bims-simsho 2025-12-28 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–12–28
thirty-two papers selected by
Chun-Chi Chang, Lunds universitet

The interplay of microbiome, molecular mechanisms, and fertility -an integrated review.
Targeting sex hormone signaling: A promising therapeutic alternative for glioblastoma.
Sex-dependent immune activation shapes disease progression in a model of Parkinson's disease.
Restraining SRD5A1 combined with BRD4 inhibitor delaying prostate cancer progression by decreasing AR expression.
The composition of lower genital tract microbiota correlates with in vitro fertilization and frozen embryo transfer outcomes in women with polycystic ovarian syndrome.
Relative contribution of gonads and sex chromosomes to sex differences in cell-type gene expression in the mouse medial septum and sex-biased disease risk.
Asymmetric Cross-Reactivity of Nuclear Receptors Reveals an Evolutionary Buffer Between Estrogen and Androgen Signaling.
Inflammaging: triggers, molecular mechanisms, immunological consequences, sex differences, and cutaneous manifestations.
Site-specