Dependent Immune Profiling Across the Colon in A Mouse Model of Ulcerative Colitis.
  22. Effects of testosterone on gene expression in males and females across 40 human tissues.
  23. Alterations in AR-FOXA1 signaling in prostate cancer progression and therapeutic resistance.
  24. Endotoxins and Metabolic Endotoxemia in Obesity and Associated Noncommunicable Diseases: A Focus on Sex Differences.
  25. The Role of Granulocyte Colony-Stimulating Factor in Endometrial Preparation for Embryo Implantation in In Vitro Fertilization.
  26. Sex differences in mitochondrial Ca2+ during ischemia/reperfusion injury: A role for S-Nitrosylation.
  27. Sex-specific proteostasis and urothelial responses to senolytic therapy in the aged mouse bladder.
  28. Aging-associated autoimmunity in genetically diverse UM-HET3 mice shows an early female sex bias.
  29. Interbreeding between Neanderthals and modern humans was strongly sex biased.
  30. Distinct DNA methylation signatures in maternal blood reveal unique immune cell shifts in preeclampsia and the pregnancy-postpartum transition.
  31. Molecular mechanisms and classification of castration-resistant prostate cancer: Insights into androgen receptor, cancer stem cells, and neuroendocrine features.
  32. The Intersection of m6A Methylation and Immune Response in PCOS: A Bioinformatics Perspective.
  33. Effects of body composition on age- and sex-related differences in resting metabolic rate from a healthy aging cohort.
  34. SASdb: a comprehensive database for sex-biased alternative splicing profiles in human tissues.
  35. A Dive into the Invisible: The Vaginal and Endometrial Microbiota in Gynecologic and Obstetric Disorders: A Narrative Review.
  36. Skin androgens regulate Staphylococcus aureus pathogenicity via quorum sensing.
  37. Lacticaseibacillus rhamnosus DACN152 effectively ameliorated letrozole-induced polycystic ovary syndrome: sex hormone homeostasis, microbiota and metabolite profiles.
  38. Epigenetic Landscape of Female Infertility: An Integrated Bioinformatics Perspective on DNA Methylation, MicroRNAs, and Gene Regulatory Networks Across PCOS, Endometriosis, and Diminished Ovarian Reserve.
  39. Male hypogonadism and testosterone therapy - facing the differences between recommendations and the real-life.
  40. Androgen insensitivity syndrome: Presentation, diagnosis, and management.
  41. Interplay of the nasal microbiome and epigenome among adolescents.
  42. Corrigendum "Role of reactive oxygen species in polycystic ovary syndrome: Signalling pathways, mechanisms, and traditional Chinese medicine treatment strategies" [Int. Immunopharmacol. 173 (2026) 116251].
  43. Sex Hormones and Keratoconus: In Search of the Link.
  44. Emerging therapies to overcome antiandrogen resistance and beyond in lethal prostate cancer.
  45. Micronutrients in polycystic ovary syndrome: molecular pathways, deficiencies, and therapeutic potential.
  46. Sex Differences in Pleomorphic Dermal Sarcoma: A SEER-Based Analysis.
  47. Sex-specific beta1-adrenergic receptor regulation of VMNdm growth hormone-releasing hormone neuron metabolic sensor and counterregulatory transmitter gene expression.
  48. Sex-based clinical and immunological differences across lupus erythematosus subtypes: a cross-sectional multicentre study from China.
  49. Beyond glycemic control: molecular mechanisms of metformin in modulating cytokine networks in polycystic ovary syndrome.
  50. Tissue-specific and spatially dependent metabolic signatures perturbed by injury in male and female mice.
  51. Distinct cytokine-producing dendritic cell profiles in females and males with major depressive disorder.
  52. Sexually Dimorphic Neuroimmune Pathways in Chronic Pain: A Comprehensive Systematic Review of Cellular and Molecular Mechanisms.
  53. Cardiomyocyte NLRP3 signaling in right heart failure is sexually dimorphic via estrogen receptor α.
  1. Front Immunol. 2026 ;17 1731024
    Sex hormone-psoriasis interactions: from sex-specific clinical features to immunoregulatory mechanisms.
    Yingying Dai, Yuanting Wang, Yuwei Huang, Xian Jiang, Jing Tan.
      Psoriasis is a chronic inflammatory skin disease mediated by T cells, characterized by distinct sex differences and variations across different reproductive stages, suggesting that sex hormones may play a significant role in its pathogenesis. In recent years, research has increasingly focused on the bidirectional effects of sex hormones in psoriasis: on one hand, changes in hormone levels can affect the onset and progression of psoriasis; on the other hand, the systemic inflammation of psoriasis can interfere with the homeostasis of the sex hormone axis. This review systematically integrates clinical epidemiological evidence of sex hormone abnormalities in cutaneous psoriasis patients, outlines the molecular mechanisms of estrogen, androgen, and progesterone in immune-inflammatory regulation of psoriasis, and further explores how psoriasis-related inflammation, through cytokines, stress responses, and metabolic abnormalities, can in turn disrupt sex hormone balance. The focus is primarily on immunopathological mechanisms, with a secondary consideration of the impact of metabolic and stress-related factors, which modulate immune responses and may indirectly influence disease progression. We highlight the complex immune-endocrine network interaction between sex hormones and cutaneous psoriasis, emphasizing the need for future sex-stratified studies, dynamic hormone monitoring, and mechanistic validation models to clarify their causal pathways. This will aid in understanding the sex-specific clinical manifestations of psoriasis and provide a theoretical basis for developing hormone-targeted intervention strategies.
    Keywords:  immune inflammation; immune-endocrine; psoriasis; sex differences; sex hormones
    DOI:  https://doi.org/10.3389/fimmu.2026.1731024
  2. Horm Behav. 2026 Feb 25. pii: S0018-506X(26)00028-0. [Epub ahead of print]179 105903
    Hormonal regulation of androgen, estrogen receptor-α, and progesterone receptor expression in the adult male rabbit brain.
    Beatriz Molina, Karina Hernández-Ortega, Laura Noemi Hernández-Lúa, Gabriela González-Mariscal, Ignacio Camacho-Arroyo.
      Sex hormones regulate a broad range of brain functions beyond reproduction via specific receptors, whose expression can be modulated by hormones. However, the regulation of sex hormone receptors across different brain regions in male rabbits remains unknown. We investigated the effects of two hormone treatments in castrated male rabbits: testosterone propionate (TP) and dihydrotestosterone plus estradiol benzoate (DHT + EB), on androgen receptor (AR), estrogen receptor alpha (ERα), and progesterone receptor (PR) expression in the brain. Adult male New Zealand White rabbits were bilaterally castrated and daily treated with TP or DHT + EB for 16 days. One day after treatments (day 17), AR, ERα, and PR mRNA and protein levels were determined in the olfactory bulb, prefrontal cortex, hippocampus, preoptic area, hypothalamus, mesencephalon, and cerebellum using RT-qPCR and Western blot. AR mRNA levels increased with both treatments in the prefrontal cortex, preoptic area, and the hypothalamus following TP treatment. Notably, AR protein content increased across all regions after TP, and in the olfactory bulb, prefrontal cortex, preoptic area, and hypothalamus following DHT + EB. Both treatments reduced ERα mRNA in the olfactory bulb, hippocampus, preoptic area, hypothalamus, and mesencephalon; DHT + EB also decreased ERα mRNA in the cerebellum, while ERα protein content remained unchanged in all regions. TP and DHT + EB reduced PR mRNA expression in most regions, with DHT + EB showing broader effects. As with ERα, PR protein content showed no significant changes after treatments. These findings indicate that androgens and estrogens regulate AR, ERα, and PR expression, notably affecting AR protein content.
    Keywords:  And rabbit brain; Androgen receptor; Estrogen receptor; Progesterone receptor; Sex hormones
    DOI:  https://doi.org/10.1016/j.yhbeh.2026.105903
  3. Endocrinology. 2026 Feb 24. pii: bqag021. [Epub ahead of print]
    Androgen Metabolism in Prostate Cancer: Recent Advances.
    Nima Sharifi.
      Androgen biosynthesis is physiologically necessary for generating the principal stimulus for androgen receptor (AR) signaling and thus plays an essential role for development of the normal prostate, prostate cancer growth and the development of resistance to hormonal therapies. Testosterone and dihydrotestosterone are both potent endogenous androgens that stimulate AR signaling. While the role of gonadal androgens has been recognized in stimulating prostate cancer progression for over 80 years, the appreciation for non-gonadal precursor steroids in prostate cancer has been more limited in duration of time, attention and focus in the field. Nevertheless, the very clearly established role of non-gonadal androgens in enabling prostate cancer progression, especially in the absence of gonadal testosterone, frames the essentiality of androgen metabolic processes for dictating prostate cancer clinical behavior. Here, the role of androgen metabolism in prostate cancer is reviewed, particularly within the context of hormonal therapy, hormone therapy resistance and with emphasis on recent advances.
    Keywords:  androgens; enzymes; metabolism; prostate cancer; steroids
    DOI:  https://doi.org/10.1210/endocr/bqag021
  4. Biol Res Nurs. 2026 Apr;28(2): 283-295
    Exploring Sex-Based Mechanisms of Inflammation and Neurodegeneration in Multiple Sclerosis.
    Stephanie Buxhoeveden, Theresa Swift-Scanlan, Myla D Goldman, Ryan Canissario, Unsong Oh.
      Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by both immune-mediated inflammation and progressive neurodegeneration. While both processes occur in all individuals with MS, females more often present with heightened inflammatory activity, whereas males tend toward accelerated neurodegeneration and disability progression. This review synthesizes current evidence on biological, hormonal, genetic, epigenetic, and environmental mechanisms underlying sex-based differences in relapsing-remitting MS (RRMS), the most common MS subtype. We integrate findings from human studies, animal models, and molecular research to examine the contribution of genetics and epigenetic regulation including sex chromosomes, single nucleotide polymorphisms (SNPs), and microRNAs (miRNAs) to MS pathophysiology. We discuss the influence of sex hormones, including estrogen, progesterone, and testosterone, and environmental risk factors such as Epstein-Barr virus infection and vitamin D3 deficiency. Evidence suggests that X-linked immune-related genes, hormone - immune interactions, and sex-specific epigenetic regulation shape differential immune responses and neuronal vulnerability in males and females with MS. miRNAs emerge as critical molecular bridges linking genetic susceptibility, hormonal milieu, and environmental exposures to downstream inflammatory and neurodegenerative pathways. Understanding the mechanisms driving sex differences in MS may enable the development of targeted interventions addressing both neuroinflammation and neurodegeneration. Integrated miRNA - mRNA analyses, explicitly powered to assess sex as a biological variable, hold promise for identifying novel biomarkers and therapeutic targets. Such approaches could inform more personalized treatment strategies and improve long-term outcomes for all people with MS.
    Keywords:  MicroRNA; epigenetics; multiple sclerosis; neurodegeneration; neuroinflammation; sex differences
    DOI:  https://doi.org/10.1177/10998004251387318
  5. mBio. 2026 Feb 26. e0396525
    Estradiol enhances influenza vaccine responses through B cell metabolic reprogramming in female mice.
    Laura A St Clair, Emily G Watters, Anna Yin, Jennifer A Liu, Sabal Chaulagain, Elizabeth A Thompson, Sabra L Klein.
      Reproductive-aged females mount stronger antibody responses to influenza vaccination than males, with the sex difference waning in older age. Estradiol has been implicated as a driver, but the mechanisms mediating how estradiol affects B cell function remain elusive. Adult (3 months) and aged (17 months) male and female mice were vaccinated and boosted with inactivated influenza vaccine. Metabolomics analysis of splenic B cells revealed that adult female B cells were enriched in lipid metabolic pathways, whereas B cells from males were enriched in central carbon-associated pathways following vaccination. B cells from vaccinated adult females exhibited greater expression of mTOR and related proteins than those from males, a difference diminished in aged mice. In adult females, estradiol depletion reduced, and replacement increased, mTOR activity in B cells, particularly in germinal center B cells and plasmablasts in lymphoid tissues, and plasma cells in bone marrow. In males, neither testosterone depletion nor repletion altered B cell metabolism. These findings are consistent with evidence that estradiol enhances mTOR activation via estrogen receptor α (ERα) signaling, suggesting coordinated regulation between estrogen and mTOR signaling in B cells. Inhibition of mTOR with rapamycin impaired vaccine-induced antibody responses and protection in adult females. In aged females, supplementation with estradiol or treatment with a selective ERα agonist increased mTOR signaling and enhanced antibody responses compared with mock-treated aged females. These data identify estrogen signaling as a regulator of B cell metabolism that supports greater expansion and function of antibody-secreting cells following vaccination in females compared with males.
    IMPORTANCE: Vaccine-induced immunity differs between the sexes, with adult females mounting stronger antibody responses to influenza vaccination than age-matched males. We show that estradiol in females regulates B cell metabolism to promote the maturation and metabolic activation of antibody-secreting B cells, thereby enhancing humoral immunity and protection following vaccination. mTOR signaling in B cells was greater in adult females than males after vaccination, which was diminished with aging or depletion of estradiol. Therapeutic treatment of aged females with either estradiol or a selective estrogen receptor α modulator increased mTOR signaling and improved vaccine-induced antibody responses, thereby eliminating the effects of aging on influenza immunity. Harnessing estrogen-signaling mechanisms to improve responses to influenza vaccines could be a novel therapeutic strategy to improve public health.
    Keywords:  aging; estrogen; immunometabolomics; influenza; neutralizing antibodies; sex difference
    DOI:  https://doi.org/10.1128/mbio.03965-25
  6. J Natl Cancer Cent. 2026 Feb;6(1): 73-87
    Transcriptional and epigenetic reprogramming, lineage plasticity and therapy resistance in prostate cancer.
    Yujun Shuai, Haojie Huang.
      Prostate cancer is the most commonly diagnosed and the second-leading cause of cancer-related mortality in men worldwide, especially in Western counties. Therapeutic resistance of prostate cancer remains a major challenge in modern oncology, necessitating new scientific understanding of the disease and devising new targeting strategies. This review examines the intricate relationship between transcriptional and epigenetic reprogramming, lineage plasticity, and therapeutic resistance in prostate cancer. Prostate cancer cells can adapt and resist various treatment modalities, including androgen deprivation therapy (ADT) and next-generation androgen receptor (AR) signaling inhibitors (ARSI), through transcriptional reprogramming and epigenetic modifications. Lineage plasticity, the ability of cells to alter their cellular identities, further drives treatment resistance. Moreover, cancer cells can adjust their gene expression profiles to evade therapy by activating key transcription factors and epigenetic regulatory mechanisms such as DNA methylation, histone modification, and non-coding RNA expression. The article concludes by discussing new therapeutic strategies targeting these reprogramming and plasticity mechanisms, emphasizing the importance of combination therapy and precision medicine in developing more effective treatments for advanced prostate cancer.
    Keywords:  Lineage plasticity; Prostate cancer; Therapy resistance; Transcriptional and epigenetic reprogramming
    DOI:  https://doi.org/10.1016/j.jncc.2025.06.001
  7. Research (Wash D C). 2026 ;2026 1128
    Intratumoral Androgens and Genetic Variants Driving Therapy Resistance in Prostate Cancer.
    Junjiang Ye, Yandong Xie, Jie Wang, Ruicheng Wu, Dengxiong Li, Koo Han Yoo, Dilinaer Wusiman, William C Cho, Zhaojie Lyu, Dechao Feng.
      The persistence of castration-resistant prostate cancer (CRPC) despite androgen deprivation therapy and androgen receptor (AR) signaling inhibition underscores the need to elucidate resistance mechanisms. The AR signaling pathway plays a central role in the development of prostate cancer. Metabolic reprogramming of androgen synthesis and aberrant activation of AR signaling collectively drive CRPC development. Under therapeutic pressure, AR signaling adapts through AR amplification, ligand-binding domain mutations, splice variants, and alternative activation by cytokines/growth factors, maintaining AR transcriptional activity in low-androgen environments. Concurrently, somatic alterations (like PTEN loss) and crosstalk with key pathways such as PI3K/AKT, coupled with the evolving multifocal spatial heterogeneity, further complicate the role of AR signaling in CRPC treatment resistance. Innovations in single-cell and spatial technologies reveal tumor heterogeneity and lineage plasticity governed by genetic and epigenetic alterations. Current therapeutic innovations, including approaches such as CYP11A1 inhibition, targeting of the AR N-terminal domain, and bipolar androgen therapy, are showing promise in clinical trials. Overcoming CRPC effectively requires cotargeting androgen/AR-associated pathways and suppressing lineage plasticity through dynamic monitoring and precision interventions.
    DOI:  https://doi.org/10.34133/research.1128
  8. bioRxiv. 2026 Feb 09. pii: 2026.02.06.703864. [Epub ahead of print]
    Differential sex-dependent responses of circulating steroid hormones and cortical gene expression in a preclinical traumatic brain injury model.
    Amberlyn Simmons, Sierra F Wilferd, Sofia Campagnuolo, Veronica Pena, Heather Bimonte-Nelson, Jason Newbern, Rachael W Sirianni, Christopher L Plaisier, Sarah E Stabenfeldt.
      Accumulating evidence supports sex differences in traumatic brain injury (TBI) outcomes, however the underlying processes that lead to sex differences are not well understood. TBI results in the initiation of molecular and cellular responses that facilitate the progression of neurodegeneration. Importantly, little is known about how the circulating hormone profile is altered in response to TBI, and whether sex differences in endocrine responses might shape secondary injury pathologies. Using intact male and female mice in a preclinical TBI model, we assessed changes in plasma hormone concentrations and cortical gene expression at 24 and 72 hours after TBI. We demonstrate that males and females exhibit sex-specific alterations in circulating levels of progesterone, testosterone, androstenedione, estradiol and dehydroepiandrosterone (DHEA) in response to TBI. We also identified sex differences in the expression of genes that are involved in immune responses and tissue remodeling after injury. Moreover, we report divergent circulating hormone and gene expression correlations between sexes.
    DOI:  https://doi.org/10.64898/2026.02.06.703864
  9. Heart Rhythm O2. 2026 Feb;7(2): 393-403
    Effect of estrogen and testosterone on cardiac electrophysiology and atrial fibrillation.
    Ashwin Venkatakrishnan, Divya Srinivasan, Anneesa Malik, Murtaza Hazareh, Muhammad Ahmad Nizami, Jun Yu Chen, Fu Siong Ng.
      The prevalence and treatment outcomes of atrial fibrillation (AF) differ between sexes, yet the mechanisms underlying these differences remain poorly understood. Given that estrogen and testosterone are the major sex hormones, they may be involved in altering cardiac electrophysiology and risk of AF. Preclinical studies demonstrate that estrogen and testosterone alter ion currents and cardiomyocyte calcium (Ca2+) handling via receptor-mediated mechanisms, but with opposite effects. Estrogen prolongs action potential duration (APD), whereas testosterone shortens it. A longer APD has antiarrhythmic effects in the atria, whereas a shorter APD is proarrhythmic. Testosterone also accelerates repolarization and enhances contractility, further increasing AF risk. However, most laboratory studies were done in animal ventricular models, limiting direct translation to human atrial physiology owing to species-specific electrophysiological differences. Human population studies suggest that decreased exposure to endogenous estrogen increases AF risk in women. In males, there is no similar consensus for the relationship between endogenous testosterone exposure and AF risk in men. Evidence from hormone replacement, testosterone replacement, and androgen deprivation therapies is similarly inconclusive, reflecting confounding factors, variation in hormone formulations, and reliance on single hormone measurements. This review provides novel insights into how estrogen and testosterone differentially influence cardiac electrophysiology and risk of AF in men and women. These findings underscore the need for personalized sex- and hormone-specific treatment strategies in AF management, addressing a critical gap in current clinical practices.
    Keywords:  Arrhythmia; Atrial fibrillation; Cardiac electrophysiology; Estrogen; Hormone replacement therapy; Pluripotent stem cell–derived cardiomyocytes; Sex hormones; Testosterone
    DOI:  https://doi.org/10.1016/j.hroo.2025.11.007
  10. Front Med (Lausanne). 2026 ;13 1710628
    Neutrophil extracellular traps in gynecological disease: pathogenic mechanisms and therapeutic opportunities.
    Meiling Wu, Jingxin Ding, Xuyin Zhang.
      Gynecologic disorders, including infections, sterile inflammatory diseases, endocrine abnormalities, and malignancies, share a common signature of dysregulated immunity within a uniquely hormone-responsive reproductive tract. Neutrophil extracellular traps (NETs) are increasingly recognized as central effectors at this interface of innate immunity, endocrine signaling, tissue remodeling, and thrombosis. In this review, we first outline the mechanistic basis of NET formation and emphasize how the cyclical anatomy, fluctuating sex hormones, and regional microbiota of the female reproductive tract shape NET induction, localization, and clearance. We then synthesize evidence across disease spectra. In infectious conditions such as pelvic inflammatory disease, genital tuberculosis, and vaginal dysbiosis, NETs confine pathogens but also drive epithelial injury, fibrosis, and infertility. In sterile inflammatory and endocrine-related disorders, including endometriosis, polycystic ovary syndrome, premature ovarian insufficiency, and primary dysmenorrhea, NET-associated oxidative stress, inflammasome activation, and profibrotic signaling link hormonal and metabolic imbalance to chronic pain and organ dysfunction. In gynecologic cancers, NETs promote tumor cell adhesion, invasion, immune escape, and thromboembolic complications within hormone-conditioned microenvironments, while circulating and tissue NET markers, as well as NET-related gene and lncRNA signatures, hold diagnostic and prognostic value. Finally, we discuss how biomaterial-based strategies in vaginal reconstruction exploit antimicrobial NET functions yet risk excessive fibrosis if NETs are not tightly controlled. Across these contexts, we highlight an emerging NET-sex hormone axis and propose endocrine-aware, biomarker-guided strategies that combine NET-targeting agents with hormonal and microbiome-based interventions to achieve more precise diagnosis, risk stratification, and therapy for gynecologic diseases.
    Keywords:  chronic inflammation; endometriosis; gynecologic cancers; neutrophil extracellular traps (NETs); reproductive endocrine disorders; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fmed.2026.1710628
  11. bioRxiv. 2026 Feb 11. pii: 2026.02.09.704879. [Epub ahead of print]
    Sexually Dimorphic Response to Dietary Restriction-induced Longevity and Muscle Rejuvenation in Nothobranchius furzeri.
    Sonia Sandhi, Hannah Somers, Matthew Cox, Celeste Nobrega, Ryan Seaman, Elizabeth Bakers, Olivia Letchner, Robyn Reeve, Romain Menard, James Godwin, Anastasia Paulmann, Aric Rogers, Dario Riccardo Valenzano, Joel Graber, Hermann Haller, Romain Madelaine.
      Age-related skeletal muscle decline (sarcopenia) is a major contributor to frailty and mortality during aging, yet the extent to which sex shapes muscle aging and its response to dietary interventions remains poorly understood. Here, we use the short-lived vertebrate Nothobranchius furzeri (African turquoise killifish; ATK) to investigate how sex and intermittent fasting (IF) interact to regulate lifespan and skeletal-muscle aging. We establish and optimize an IF regimen that significantly extends lifespan in both male and female killifish, albeit with classical trade-offs including reduced growth and reproductive output. Despite these costs, IF markedly improves swimming performance in aged animals of both sexes. Structural analyses of killifish on a normal diet reveal pronounced sexual dimorphism in muscle aging. Males exhibit age-associated myofiber hyperplasia, whereas females maintain fiber number but undergo hypertrophic remodeling. IF partially reverses both phenotypes, restoring a more youthful fiber size distribution in both males and females. Single-nucleus RNA sequencing uncovers sex-specific remodeling of muscle-fiber composition in killifish on a normal diet, with females displaying an age-associated shift toward oxidative slow-twitch fibers that is reversed by IF, while males show relatively stable fiber-type proportions under normal and IF feeding regimens. Cell-cell communication analyses further reveal a global decline in intercellular signaling with age, alongside sex-specific restoration of distinct pathways under IF, including axon guidance and IGF signaling in females and metabolic ANGPTL signaling in males. Finally, bulk transcriptomic profiling demonstrates that aging follows largely sexually dimorphic molecular trajectories, whereas IF induces both sex-specific and shared responses. Notably, under IF, both sexes exhibit upregulation of ribosome biogenesis and genes supporting myofibrillar organization and contraction, likely underlying preserved muscle function. Together, these findings demonstrate that IF promotes longevity and muscle health through conserved anabolic mechanisms alongside sex-specific cellular and molecular rejuvenation strategies. Our work highlights the importance of incorporating sex as a biological variable when designing dietary interventions to promote healthy aging.
    DOI:  https://doi.org/10.64898/2026.02.09.704879
  12. Int J Mol Sci. 2026 Feb 10. pii: 1712. [Epub ahead of print]27(4):
    Impact of Sex on Plasma Biomarkers in ob/ob Mice.
    Yunha Suh, Kwang-Eun Kim.
      Sex is a critical biological variable that influences disease incidence, progression, and therapeutic responses; therefore, it must be incorporated into biomedical research. Despite this, most mouse studies historically have not compared animals by sex. Recently, growing evidence has indicated that sex-specific analyses are important in obesity and metabolic disorders. The ob/ob mouse is a widely used model for metabolic disease research; however, sex differences in plasma biomarkers have not been fully characterized in this model. In this study, male and female ob/ob mice at 8 weeks of age exhibited comparable body weight, blood glucose levels, and adipose tissue mass. Plasma proteomics analysis using the Olink platform revealed that 27% (23/84) of quantified proteins exhibited sex differences, with 91% (21/23) of these proteins elevated in females. Notably, Enolase 2 (ENO2), also known as neuron-specific enolase (NSE), was consistently elevated in female ob/ob mice and showed a similar sex-associated pattern in female patients with non-alcoholic steatohepatitis (NASH). While the human NASH data provide correlative support rather than direct clinical validation, these observations underscore the importance of considering sex as a biological variable in metabolic disease research. Incorporating sex-specific biomarker profiles may help refine mechanistic interpretation and inform future studies toward personalized therapeutic approaches.
    Keywords:  ENO2; NSE; biomarker; ob/ob; plasma proteome; sex differences
    DOI:  https://doi.org/10.3390/ijms27041712
  13. Mol Biol Evol. 2026 Feb 26. pii: msag050. [Epub ahead of print]
    Escape from X inactivation drives sex differences in gene expression.
    Carrie Zhu, Liaoyi Xu, Arbel Harpak.
      X chromosome inactivation (XCI) partially balances gene dosage between sexes, yet many genes are expressed from the inactive X (Xi) to a variable degree. In this study, we investigate whether variation in Xi expression among genes predicts transcriptional and phenotypic consequences of X-linked variation. We find that Xi expression levels are a strong linear predictor of female-male expression differences, suggesting that other compensatory or regulatory mechanisms play a more minor role in sex differences in X-linked gene expression. Among females, we identify traits-including BMI, estradiol, and testosterone levels-for which higher Xi expression correlates with the strength of evidence for either additive or dominance effects on the trait. We hypothesize that an underappreciated mechanism could generate dominance effects of X-linked variants on a trait-specifically when the variant influences skew in X inactivation. This work establishes Xi expression as important for understanding transcriptional sex differences and physiological variation among females.
    DOI:  https://doi.org/10.1093/molbev/msag050
  14. Biol Sex Differ. 2026 Feb 21.
    Sex-specific hypothalamic PVN transcriptomic signatures of blood pressure autonomic regulation and neuroinflammation in hypertension.
    Duque V J, Nani J V, Jovanovic M, Lozić M, Šarenac O, Pauža A G, Murphy D M, Japundžić-Žigon N Z, Mecawi A S.
       INTRODUCTION: Hypertension is a multifactorial condition of unknown cause that affects more than 1.28 billion adults worldwide and impacts the sexes differently. The hypothalamic paraventricular nucleus (PVN) plays a central role in blood pressure (BP) regulation by modulating sympathetic tone and releasing neuropeptides that affect the cardiovascular function. In this study, we investigated the transcriptomic profile of the PVN in hypertensive strains and across sexes, aiming to identify novel sex-specific molecular pathways involved in the regulation of BP.
    METHODS: To accomplish this goal, we sequenced RNA from the PVNs of normotensive Wistar rats and Spontaneously Hypertensive Rats (SHR), both male and female. We also performed a cardiovascular assessment based on blood pressure (BP) measurements and their variability.
    RESULTS: Cardiovascular assessment revealed higher SBP in SHRs than in Wistar rats; while males exhibited greater autonomic regulation associated with vasomotor and neurohumoral mechanisms, while females maintained comparable SBP levels primarily through an increase in heart rate, reflecting distinct autonomic adaptations. Hypertension also impacted gene expression, with influences from both the hypertensive state and sex. Compared with female SHRs, male SHRs presented a marked increase in differentially expressed genes (DEGs). Key upregulated genes in males, including Brain-Derived Neurotrophic Factor (Bdnf) and Hypocretin (Hcrt), have already been linked to elevated BP, and Angiotensin II Receptor Type 1 (Agtr1a) is possibly associated with increased SBP-VLF variability, which serves as an indirect measure of enhanced sympathetic tone. In contrast, the female transcriptomic signature was characterized by the upregulation of anti-inflammatory pathways, with upregulation of NLR Family CARD Domain Containing 3 (Nlrc3) and Paired Ig-like Receptor B (Pirb), and downregulation of Absent in Melanoma 2 (Aim2), and S100 Calcium Binding Protein B (S100b). Notably, genes associated with neuroinflammation, such as the downregulation of Annexin A1 (Anxa1) and the upregulation of Solute Carrier Family 11 Member 1 (Slc11a1), were consistently altered in both sexes.
    CONCLUSION: These results provide new insights into the cardiovascular and molecular basis of sex differences in hypertension, suggesting distinct neurohumoral autonomic profile in males, whereas in females a greater anti-inflammatory component. These findings offer a valuable framework for developing future sex-specific therapeutic strategies.
    Keywords:  Anti-inflammatory; Blood pressure; Cardiovascular; Hypertension; Inflammation; Paraventricular nucleus; RNA-Seq; Sex differences; Transcriptomics
    DOI:  https://doi.org/10.1186/s13293-026-00855-3
  15. Int J Mol Sci. 2026 Feb 18. pii: 1962. [Epub ahead of print]27(4):
    Androgen Signaling Represses Homeobox C9, an Inhibitor of Androgen Receptor, in Prostate Cancer Cells.
    Takao Susa, Eiki Tsuboi, Tomoko Okada, Miho Akimoto, Noriyuki Okudaira, Hiroko Okinaga, Masayoshi Iizuka, Tomoki Okazaki, Mimi Tamamori-Adachi.
      Because prostate cancer proliferates in an androgen-dependent manner, various inhibitors of androgen production and antagonists of the androgen receptor (AR) are used as therapeutic agents. However, the emergence of castration-resistant prostate cancer has prompted the development of additional treatment strategies. In this study, we focused on the antiprostate cancer effects of vitamin D3 and examined novel antiproliferative effects through the crosstalk with androgen signaling. In human prostate cancer LNCaP cells, homeobox C9 (HOXC9) was identified as a common regulated target gene by dihydroxytestosterone and 1α,25-dihydroxyvitamin D3, but in opposite directions. Ligand-stimulated AR and vitamin D receptor competitively shared binding sites in the HOXC9 regulatory region, but dihydroxytestosterone stimulation preferentially suppressed HOXC9 expression due to the stronger binding properties of AR and the induction of DNA methylation. Forced expression of HOXC9 inhibited androgen signaling to eliminate the androgen-dependent proliferation by associating with the AR transcription complex, in part due to interference with AR binding to some of its targets in LNCaP cells. In summary, this study provides evidence for the involvement of HOXC9 in antiproliferative effects through a regulatory mechanism mediated by a crosstalk between vitamin D receptor and AR.
    Keywords:  AR; HOXC9; LNCaP; VDR; androgen; prostate cancer; vitamin D3
    DOI:  https://doi.org/10.3390/ijms27041962
  16. Technol Cancer Res Treat. 2026 Jan-Dec;25:25 15330338261424322
    The Gut-Prostate Axis: Decoding the Interplay of Environmental Factors, Microbial Metabolites, and Hormonal Regulation in Prostate Cancer Pathogenesis.
    Gopu Sandeep, Srijoni Pahari, Vinayak Nayak, Rohit Gundamaraju, Parul Mishra, Ashish Misra.
      Prostate cancer remains one of the most common malignancies in men, with its progression strongly influenced by androgen signaling. While genetic alterations are well-documented in prostate cancer, growing evidence highlights the contribution of environmental factors, particularly diet and the gut microbiome, in modulating disease risk and therapy response. The gut microbiota plays a crucial role in regulating host metabolism, immune responses, and hormone activity. Recent findings suggest that specific microbial communities influence androgen biosynthesis and metabolism through enzymes such as β-glucuronidase, altering systemic androgen availability and imp acting tumor progression. Additionally, microbial metabolites, including short-chain fatty acids, secondary bile acids, and bacterial genotoxins, can affect inflammatory pathways and cellular signaling relevant to prostate tumorigenesis. Experimental studies also indicate that modifying the gut microbiota through dietary interventions, probiotics, or fecal microbiota transplantation can influence tumor growth and improve responses to immunotherapy and hormone-based treatments. In this review we present the current knowledge on gut-prostate axis, examine the mechanistic links between microbial activity and prostate cancer biology, and discuss emerging microbiome-based strategies as potential therapies. A deeper understanding of this bidirectional crosstalk could pave the way for microbiome-informed approaches to prevention, diagnosis, and personalized treatment of prostate cancer.
    Keywords:  androgen metabolism; castration-resistant prostate cancer (CRPC); gut microbiota; hormonal dysregulation; microbiota-gut-testis axis; prostate cancer
    DOI:  https://doi.org/10.1177/15330338261424322
  17. Life (Basel). 2026 Feb 20. pii: 359. [Epub ahead of print]16(2):
    Selective Androgen Receptor Modulators in Women: What Do We Know, and What Is Still Missing.
    Veselin Vasilev, Katerina Georgieva, Maria Kraeva, Raina Ardasheva, Rumyana Etova, Nikolay Boyadjiev.
      Androgens and androgen receptor (AR) signaling influence many aspects of female physiology, including reproduction, musculoskeletal health, metabolism, and neurological regulation, yet are less studied than in males. Selective androgen receptor modulators (SARMs) were developed to provide tissue-selective anabolic effects with reduced androgenic side effects, but their effects in women are not well defined. This narrative review summarizes preclinical and clinical evidence on SARM use in female rodents and women, focusing on AR biology, tissue selectivity, therapeutic potential, and safety. A literature search of PubMed, Scopus, and Google Scholar identified relevant experimental and clinical studies addressing sex-specific AR signaling and SARM effects in females. Preclinical data indicate that SARMs can enhance sexual motivation and improve muscle and bone outcomes in ovariectomized models, with compound-dependent effects on reproductive tissues. Clinical studies in postmenopausal women demonstrate increases in lean body mass with generally limited androgenic effects, although functional benefits are inconsistent and alterations in lipid profiles and liver enzymes have been reported. Evidence also supports antitumor activity of AR-targeted SARMs in selected breast cancer subtypes. Overall, while SARMs show therapeutic potential in women, long-term safety and efficacy remain insufficiently characterized, warranting further sex-specific clinical investigation.
    Keywords:  SARMs; androgen receptor; androgens; women
    DOI:  https://doi.org/10.3390/life16020359
  18. Front Endocrinol (Lausanne). 2026 ;17 1734041
    BMI-stratified phenotypes of polycystic ovary syndrome: advances in gut microbiota research and personalized management strategies.
    Bisha Su, Yining Cao, Lin Ma, Jian Huang.
      Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine-metabolic disorder affecting 11%-13% of women of reproductive age. Based on body mass index (BMI), patients can be phenotypically classified into obese and non-obese subgroups: the obese PCOS is characterized by insulin resistance, hyperandrogenemia, and metabolic syndrome, with more pronounced metabolic risks; non-obese PCOS primarily manifests as reproductive endocrine dysfunction. In recent years, studies have shown that the Gut microbiota plays a key role in the pathogenesis of PCOS, and dysbiosis in the obese subgroup is generally more pronounced, potentially amplifying metabolic abnormalities through pathways such as short-chain fatty acids, bile acid disturbances, and endotoxin-related low-grade inflammation. This review systematically summarizes the clinically heterogeneous features of BMI-stratified PCOS and its gut microbiota characteristics, with a focus on elucidating the mechanistic differences between obese and non-obese individuals in terms of inflammation, metabolites, and endocrine regulatory pathways. Based on current evidence, individualized intervention strategies targeting different BMI subtypes are proposed, including dietary and lifestyle modifications, interventions with probiotics/prebiotics/synbiotics, and exploration of emerging precision microbiome therapies such as fecal microbiota transplantation. The interaction between BMI and gut microbiota provides new directions for stratified management and personalized treatment of PCOS; however, high-quality longitudinal and interventional studies are still needed to clarify causal relationships and optimize microbiota-targeted strategies.
    Keywords:  body mass index; gut microbiota; non-obese polycystic ovary syndrome; obese polycysticovary syndrome; personalized treatment; polycystic ovary syndrome
    DOI:  https://doi.org/10.3389/fendo.2026.1734041
  19. Int J Mol Sci. 2026 Feb 13. pii: 1815. [Epub ahead of print]27(4):
    Double Knockdown of the Androgen Receptor Target Genes DKK1 and SFRP1 Does Not Potentiate the Hair Growth-Promoting Effect of SFRP1 Silencing in Healthy Human Hair Follicles Ex Vivo.
    David Broadley, Alizée Le Riche, Ying Yu, Helene El-Bacha, Hanieh Erdmann, Francisco Jimenez, Mikhail Geyfman, Neil Poloso, Janin Edelkamp, Marta Bertolini.
      Androgen receptor (AR) signaling plays a key role in male pattern baldness. We investigated whether targeting Dickkopf 1 (DKK1) and Secreted frizzled-related protein 1 (SFRP1), two AR-regulated genes, offers a novel therapeutic strategy for hair loss. AR expression was validated in freshly frozen human scalp hair follicles (HFs). AR knockdown was induced in human HFs using AR spherical nucleic acid (SNA). DKK1 and SFRP1 siRNA treatment were performed in HEK293 cells, human dermal papilla cells (hDPC), and human HFs ex vivo. Functional effects of single and combined DKK1 and SFRP1 knockdown were analyzed in human HFs ex vivo by quantitative (immuno)histomorphology. AR knockdown decreased SFRP1 and DKK1 expression. We found reciprocal mRNA upregulation between DKK1 and SFRP1 following their siRNA knockdown in HEK293 and hDPC. We therefore applied a single and combined treatment of DKK1 and SFRP1 siRNA in HFs ex vivo. SFRP1 knockdown prolonged anagen, increased hair matrix keratinocyte proliferation, reduced apoptosis, and increased DKK1 levels in HFs ex vivo, whereas DKK1 knockdown had no effect, and combined knockdown did not enhance SFRP1's benefits. The culture-dependent compensatory regulation of SFRP1 and DKK1 underscores Wnt-signaling complexity in hair growth and strengthens the rationale for SFRP1 based therapies in anagen maintenance and hair loss.
    Keywords:  Dickkopf 1 (DKK1); Secreted frizzled-related protein 1 (SFRP1); Wnt signaling; androgen receptor; male pattern hair loss
    DOI:  https://doi.org/10.3390/ijms27041815
  20. Neuroscience. 2026 Feb 21. pii: S0306-4522(26)00127-2. [Epub ahead of print]600 1
    Are we truly accounting for sex differences in experimental neuroscience?
    Rita Sangtani.
      The recognition of sex as a biological variable has significantly influenced policies in preclinical neuroscience. Despite increased inclusion of both male and female subjects, meaningful integration of sex-based analyses remains inconsistent. Many studies lack adequate statistical power, mechanistic exploration, or transparent reporting of sex-disaggregated findings. Emerging evidence demonstrates that sex differences influence neural circuitry, neuroimmune interactions, and disease vulnerability, underscoring their biological relevance. Strengthening experimental design through prospective powering and mechanistic investigation is essential to enhance reproducibility, translational validity, and scientific rigor in contemporary neuroscience research.
    Keywords:  Neuroinflammation; Preclinical neuroscience; Reproducibility; Sex as a biological variable; Sex differences
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.02.030
  21. FASEB J. 2026 Mar 15. 40(5): e71622
    Regional and Sex-Dependent Immune Profiling Across the Colon in A Mouse Model of Ulcerative Colitis.
    Diane M Tshikudi, Fola Olayinka-Adefemi, Fazia Ait Zenati, Christine Zhang, Aaron J Marshall, Charles N Berstein, Jean-Eric Ghia.
      Ulcerative colitis (UC), an incurable inflammatory bowel disease, is characterized by a dysregulated immune system leading to mucosal damage along the large intestine. Sex-related differences in immune responses may influence the pathogenesis and disease course in UC. Given the distinctive immune profile across the gastrointestinal tract, determining how the immune system changes along the large intestine in healthy and disease conditions between sexes is critical for understanding UC pathophysiology. Here, we characterized the profile of immune cells and cytokines across segments (cecum, proximal, medial, and distal colon) of the large intestine collected from C57BL/6 male and female mice treated with 5% dextran sodium sulfate to induce colitis or water (healthy) using flow cytometry and Multiplex ELISA. Our study reveals that at steady states, females have a higher proportion of most myeloid and lymphoid cells than males, accompanied by a gradual increase in innate immune cells from the cecum to the distal colon in healthy females. Males had a higher level of several T helper 17 (TH17) cytokines in the medial and distal colon than females. Colitis was associated with increased granulocytes and tolerogenic immune cells in the medial and distal colon, and a shift in proinflammatory and TH17 cytokine levels toward the cecum in males. The immune profile differs along the large intestine between males and females at steady state and in colitic conditions, highlighting the importance of considering regional differences along the large intestine between sexes during diagnosis and while assessing the efficacy of new therapies using UC mouse models.
    Keywords:  cells; colitis; colon; cytokines; female; immunity; large intestine; male; sex factors; spatial analysis
    DOI:  https://doi.org/10.1096/fj.202503236RR
  22. Sci Rep. 2026 Feb 23.
    Effects of testosterone on gene expression in males and females across 40 human tissues.
    Evans Kiptoo Cheruiyot, Zhu Zhihong, Allan F McRae.
      
    Keywords:  GTEx; GWAS; Gene expression; Sex difference; Testosterone; UK Biobank
    DOI:  https://doi.org/10.1038/s41598-026-40863-2
  23. J Natl Cancer Cent. 2026 Feb;6(1): 58-72
    Alterations in AR-FOXA1 signaling in prostate cancer progression and therapeutic resistance.
    Shuai Gao, Nolan D Patten, Changmeng Cai.
      The androgen receptor (AR) is instrumental in the onset and progression of prostate cancer (PCa), establishing androgen deprivation therapy (ADT) as the first-line treatment for metastatic disease. However, the effectiveness of ADT is commonly short-lived. Many patients eventually relapse and develop castration-resistant prostate cancer (CRPC), commonly marked by reactivated AR signaling. Although next-generation AR signaling inhibitors (ARSi) provide temporary control, resistance inevitably emerges. While a small subset of CRPC cases may evolve through AR-independent pathways, most regain partial AR function through multiple mechanisms. A key regulator of AR activity is the pioneer transcription factor FOXA1, which governs AR binding to chromatin. The AR-FOXA1 axis is essential for prostate luminal epithelial cell lineage determination and drives the development of prostate adenocarcinoma. Emerging evidence shows profound alterations in this axis in CRPC and in tumors resistant to ARSi therapies. In this review, we highlight the genetic, epigenetic, transcriptional, and posttranscriptional changes within the AR-FOXA1 axis in PCa following ADT and ARSi treatments.
    Keywords:  Androgen receptor; Castration-resistant prostate cancer; FOXA1; Prostate cancer; Transcriptional reprogramming
    DOI:  https://doi.org/10.1016/j.jncc.2025.05.003
  24. Biomolecules. 2026 Feb 02. pii: 226. [Epub ahead of print]16(2):
    Endotoxins and Metabolic Endotoxemia in Obesity and Associated Noncommunicable Diseases: A Focus on Sex Differences.
    Manuela Del Cornò, Anna Aureli, Barbara Varano, Lucia Conti.
      Metabolic endotoxemia has been proposed as a possible mechanism to explain the strong link between inflammation, obesity, and obesity-associated disorders. Gut dysbiosis is a hallmark of obesity, and diet has been reported to regulate both inflammation and disease risk by affecting the composition of gut microbiota and gut barrier function. In the condition of microbial imbalance and impaired intestinal mucosa, bacterial endotoxins, specifically lipopolysaccharides, translocate from the gut into the bloodstream, where they can sustain a prolonged, sterile, low-grade inflammation, raising the risk of several non-communicable diseases. Increasing evidence indicates that the risk and incidence of obesity and several obesity-associated disorders are sex-specific, although the underlying mechanisms are only just emerging. Notably, most of the factors influencing metabolic endotoxemia exhibit sexual dimorphism. This review aims to summarize the human studies investigating the role of metabolic endotoxemia in obesity and associated diseases, with a focus on those highlighting sex differences. We also discuss the clinical relevance of circulating endotoxins in metabolic derangements and their potential role as sex-related and modifiable risk factors to consider in future prevention strategies.
    Keywords:  diet; endotoxin; inflammation; metabolic endotoxemia; noncommunicable diseases; obesity; sex differences
    DOI:  https://doi.org/10.3390/biom16020226
  25. Life (Basel). 2026 Feb 18. pii: 351. [Epub ahead of print]16(2):
    The Role of Granulocyte Colony-Stimulating Factor in Endometrial Preparation for Embryo Implantation in In Vitro Fertilization.
    Charalampos Voros, Fotios Chatzinikolaou, Georgios Papadimas, Iwakeim Sapantzoglou, Aristotelis-Marios Koulakmanidis, Vaitsis Dimitrios, Diamantis Athanasiou, Vasiliki Kanaka, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Ioannis Papapanagiotou, Charalampos Tsimpoukelis, Athanasios Karpouzos, Maria Anastasia Daskalaki, Nikolaos Kanakas, Marianna Theodora, Nikolaos Thomakos, Panagiotis Antsaklis, Dimitrios Loutradis, Georgios Daskalakis.
      Granulocyte colony-stimulating factor (G-CSF) has been suggested as a supplementary approach for endometrial preparation in IVF. Clinical results continue to be inconsistent. This narrative review synthesises molecular and clinical information to elucidate the function of G-CSF in modifying endometrial receptivity and to identify patient categories most likely to benefit. A thorough assessment was conducted on published research on G-CSF administration in women with treatment-resistant thin endometrium, recurrent implantation failure, and unselected IVF populations. The research demonstrates that G-CSF has phenotype-dependent effects. Improvements in pregnancy and live birth rates are inconsistent and seem dependent on the reversibility of underlying tissue disease; nevertheless, G-CSF reliably increases endometrial thickness in instances of thin endometrium and may restore eligibility for transfer. G-CSF improves implantation and early pregnancy outcomes in repeated implantation failure patients without modifying endometrial morphology, indicating a functional mechanism linked to immune-stromal synchronisation rather than structural expansion. In contrast, randomised controlled studies show no therapeutic benefit in unselected IVF groups. Discrepancies in research outcomes may mostly be attributed to variations in patient phenotype, initial endometrial function, and the therapy setting. Thus, G-CSF should be considered a specific approach for endometrial conditioning rather than just a supplementary component of IVF.
    Keywords:  embryo implantation; endometrial receptivity; granulocyte colony-stimulating factor; immune stromal interaction; in vitro fertilization; recurrent implantation failure; thin endometrium
    DOI:  https://doi.org/10.3390/life16020351
  26. J Mol Cell Cardiol. 2026 Feb 19. pii: S0022-2828(26)00031-3. [Epub ahead of print]214 1-10
    Sex differences in mitochondrial Ca2+ during ischemia/reperfusion injury: A role for S-Nitrosylation.
    Barbara Roman, Courtney E Petersen, Junhui Sun, Elizabeth Murphy.
      Sex differences in cardiac ischemia/reperfusion (I/R) injury have been reported, but the mechanisms underlying these differences remain poorly understood. As mitochondrial Ca2+ accumulation plays an important role in I/R injury, we examined whether sex specific differences occur. To monitor mitochondrial Ca2+ in Langendorff perfused hearts, we used a genetically encoded, mitochondrially targeted Ca2+ indicator (R-GECO1) delivered via an adeno-associated viral vector (AAV9). Male hearts accumulated significantly more mitochondrial Ca2+ during 20 min of ischemia than female hearts. Interestingly, sex differences in Ca2+ accumulation during ischemia were not observed in hearts from mice lacking the mitochondrial Ca2+ uniporter (MCU), suggesting an important role for MCU. As nitric oxide (NO) and its posttranslational modification S-nitrosylation have been suggested to modulate sex differences in Ca2+ homeostasis, we inhibited NO signaling in female hearts, which increased mitochondrial Ca2+ accumulation, while treatment of male hearts with an NO donor reduced mitochondrial Ca2+ levels, indicating that S-nitrosylation modulates Ca2+ uptake during ischemia in a sex-dependent manner. Using a biotin-switch assay in isolated mitochondria, we found increased S-nitrosylation of MCU in females compared to males. Finally, isolated male mitochondria exposed to an NO donor exhibited reduced Ca2+ uptake, comparable to untreated female mitochondria. Taken together, these findings suggest that S-nitrosylation of MCU reduces mitochondrial Ca2+ uptake during ischemia, uncovering a new layer of redox regulated mitochondrial function, with sex as a critical determinant.
    Keywords:  Ischemia-reperfusion; MCU; Mitochondrial calcium; S-Nitrosylation; Sex differences
    DOI:  https://doi.org/10.1016/j.yjmcc.2026.02.007
  27. J Gerontol A Biol Sci Med Sci. 2026 Feb 25. pii: glag059. [Epub ahead of print]
    Sex-specific proteostasis and urothelial responses to senolytic therapy in the aged mouse bladder.
    Sumiran Kasturi, Arnold M Salazar, Cara Hardy, Ron Korstanje, Indira U Mysorekar.
      Lower urinary tract dysfunction (LUTD) increases with age and disproportionately affects women, yet the molecular mechanisms underlying this sex bias remain poorly defined. The aging bladder plays a central role in this decline, and our previous work identified increased cellular senescence, oxidative stress, and activation of the PERK arm of the unfolded protein response (UPR) as key features of bladder aging. In this study, conducted as part of the NIH Common Fund SenNet program to investigate cellular senescence in mice, we explored the therapeutic potential of a senolytic drug combination of Dasatinib and Quercetin (D&Q) in male and female aged (25-month-old) bladders from genetically diverse Diversity Outbred mice. We first assessed sex differences in aged bladders (>20 months of age), then evaluated whether D&Q treatment could improve bladder health by modulating ER stress. We identified significant baseline sex differences in UPR and ER-associated degradation (ERAD) proteins, with higher expression of PERK pathway ER stress components in females and more efficient ERAD and autophagy flux in males. While D&Q did not broadly alter ER stress or autophagy markers, it selectively increased ERAD markers in females. D&Q also enhanced uroplakin expression and urothelial thickness in aged females, suggesting potential benefit to urothelial integrity. These findings suggest a potential sex-specific regulatory mechanism within the UPR pathway that may contribute to the increased vulnerability of aged females to bladder dysfunction.
    Keywords:  Dasatinib and Quercetin; ER Stress; Protein homeostasis; Sexual dimorphism
    DOI:  https://doi.org/10.1093/gerona/glag059
  28. Geroscience. 2026 Feb 23.
    Aging-associated autoimmunity in genetically diverse UM-HET3 mice shows an early female sex bias.
    Harini Bagavant, Natalia Guzniczak, Magdalena Makuch, Makayla Tillett, Angelika Mazur, Elizabeth Fernandez, Umesh S Deshmukh.
      Sjögren's disease, an autoimmune disorder characterized by the presence of circulating autoantibodies and lymphocytic infiltrates in salivary glands, predominantly affects women later in life. By leveraging genetically heterogeneous UM-HET3 mice, this study tested the hypothesis that female sex and aging interact to shape susceptibility to autoimmunity and salivary gland inflammation. Female and male UM-HET3 mice were evaluated across the adult lifespan for the development of glandular inflammation and autoantibodies. Aging female mice spontaneously develop Sjögren's-like salivary gland inflammation and systemic autoimmunity, whereas age-matched males exhibit only modest immune alterations. Histopathology and flow cytometry revealed significantly higher numbers of lymphocytic foci and immune cell infiltrates in the salivary glands of older females, including expansions of T follicular helper cells and atypical B cells associated with autoantibody production. Concordantly, aged females produced high-titer IgG autoantibodies recognizing nuclear and cytoplasmic antigens. Notably, even before the onset of overt glandular pathology, young adult females exhibited heightened baseline activation of splenic T and B cells, as well as upregulation of immune-activation genes, compared with males. Together, these findings demonstrate that in a genetically diverse background, female sex and aging synergize to drive spontaneous organ-specific inflammation and systemic autoimmunity. Considering that female UM-HET3 mice have a longer lifespan than male mice, the autoimmune response in females appears to remain benign. Thus, aged UM-HET3 mice provide a tractable model to dissect how gene-environment interactions transform benign age-associated autoimmunity into a pathogenic clinical disease.
    Keywords:  Aging; Autoimmunity; Mouse; Salivary glands; Sjögren's Disease; UM-HET3
    DOI:  https://doi.org/10.1007/s11357-026-02158-2
  29. Science. 2026 Feb 26. 391(6788): 922-925
    Interbreeding between Neanderthals and modern humans was strongly sex biased.
    Alexander Platt, Daniel N Harris, Sarah A Tishkoff.
      Sex biases in admixture and other demographic processes are recurrent features throughout human evolution. For admixture between Neanderthals and anatomically modern humans (AMHs), sex bias has been proposed as an explanation for the relative lack of Neanderthal ancestry in modern human X chromosomes compared with that in modern human autosomes. By observing a 62% relative excess of AMH ancestry in Neanderthal X chromosomes, we characterized the interbreeding between the two groups as predominantly male Neanderthals with female AMHs. Analytic and numerical modeling presents mate preference as a more parsimonious cause of the sex bias than purely demographic processes with differential patterns of male and female migration.
    DOI:  https://doi.org/10.1126/science.aea6774
  30. PLoS One. 2026 ;21(2): e0343041
    Distinct DNA methylation signatures in maternal blood reveal unique immune cell shifts in preeclampsia and the pregnancy-postpartum transition.
    Laiba Jamshed, Keaton W Smith, Samantha L Wilson.
      Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by immune dysregulation and significant risks to maternal and fetal health. While current management relies on high-risk patient monitoring and early diagnosis, these methods are costly and burdensome, especially for low-risk pregnancies. DNA methylation (DNAm) is a type of chemical modification that influences gene expression and has been associated with immune cell dynamics and PE pathogenesis. This study explores whether DNAm-based immune cell composition profiling can provide insights into immune dysregulation associated with PE. By also examining changes in immune cell composition across gestational timepoints and into the postpartum period, we aimed to establish a baseline of healthy immune adaptation during pregnancy, against which PE-related disruptions can be better understood. We conducted a search in the Gene Expression Omnibus (GEO) for DNAm datasets using Illumina 27K, 450K, and EPIC arrays from maternal blood in both healthy and PE pregnancies. We found two studies (GSE37722 and GSE192918) that met our criteria, involving a total of 24 healthy pregnancies and 14 with PE. To estimate immune cell composition (CD8 + T cells, CD4 + T cells, monocytes, granulocytes, natural killer cells, and B cells) from DNAm data, we applied the deconvolution algorithm developed by Houseman et al (2012). A linear model was used to assess statistical differences in immune cell proportions between PE cases and controls. Longitudinal analyses were also conducted to examine immune cell shifts during pregnancy and postpartum. No significant differences were observed between PE and control groups in any immune cell type. However, longitudinal analyses revealed substantial immune remodeling in the postpartum period, characterized by decreased monocytes and granulocytes, and increased natural killer cells, B cells, and T cells. While subgroup analyses showed some variability in significance, particularly in GSE192918, the overall trends were consistent across datasets, emphasizing the importance of gestational age in immune dynamics. These findings support the use of DNAm profiling as a valuable tool for characterizing immune cell dynamics during pregnancy. Although immune differences between PE cases and controls were not observed with the Houseman method, longitudinal shifts were consistently captured and provide additional insights into the evolution of immune changes from pregnancy to postpartum, supporting the potential of DNAm-based profiling for developing predictive and monitoring tools for pregnancy and pregnancy-related pathology. It is important to note that these analyses were based on a single deconvolution approach applied to a cohort with well-matched clinical criteria; and that differences in study design, timing of sample collection, and cohort characteristics may limit broader generalizability. Future studies leveraging pregnancy-included reference matrices in deconvolution methods and larger, more diverse cohorts are essential to refine the application of DNAm-based immune profiling in pregnancy and pregnancy complications.
    DOI:  https://doi.org/10.1371/journal.pone.0343041
  31. Curr Urol. 2026 Jan;20(1): 1-14
    Molecular mechanisms and classification of castration-resistant prostate cancer: Insights into androgen receptor, cancer stem cells, and neuroendocrine features.
    Yuan Shao, Zihao Liu, Jialu Ma, Yuankang Feng, Jianpeng Yu, Hua Huang, Yang Liu, Yuanjie Niu, Yong Wang.
      Castration-resistant prostate cancer (CRPC) is a considerable clinical challenge, driven by complex molecular mechanisms that enable tumors to evade androgen deprivation therapy. This review explores the molecular mechanisms driving CRPC progression, focusing on androgen receptor (AR) signaling, cancer stem cells (CSCs), and neuroendocrine differentiation (NED). In AR-dependent CRPC, AR signaling remains pivotal in disease progression. Mutations, splice variants, alternative pathways, and transcriptional regulation facilitate sustained AR activation despite androgen deprivation therapy. In addition, CSCs promote tumor recurrence and treatment resistance by maintaining cellular heterogeneity and evading conventional therapies. Furthermore, castration-resistant neuroendocrine prostate cancer, an aggressive subtype of CRPC, is characterized by AR independence and NED, making treatment challenging. These findings underscore the need for therapeutic strategies targeting AR-, CSC-, and NED-specific mechanisms. Crucially, the molecular classification of CRPC into AR-dependent CRPC, stem cell-like CRPC, and castration-resistant neuroendocrine prostate cancer subtypes-based on the interplay between AR signaling, CSCs, and neuroendocrine features-is essential for advancing precision medicine. Tailoring treatments to the molecular subtype and characteristics of each patient offers the potential to substantially improve prognosis and survival in CRPC.
    Keywords:  Androgen receptor signaling; Biomarker; Cancer stem cell; Castration-resistant prostate cancer; Molecular subtype; Neuroendocrine prostate cancer
    DOI:  https://doi.org/10.1097/CU9.0000000000000312
  32. Immun Inflamm Dis. 2026 Feb;14(2): e70376
    The Intersection of m6A Methylation and Immune Response in PCOS: A Bioinformatics Perspective.
    Wenting Xu, Lingli Shi, Aifang Lu, Lijuan Cui, Haiqing Qian, Jiahui Wang, Mengyu Tang, Lili Zhu, Lihong Wang.
       BACKGROUND: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder, the molecular underpinnings of which remain largely undefined. The most common methylation modification of RNA, N6-methyladenosine (m6A), plays an important role in various reproductive and endocrine disorders. This study investigates key m6A genes in PCOS and their association with immune cell infiltration using advanced bioinformatics methods.
    METHODS: We utilized gene expression data and clinical information from the Gene Expression Omnibus database data sets GSE137684, GSE80432, and GSE114419. The expression of m6A-related genes was analyzed across all samples. Using the GSVA and CIBERSORT packages in R, we developed a diagnostic model based on the m6A gene-protein interaction network, conducted enrichment analysis of hub genes, and assessed the correlation between these genes and immune cell infiltration.
    RESULTS: Analysis of data sets GSE137684 and GSE804322 identified variable expression patterns among three categories of m6A genes. A diagnostic model centered on m6A gene expression was established, highlighting five genes-WTAP, METTL14, ZC3H13, PCIF1, and RBM15-with significant effect coefficients. Unsupervised clustering of hub genes indicated that METTL14, HNRNPA2B1, YTHDF3, YTHDF2, YTHDC1, and YTHDC2 are potential discriminators in PCOS. The analysis of immune infiltration revealed a correlation between m6A regulators and immune cell levels, with METTL3 showing the most significant regulatory impact.
    CONCLUSION: N6-methyladenosine RNA methylation regulators are intricately linked with the development of PCOS and may influence immune cell infiltration in affected individuals. This study enhances our understanding of the molecular interactions in PCOS and suggests potential biomarkers for diagnosis and targets for therapeutic intervention.
    Keywords:  bioinformatics; immune infiltration; methylation; polycystic ovary syndrome
    DOI:  https://doi.org/10.1002/iid3.70376
  33. Exp Gerontol. 2026 Feb 25. pii: S0531-5565(26)00062-8. [Epub ahead of print] 113084
    Effects of body composition on age- and sex-related differences in resting metabolic rate from a healthy aging cohort.
    Marcos Moliné, Stephanie R Heimler, Nikki Bergstrom, Lina Scandalis, David Wing, Daniel Moreno, Howard J Phang, Anthony J A Molina.
      Resting metabolic rate (RMR) accounts for the majority of the total energy expenditure. While RMR is known to decline with advancing age and is recognized to be lower in females compared to males, the mechanisms underlying these differences remain unclear. Changes in body composition are posited to account for age- and sex-related differences in RMR, but to what extent lacks consensus. We characterized 80 healthy adults aged 23-82 years from the San Diego Nathan Shock Center (SD-NSC) clinical cohort for body composition and RMR using dual-energy x-ray absorptiometry (DXA) and indirect calorimetry techniques, respectively. Body composition metrics-body surface area (BSA), lean tissue mass (LTM), and total body fat (TBF)-were modelled as predictive variables to assess their explanatory power against the age and sex effects on RMR. We found that the negative association between RMR and age persists even after adjusting for body composition and sex, with a predicted decrease in RMR per decade of 62.6 kcal/day (ꞵ = -62.6, P < 0.0001). While individual body composition metrics do not account for the observed sex differences in RMR, adjusting for all body composition metrics together explained the observation that females have lower RMR compared to males. Our results suggest that while differences in body composition can explain sex differences in RMR, additional factors independent of body composition contribute to age-related differences. These results provide new insights into RMR differences among healthy individuals across the human life-course, which may inform age-appropriate interventions for optimizing metabolism.
    Keywords:  Age-related changes; Aging; Basal metabolic rate; Body composition; Calorimetry; Dual-energy x-ray absorptiometry (DXA); Energy expenditure; Healthy aging; Metabolic decline; Metabolism; RMR; Resting metabolic rate; Sex-specific metabolism; Skeletal muscle metabolism
    DOI:  https://doi.org/10.1016/j.exger.2026.113084
  34. Biol Sex Differ. 2026 Feb 26.
    SASdb: a comprehensive database for sex-biased alternative splicing profiles in human tissues.
    Xi Chen, Yueqi Lu, You Duan, Yongfeng Bai, Weidong Ye, Sijia Chen, Hang Zhou, Heng Xu, Le Xu, Cheng Guo.
      Alternative splicing (AS) significantly enhances transcriptomic diversity, and its dysregulation is implicated in numerous human diseases. However, no public database systematically compiles sex-related AS events across human tissues. We developed SASdb (http://www.gdbioinfo.top/sasdb), a comprehensive database contains 2,951,059 AS events and 46,418 sex-biased alternative splicing (SAS) events, covering 22 human tissues. SASdb reveals extensive sex-specific splicing patterns, offering new insights into molecular sex differences. A case study on NSCLC-specific SAS events, absent in healthy tissues, highlights their enrichment in cancer-related pathways like autophagy, GPI-anchor biosynthesis, and AMPK/mTOR signaling. SASdb's intuitive visualization supports research in sex biology and precision medicine.
    Keywords:  Alternative splicing; Database; Human tissues; Precision medicine; Sex differences
    DOI:  https://doi.org/10.1186/s13293-026-00861-5
  35. Life (Basel). 2026 Feb 17. pii: 344. [Epub ahead of print]16(2):
    A Dive into the Invisible: The Vaginal and Endometrial Microbiota in Gynecologic and Obstetric Disorders: A Narrative Review.
    Giorgia Schettini, Emilio Pieri, Cristina Rizzo, Matteo Giorgi, Virginia Mancini, Nassir Habib, Ramon Rovira, Gabriele Centini.
      The human microbiota is increasingly recognized as a key component of women's reproductive health. This narrative review examines the vaginal, endometrial, and gut microbiota and their roles in the pathogenesis of gynecologic and obstetric disorders, aiming to integrate current evidence into a clinically relevant framework. We review intrinsic (genetic, hormonal, and immunological) and extrinsic (environmental, lifestyle, and pharmacological) factors shaping microbial composition, with particular focus on dysbiosis and the role of the gut estrobolome within the microbiome in estrogen metabolism. The review synthesizes data on microbiota alterations associated with endometriosis, adenomyosis, uterine fibroids, endometrial polyps and hyperplasia, gynecologic malignancies, pelvic inflammatory disease, bacterial vaginosis, infertility, and adverse obstetric outcomes, including preterm birth and fetal growth restriction. Methodological approaches used to characterize the reproductive tract microbiota, such as vaginal swabs, endometrial sampling, and fecal analysis, are critically discussed, together with limitations related to low-biomass environments and contamination risk. Evidence regarding therapeutic modulation of the microbiota, including antibiotics, probiotics, hormonal therapies, and emerging microbiota-based interventions, is summarized, alongside the impact of gynecologic surgery on microbial translocation and long-term microbial balance. Overall, the available literature supports an association between microbiota alterations and multiple reproductive conditions, although causality remains incompletely established. Further standardized and longitudinal studies are needed to clarify mechanisms and guide microbiota-informed diagnostic and therapeutic strategies.
    Keywords:  dysbiosis; endometrial microbiota; estrobolome; gut–uterus axis; gynecologic diseases; infertility; microbiome; obstetric outcomes; reproductive tract microbiota; vaginal microbiota
    DOI:  https://doi.org/10.3390/life16020344
  36. Nat Microbiol. 2026 Feb 27.
    Skin androgens regulate Staphylococcus aureus pathogenicity via quorum sensing.
    Maria Sindhura John, Mahendran Chinnappan, Camille I Sturges, Methinee Artami, Mohini Bhattacharya, Rebecca A Keogh, Jeffrey S Kavanaugh, Shivani Jain, Hanna Gedamu, Jessica Komarovsky, Mauricio Velasquez, Tripti Sharma, Jeffrey G McDonald, Alexander R Horswill, Tamia A Harris-Tryon.
      Skin cells secrete testosterone, with greater amounts secreted at the skin surface of males compared with females. Males are also more susceptible to skin infections than females. Here we report that mice engineered with testosterone-deficient skin are resistant to methicillin-resistant Staphylococcus aureus infections. Testosterone promoted the expression of S. aureus cytotoxic virulence factors by activating the accessory gene regulator (agr) quorum-sensing pathway in a concentration-dependent manner and independent of quorum-sensing-activating auto-inducing peptides. Mutational analysis revealed that a functional histidine kinase AgrC in S. aureus was required for testosterone to exert its effect, with in silico evidence indicating a direct interaction between testosterone and AgrC. An isomer of testosterone, enantiomer-testosterone, that blocked bacterial quorum sensing, inhibited S. aureus-induced cytotoxicity of human cells. These findings advance our understanding of how the skin regulates bacterial virulence and reveals a potential therapeutic strategy for the management of infections.
    DOI:  https://doi.org/10.1038/s41564-026-02261-2
  37. Food Funct. 2026 Feb 26.
    Lacticaseibacillus rhamnosus DACN152 effectively ameliorated letrozole-induced polycystic ovary syndrome: sex hormone homeostasis, microbiota and metabolite profiles.
    Xiaoyong Chen, Xiao Liu, Jiajing Wang, Amel Ahmed Ibrahim, Zsolt Zalán, Huayi Suo.
      This study investigated the potential role of Lacticaseibacillus rhamnosus DACN152 (DACN152) in ameliorating polycystic ovary syndrome (PCOS). Using a letrozole-induced PCOS murine model, we demonstrated that DACN152 attenuated ovarian histopathological damage, restored estrous cyclicity, and normalized sex hormone levels. Furthermore, DACN152 enhanced ovarian steroidogenesis by regulating key steroidogenic genes (StAR, CYP17A1, and CYP19A1) and sex hormone receptors (Lhr and Pgr), while concurrently suppressing ovarian apoptosis through modulation of apoptotic regulators (Bax and Bcl-2). These changes were corroborated at the protein level. Additionally, DACN152 significantly restructured the gut microbiota composition in PCOS mice, marked by reduced abundances of Bacteroidota, Verrucomicrobiota, Dubosiella, and Akkermansia, alongside increased abundances of Firmicutes, Campylobacterota, Allobaculum, Ruminococcus, and Blautia. Serum metabolomic analysis revealed elevated levels of bile acids, including chenodeoxycholic acid (CDCA), taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA), and cholic acid (CA). Collectively, these findings provide a theoretical basis for the development of probiotic-functional foods for PCOS.
    DOI:  https://doi.org/10.1039/d5fo03870g
  38. Int J Mol Sci. 2026 Feb 12. pii: 1785. [Epub ahead of print]27(4):
    Epigenetic Landscape of Female Infertility: An Integrated Bioinformatics Perspective on DNA Methylation, MicroRNAs, and Gene Regulatory Networks Across PCOS, Endometriosis, and Diminished Ovarian Reserve.
    Maroua Jalouli, Md Ataur Rahman, Saber Nahdi, Abdel Halim Harrath.
      Female infertility diseases such as polycystic ovary syndrome (PCOS), endometriosis, diminished ovarian reserve (DOR), and recurrent implantation failure (RIF) have different clinical phenotypes. However, they might be epigenetically convergent, and thus the therapeutic targets may be potential. This study utilized transcriptome data, microRNA (miRNA), and DNA methylation data from the granulosa cells of four Gene Expression Omnibus (GEO) datasets, GSE138518, GSE105765, GSE232306, and GSE92324, to conduct integrated bioinformatics analysis. We focused on differentially expressed genes (DEGs), constructed a miRNA-mRNA network, performed ROC curve analysis, and conducted function enrichment and drug repurposing studies. Our findings identified eight dysregulated genes (H19, SULT1A4, HCK, SPI1, CARD16, NFE2, LST1, and KRT8) common to PCOS, DOR, and RIF, which may serve to distinguish PCOS specifically. Moreover, these DEGs are associated with pathways such as innate immune activation, inflammatory responses, the NOD-like receptor signaling pathway, and Fc gamma R-mediated phagocytosis. Notably, MiRNAs differentially expressed in endometriosis (specifically hsa-miR-202-5p and hsa-miR-141-3p) were found to directly target this gene set, highlighting the role of epigenetic regulation across infertility diseases. Additionally, our drug repurposing analysis identified several FDA-approved drugs, including Abacavir and Peginterferon Alfa-2b, suggesting that the HCK gene may be a viable target for drug development to address female infertility. Furthermore, we identified 192 genes that correlated with DNA methylation and expression levels in PCOS. Thus, this study underscores the epigenetic convergence of different female infertility diseases and highlights potential biomarkers and therapeutic options that could enhance treatment in reproductive medicine.
    Keywords:  DNA methylation; PCOS; bioinformatics; endometriosis; epigenetics; female infertility; microRNA; ovarian reserve
    DOI:  https://doi.org/10.3390/ijms27041785
  39. J Clin Endocrinol Metab. 2026 Feb 23. pii: dgag075. [Epub ahead of print]
    Male hypogonadism and testosterone therapy - facing the differences between recommendations and the real-life.
    Alberto Ferlin, Andrea Graziani.
      
    Keywords:  Male hypogonadism; online information; real-life; testosterone; testosterone therapy
    DOI:  https://doi.org/10.1210/clinem/dgag075
  40. Nurse Pract. 2026 Mar 01. 51(3): 32-38
    Androgen insensitivity syndrome: Presentation, diagnosis, and management.
    David E Harris.
       ABSTRACT: Androgen insensitivity syndrome (AIS) is a genetic disorder impacting 46,XY individuals. It occurs in a complete form, producing a 46,XY female with female genitalia but no internal female reproductive organs; a partial form, producing a 46,XY newborn with genitalia intermediate between the classic male and female types; and a mild form, producing a 46,XY male with male genitalia but oligospermia. This review examines the pathophysiology, presentation, diagnosis, and management of AIS. Its goal is to prepare the advanced practice registered nurse to recognize AIS, facilitate its diagnosis, and contribute to the multidisciplinary team needed for effective management.
    Keywords:  androgen insensitivity syndrome; differences of sex development
    DOI:  https://doi.org/10.1097/01.NPR.0000000000000414
  41. Clin Epigenetics. 2026 Feb 27.
    Interplay of the nasal microbiome and epigenome among adolescents.
    Anne K Bozack, Javier Perez-Garcia, Sheryl Rifas-Shiman, Yanjiao Zhou, Joanne Sordillo, Jenny Jyoung Lee, Brent Coull, Peggy S Lai, Emily Oken, Marie-France Hivert, Diane R Gold, Andres Cardenas.
       BACKGROUND: The respiratory microbiome, including that of the nasal cavity, is involved in host defense and airway pathophysiology. Interactions of the microbiome with the host immune system may impact health and disease susceptibility through changes in the epigenome. In this study, we aimed to analyze cross-sectional associations of nasal microbiome composition and the nasal epigenome among adolescents in the Project Viva cohort (N = 372, mean age: 13.0 years). We collected nasal swabs from anterior nares, profiled the microbiome by 16 S rRNA gene sequencing, and grouped samples into 6 clusters using partitioning around medoids. Nasal cell DNA methylation was measured with the Illumina MethylationEPIC BeadChip. In an epigenome-wide association study, we tested for associations of microbiome cluster assignment and DNA methylation using robust linear models adjusting sociodemographics, season, batch, and surrogates of cell type composition. Among significant loci, we conducted differential abundance analysis to identify individual bacterial genera associated with DNA methylation levels.
    RESULTS: A total of 45 loci had differential methylation between two or more microbiome clusters (pBonferroni< 0.05). Methylation differences between clusters ranged from 0.20 to 12.45% (median = 0.95%). Differentially methylated loci were near genes related to asthma (ITPR2, MAPK1), lung function (FKBP11), mitochondrial function (MRPL20, SPTBN1), inflammation (C3), and immune function (N4BP3, EIF5). The abundance of individual taxa, particularly Propionibacterium, was associated with methylation at 15 of these loci (FDR < 0.05). In addition, we found greater Corynebacterium abundance was associated with lower nasal epigenetic aging (FDR < 0.05).
    CONCLUSIONS: Our findings support the hypothesis that the nasal microbiome is associated with small-to-modest variation in the nasal epigenome. Future research is needed to investigate how the relationship between the nasal microbiome and epigenome is impacted by environmental exposures, as well as the health effects of microbial and epigenetic variation in early life and across the life course.
    Keywords:  Epigenetic aging; Multi-omics; Nasal DNA methylation; Nasal microbiome; Respiratory microbiome
    DOI:  https://doi.org/10.1186/s13148-026-02093-1
  42. Int Immunopharmacol. 2026 Feb 21. pii: S1567-5769(26)00219-5. [Epub ahead of print] 116375
    Corrigendum "Role of reactive oxygen species in polycystic ovary syndrome: Signalling pathways, mechanisms, and traditional Chinese medicine treatment strategies" [Int. Immunopharmacol. 173 (2026) 116251].
    Ziyi Wang, Shuyuan Liu, Mengyao Gao, Ying Shen, Miao Sun, Songli Hao.
      The biological role reactive oxygen species (ROS), both as byproduct of cellular respiration and as crucial secondary messengers, has been extensively acknowledged in scientific literature. Key ROS-generating enzymes and organelles, including mitochondria, NADPH oxidase, and the endoplasmic reticulum, have been found closely linked to the regulation of metabolic processes. An imbalance between oxidative and antioxidant systems, resulting from abnormal ROS production and leading to oxidative stress (OS), has been implicated as a significant pathogenic in a variety of diseases, such as polycystic ovary syndrome (PCOS). PCOS is a prevalent endocrine disorder that adversely affects reproductive health and metabolic homeostasis in women of reproductive age. This review provides a systematic examination of the three primary sources of ROS production, and explores the mechanisms through which excessive ROS production triggers the dysregulation of key signalling pathways. These pathways are central to the fundamental pathological features of PCOS, such as ovulatory dysfunction, obesity phenotype, insulin resistance, and hyperandrogenism, with a specific emphasis on the interactions within ROS signalling pathways. Grounded in the holistic regulation principles of Chinese medicine and targeting the core signalling pathway as the intervention focal point, we propose a comprehensive intervention strategy. This strategy incorporates natural compounds, herbal compounds, acupuncture, dietary supplements, and other therapeutic approaches, which will provide a new theoretical framework and research direction for enhancing the clinical management of PCOS.
    Keywords:  Natural compounds; Polycystic ovary syndrome; Reactive oxygen species; Signalling pathways; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.intimp.2026.116375
  43. J Clin Med. 2026 Feb 14. pii: 1528. [Epub ahead of print]15(4):
    Sex Hormones and Keratoconus: In Search of the Link.
    Iasonas Makrypoulias, Irini Chatziralli, Dimitris Papaconstantinou, Konstantinos Panagiotopoulos, Stylianos A Kandarakis, Petros Petrou, Anke Messerschmidt-Roth, Konstantinos Droutsas.
      Background: Keratoconus (KC) is the most common ectatic corneal disorder, causing progressive corneal deformation, visual impairment, and reduced quality of life. Although KC pathogenesis is multifactorial, the contribution of systemic factors, including hormonal regulation, remains incompletely understood. This study aimed to investigate the role of sex hormones and gonadotropins in KC in a predominantly Greek population. Methods: We recruited 105 KC patients and 71 healthy controls (HC). Plasma levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL), testosterone (TES), dehydroepiandrosterone sulfate (DHEA-S), and progesterone (PRG) were measured and analyzed in relation to corneal tomographic and biomechanical parameters, as well as treatment modality. Results: LH showed positive correlations with corneal biomechanical parameters. KC patients who underwent penetrating keratoplasty exhibited higher FSH levels and a reduced LH/FSH ratio compared with those treated with corneal cross-linking. E2 levels were increased in women over 46 years of age, while PRL correlated with Kmax and Q-value. Men with KC demonstrated reduced TES associated with corneal morphology and biomechanics, increased PRG levels, and reduced DHEA-S in keratoplasty-treated patients. Conclusions: These findings suggest that sex hormones and gonadotropins may contribute to KC pathophysiology, supporting a systemic hormonal component in disease progression.
    Keywords:  corneal biomechanics; keratoconus; sex hormones
    DOI:  https://doi.org/10.3390/jcm15041528
  44. J Natl Cancer Cent. 2026 Feb;6(1): 42-57
    Emerging therapies to overcome antiandrogen resistance and beyond in lethal prostate cancer.
    Furong Huang, Kexin Li, Jeffrey W Shevach, Qianben Wang.
      Prostate cancer remains the second most common malignancy among men worldwide, with treatment paradigms evolving dramatically over the last two decades. Despite the longstanding efficacy of androgen deprivation therapy (ADT) and its combination with next-generation androgen receptor (AR) signaling inhibitors or chemotherapy in metastatic hormone-sensitive settings, most tumors ultimately develop resistance and progress to lethal castration-resistant prostate cancer (CRPC). This resistance often stems from a range of molecular alterations, including AR mutations, amplifications, splice variants, and tumor suppressor gene lesions (e.g., TP53, RB1). Recent advances in genomic and translational research underscore the importance of biomarker-guided patient stratification to optimize therapeutic choices. Novel strategies to circumvent resistance include non-ligand-binding-domain AR inhibitors, potent AR degraders (e.g., proteolysis-targeting chimeras [PROTACs]), bipolar androgen therapy, and combination regimens incorporating PARP inhibitors or immunotherapies for selected subsets of patients. Additionally, gene-editing approaches targeting "undruggable" genetic lesions offer promise in preclinical models. Moving forward, clinical development of these emerging agents and personalized treatment approaches, supported by robust genomic profiling, is poised to enhance tumor control, extend survival, and improve quality of life for patients with advanced prostate cancer.
    Keywords:  Androgen receptor signaling; Emerging therapies; Precision medicine; Prostate cancer; Therapy resistance
    DOI:  https://doi.org/10.1016/j.jncc.2025.04.004
  45. Front Endocrinol (Lausanne). 2026 ;17 1766838
    Micronutrients in polycystic ovary syndrome: molecular pathways, deficiencies, and therapeutic potential.
    Madhumitha Natarajan, Shweatha H E, Raghu Nataraj.
      Polycystic Ovary Syndrome (PCOS) represents a complex endocrine-metabolic condition which presents with hyperandrogenism and anovulation together with insulin resistance and chronic low-grade inflammation affecting 21% of women during their reproductive years globally. Nutrition has always played a pivotal role in managing PCOS. Emerging evidence demonstrates that micronutrients play an essential part in regulating molecular processes that drive the pathophysiology of PCOS. The deficiency of micronutrients exacerbates insulin resistance, oxidative stress and hormonal dysregulation through their negative impact on PI3K/Akt, NF-κB and Nrf2 and steroidogenic enzyme signaling pathways, all of which play a key role in the pathophysiology of PCOS. This review synthesizes a comprehensive analysis of scientific findings which demonstrate how micronutrient levels influence the regulation of insulin function, inflammatory reactions, oxidative balance, methylation activities and ovarian health in PCOS patients. It also evaluates the potential advantages of targeted micronutrient supplementation used alongside standard management strategies, considering factors such as bioavailability and nutrigenomics, while emphasizing the need for robust large-scale randomized clinical trials. Overall, a molecularly targeted approach to micronutrients represents an emerging precision-nutrition strategy aimed at improving metabolic, reproductive, and inflammatory outcomes in women with PCOS.
    Keywords:  inflammation; insulin resistance; micronutrients; oxidative stress; polycystic ovary syndrome; precision nutrition
    DOI:  https://doi.org/10.3389/fendo.2026.1766838
  46. J Am Acad Dermatol. 2026 Feb 19. pii: S0190-9622(26)00269-0. [Epub ahead of print]
    Sex Differences in Pleomorphic Dermal Sarcoma: A SEER-Based Analysis.
    Eva M Shelton, Mitchell A Taylor, Yaohui G Xu.
      
    Keywords:  Pleomorphic dermal sarcoma; SEER database; cutaneous oncology; high-risk tumors; sex differences
    DOI:  https://doi.org/10.1016/j.jaad.2026.02.055
  47. Neuroscience. 2026 Feb 23. pii: S0306-4522(26)00141-7. [Epub ahead of print]
    Sex-specific beta1-adrenergic receptor regulation of VMNdm growth hormone-releasing hormone neuron metabolic sensor and counterregulatory transmitter gene expression.
    Rami Shrestha, Karen P Briski.
      Ventromedial hypothalamic nucleus/dorsomedial division (VMNdm) metabolic-sensory growth hormone-releasing hormone (Ghrh)/steroidogenic factor-1 (SF-1) neurons operate within the brain glucostatic circuitry. Noradrenergic neurotransmission conveys hindbrain metabolic sensor cues to as-yet-unidentified hypothalamic targets to control glucose counterregulatory hormone secretion. Current studies addressed the premise that norepinephrine may regulate this endocrine outflow by control of VMNdm Ghrh/SF-1 neuron counterregulatory transmission. Single cell-multiplex qPCR analysis of laser-catapult-microdissected Ghrh/SF-1 neuron transmitter marker gene profiles showed that VMN beta1-adrenergic receptor (β1-AR) gene silencing elicited divergent adjustments in Ghrh and glutaminase gene expression in hypoglycemic male versus female rats. This genetic manipulation prevented hypoglycemic inhibition of glutamate decarboxylase (GAD)-1 (males only) and -2 (both sexes) mRNAs and augmented neuronal nitric oxide synthase and SF-1 transcripts in insulin-injected females only. VMN β1-AR siRNA pretreatment diminished hypoglycemic patterns of Ghrh/SF-1 nerve cell glucose transporter-2 (males) and glucokinase (both sexes) gene expression. This gene knockdown paradigm caused opposite shifts in hypoglycemic 5'-AMP-activated-protein kinase-alpha subunit-1 and -2 gene transcription (i.e. down-regulated/males versus up-regulated/females). VMN β1-AR siRNA silencing had sex-specific effects on hypoglycemic patterns of counterregulatory hormone release. These results may suggest that VMNdm Ghrh/SF-1 neuron are direct targets for sex-dimorphic β1-AR-mediated norepinephrine control of metabolic sensory function and counterregulatory neurotransmission and may indicate that β1-AR - dependent neurochemical signaling by this distinctive nerve cell type is a critical determinant of sex-specific neural control of glucose homeostasis.
    Keywords:  AMPK; Ghrh; Glucokinase; Lactate; Laser-catapultmicrodissection; Sex differences
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.02.038
  48. Lupus Sci Med. 2026 Feb 23. pii: e001783. [Epub ahead of print]13(1):
    Sex-based clinical and immunological differences across lupus erythematosus subtypes: a cross-sectional multicentre study from China.
    Yu Pan, Hui Jin, Shihang Zhou, Zhang Ying, Leilei Bai, Qianjin Lu.
       OBJECTIVE: To investigate sex-related differences in clinical and immunological features across lupus erythematosus (LE) subtypes.
    METHODS: This cross-sectional analysis, based on the Lupus Erythematosus Multicenter Case-Control Study in Chinese populations (ChiCTR2100048939), included patients with SLE and major cutaneous LE (CLE) subtypes. Sex-specific comparisons were performed using R V.4.4.2.
    RESULTS: In 2097 patients (1865 SLE, 1648 CLE), female predominance was observed in all subtypes, with female-to-male ratios ranging from 11.3:1 (acute CLE, ACLE) to 2.1:1 (isolated CLE, iCLE). Except for ACLE, females had earlier or similar onset than males in all other subtypes. ACLE lesions were most common in females (67%). In male patients with LE, the proportion of discoid LE (DLE) lesions was higher than female patients (31% vs 12%). Compared with males, females exhibited higher frequencies of arthritis in SLE, ACLE, DLE and chilblain LE (CHLE). In DLE, renal involvement, haematological abnormalities and serositis were more frequently observed in females. In subacute CLE (SCLE), haematological abnormalities were significantly more common in females. Additionally, non-scarring alopecia was more common in females than in males. Females had higher autoantibody positivity in iCLE and chronic CLE, with significant differences in anti-double-stranded DNA, anti-Smith, anti-U1-nuclear ribonucleoprotein and anti-ribosomal P antibodies.
    CONCLUSIONS: Across the subtypes, several clinical manifestations show a consistent sex distribution: ACLE lesions, arthritis, non-scarring alopecia, Raynaud's phenomenon and autoantibodies occur more frequently in women with LE, whereas the proportions of DLE and SCLE lesions are higher in men with LE. In addition, certain features exhibit subtype-specific sex differences: among patients with SCLE, DLE and CHLE, women show a greater propensity for systemic involvement, whereas in those with SLE and ACLE, men demonstrate a higher tendency toward systemic disease.
    TRIAL REGISTRATION NUMBER: ChiCTR2100048939.
    Keywords:  Antibodies; Autoimmune Diseases; Autoimmunity; Lupus Erythematosus, Systemic
    DOI:  https://doi.org/10.1136/lupus-2025-001783
  49. Front Endocrinol (Lausanne). 2026 ;17 1749906
    Beyond glycemic control: molecular mechanisms of metformin in modulating cytokine networks in polycystic ovary syndrome.
    Amin Ullah, Yongxiu Chen, Fan Zhang, Bairong Shen.
      Polycystic ovary syndrome (PCOS) is a well-known hormonal and metabolic condition linked to immune system irregularities and persistent inflammatory responses. Cytokines play a central role in PCOS, contributing to insulin resistance (IR), ovarian dysfunction, and systemic inflammation. Metformin (Met), a first-line treatment for IR, exhibits immunomodulatory properties beyond its glucose-lowering effects. This review critically evaluates the molecular mechanisms by which Met modulates pro- and anti-inflammatory cytokines in PCOS, synthesizing preclinical and clinical evidence while highlighting inconsistencies and therapeutic implications. Met suppresses inflammation by reducing pro-inflammatory cytokines such as IL-6, IL-1, IL-17, TNF-α, and others. Met also regulates TGF-β signaling, mitigating ovarian fibrosis while promoting follicular development and oocyte maturation through increased expression of TGF-β family members such as GDF-9 and BMP-15. These effects highlight Met's dual role in modulating inflammation and fibrosis. Additionally, Met influences inflammatory chemokines such as CXCL13, fractalkine, and others, further regulating immune responses and reducing inflammation. Moreover, combining Met with anti-inflammatory agents, such as resveratrol and probiotics, shows synergistic benefits in PCOS management. Understanding Met's immunomodulatory mechanisms offers new insights into its therapeutic potential beyond glucose metabolism. Future large-scale, phenotype-stratified clinical trials are warranted to validate these mechanisms and translate the immunomodulatory potential of metformin into tailored therapeutic strategies for PCOS.
    Keywords:  inflammation; metformin; molecular mechanisms; polycystic ovary syndrome; pro and anti-inflammatory cytokines
    DOI:  https://doi.org/10.3389/fendo.2026.1749906
  50. Arthritis Rheumatol. 2026 Feb 23.
    Tissue-specific and spatially dependent metabolic signatures perturbed by injury in male and female mice.
    Hope D Welhaven, Avery H Welfley, Priyanka P Brahmachary, Mark Greenwood, Donald F Smith, Brian Bothner, Ronald K June.
       OBJECTIVE: Osteoarthritis-the leading cause of disability worldwide-disproportionately affects females, yet sex remains an overlooked determinant. This disparity stems from sex-specific differences in injury susceptibility-a major risk factor for disease. Using a non-invasive injury model, we demonstrate that injury drives local and systemic metabolic alterations and that these responses differ by sex.
    METHODS: Male and female mice were subjected to non-invasive joint injury. Eight days post-injury, serum, synovial fluid, and whole joints were collected for metabolomics. Additionally, whole joints were harvested for MALDI-MSI to capture spatial distribution of molecular species and identify osteochondral regions perturbed by injury.
    RESULTS: Comparative analyses between injured, contralateral, and naïve mice revealed metabolomic alterations across sample types. Data indicates that injury influences metabolic profiles in whole joints, synovial fluid, and serum, with consistent dysregulation of amino acid, purine, and pyrimidine metabolism, indicating a systemic effect of localized injury. Additionally, sex-dependent differences emerged across tissues, highlighting sexually dimorphic pathways following injury. MALDI-MSI generated 2D ion images of bone, the joint interface, and bone marrow, identifying region-specific metabolic changes following injury.
    CONCLUSION: Joint injury induces coordinated metabolic responses locally and systemically that extend beyond the injured joint and are influenced by sex. Integrating metabolomic and spatial analyses reveals how injury modulates joint pathophysiology across tissues and reveals sex-specific patterns relevant to PTOA risk. These findings improve pre-clinical PTOA models and deepen our understanding of the complex role of injury and sex in osteoarthritis pathogenesis, laying the foundation for targeted therapeutic strategies.
    DOI:  https://doi.org/10.1002/art.70098
  51. Front Cell Neurosci. 2026 ;20 1753241
    Distinct cytokine-producing dendritic cell profiles in females and males with major depressive disorder.
    Anna-Lena Boller, Jana Freff, Maximilian Bast, Kathrin Schwarte, Udo Dannlowski, Bernhard T Baune, Stefanie Scheu, Judith Alferink.
       Introduction: Major depressive disorder (MDD) is a revalent and disabling condition increasingly associated with immune dysregulation. Dendritic cells (DCs) are key immune sentinels that shape inflammatory responses and T-cell polarization, including Th17 pathways implicated in depression-related mild inflammation. Given well-documented sex differences in immune responses and cytokine profiles in MDD, differential DC activation may represent a mechanistic link between sex-associated immune cell profiles in depression. However, DCs remain insufficiently characterized in MDD.
    Methods: We performed an exploratory study using flow cytometry-based immunophenotyping to assess circulating DC subsets, including CD1c+ and CD141+ conventional DCs (cDCs), plasmacytoid DCs (pDCs), and their cytokine profiles in individuals with MDD (n = 55) and healthy controls (HC, n = 32). Stratification by depression severity and sex, together with correlation and multivariate linear regression analyses, and cluster analysis, was used to examine associations between DC subsets and depressive symptom severity in females and males.
    Results: Stratification by HAM-D17 scores revealed reduced counts of pDCs and increased frequencies of CD11c+ cDCs in the peripheral blood (PB) of severely depressed participants compared to HC or mildly depressed patients, respectively. Regarding cytokine-producing DCs, sex-stratified analyses showed that frequencies of IL-23+ cDCs were elevated and symptom-associated only in females with MDD compared to sex-matched controls, whereas frequencies of TNF+, IL-1β+, and IL-6+ cDCs were selectively increased in depressed males. Cluster analyses identified distinct female- and male-specific DC subset patterns distinguishing individuals with MDD from HC. Multivariate linear regression revealed a significant predictive contribution of cytokine-producing DCs, together with age and BMI, in females but not in males.
    Discussion: These findings demonstrate sex-specific alterations in cytokine-producing DCs in MDD and a strong association between IL-23+ cDCs and depressive symptom severity, suggesting a key role for these cells in immune dysregulation, particularly in females with depression.
    Keywords:  IL-23; cytokines; dendritic cells; female; immune system; inflammation; major depressive disorder; male
    DOI:  https://doi.org/10.3389/fncel.2026.1753241
  52. Biomolecules. 2026 Feb 05. pii: 258. [Epub ahead of print]16(2):
    Sexually Dimorphic Neuroimmune Pathways in Chronic Pain: A Comprehensive Systematic Review of Cellular and Molecular Mechanisms.
    Nebojsa Brezic, Strahinja Gligorevic, Aleksandar Sič, Vasilis-Spyridon Tseriotis, Nebojsa Nick Knezevic.
      Chronic pain is a highly prevalent and disabling condition with a well-documented female predominance in incidence, severity and persistence. These sex differences are driven by sexually dimorphic neuroimmune mechanisms rather than psychosocial factors alone. This systematic review was conducted to comprehensively synthesize human clinical and translational evidence on sex-specific neuroimmune and glial cell pathways underlying chronic pain. Scientific literature was systematically searched from database inception to December 2025 across multiple biomedical databases to identify relevant clinical and translational studies. Across pain conditions, convergent evidence demonstrated that chronic pain mechanisms diverge by sex at cellular and molecular levels. Male-predominant pathways were characterized by microglial activation, particularly P2X4 receptor-mediated signaling and brain-derived neurotrophic factor-dependent neuronal disinhibition, supported by neuroimaging, transcriptomic, and pharmacological data. In contrast, female-predominant mechanisms involved adaptive immune processes, including CD4+ and CD8+ T cell infiltration, pannexin-1-dependent leptin release, chemokine signaling, and astrocyte-mediated neuroimmune crosstalk. Sex-specific cytokine and chemokine profiles, differential glial activation patterns, and divergent neuroimmune-endocrine interactions further distinguished pain pathways between males and females. Despite consistent mechanistic trends, substantial heterogeneity within each sex, limited sex-stratified power in many studies, and variability in outcome measures constrained quantitative synthesis and generalizability. The findings indicate that chronic pain is not a unitary disorder but rather a collection of mechanistically distinct conditions shaped by biological sex. These results highlight the limitations of sex-neutral therapeutic strategies and support the development of precision medicine approaches incorporating sex-informed neuroimmune biomarkers and mechanism-matched interventions. Future studies should prioritize adequately powered sex-stratified analyses, integration of neuroimmune biomarkers and clinical trial designs capable of detecting sex-by-treatment interactions.
    Keywords:  chronic pain; microglia; neuroinflammation; precision medicine; sex differences
    DOI:  https://doi.org/10.3390/biom16020258
  53. bioRxiv. 2026 Feb 13. pii: 2026.02.12.705548. [Epub ahead of print]
    Cardiomyocyte NLRP3 signaling in right heart failure is sexually dimorphic via estrogen receptor α.
    Rafael Sobrano Fais, Erica das Neves Palotta, Katrina W Kopf, Karina M Massad, Evandro M Neto-Neves, Christopher Hoffer, Avram D Walts, Andrea L Frump, Neil M Goldenberg, Sophie Givens, Alice Bourgeois, Chen-Shan C Woodcock, Irina Petrache, Naomi C Chesler, Kathleen C Woulfe, Soni S Pullamsetti, Olivier Boucherat, Steve Provencher, Brenda M Ogle, Sébastien Bonnet, Tim Lahm.
       Rationale: RV adaptation in pulmonary hypertension is sexually dimorphic and more preserved in women. NLRP3 inflammasome activation contributes to RV failure (RVF) development. However, regulators and downstream effects of NLRP3 activation in the RV remain unknown.
    Objectives: We investigated whether NLRP3 inflammasome activation in RVF is sexually dimorphic, whether NLRP3 is active in RV cardiomyocytes (RVCMs) and causes RVCM contractile dysfunction, and whether 17β-estradiol (E2) and its receptor ERα attenuate this process.
    Methods: We studied RV tissues from PAH patients with RVF, RV tissues and RVCMs isolated from wild-type and ERα loss-of-function mutant rats with RVF, isolated perfused rat hearts, and human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. NLRP3 activation was assessed via RNA-sequencing, proteomics, immunostaining, and downstream target quantification. RV contractility was assessed via pressure-volume loops, perfused heart studies, and contractility and calcium assessments in isolated RVCMs.
    Measurements and Main Results: NLRP3 was upregulated in RVCMs during RVF and resulted in altered RVCM calcium handling and RVCM contractile dysfunction. In human RVs, hiPSC-cardiomyocytes and rat RVs, NLRP3 activation and NLRP3-induced RVCM contractile dysfunction were sexually dimorphic and male-biased. Ovariectomy and loss of ERα in females eliminated this sex bias. E2, via ERα, prevented RVCM NLRP3 activation and NLRP3-induced RVCM contractile dysfunction in males and ovariectomized females during both acute and chronic RV pressure overload. ERα directly interacted with NLRP3.
    Conclusions: NLRP3-driven RVCM contractile dysfunction is male-biased. E2 inhibits NLRP3 through ERα to preserve RVCM contractility. Targeting E2-ERα-NLRP3 signaling may offer novel therapeutic strategies for RVF in low estrogen states.
    Impact: This is the first study to define a novel estradiol-estrogen receptor α-NLRP3 axis that modulates RV cardiomyocyte function and RV adaptation in pulmonary hypertension. We demonstrate for the first time that NLRP3 activation is therapeutically targetable in low estrogen states via NLRP3 inhibitors or 17β-estradiol. These findings have direct implications for therapeutic strategies aimed at preserving or restoring RV contractile function in pulmonary hypertension, a current area of unmet clinical need.
    DOI:  https://doi.org/10.64898/2026.02.12.705548
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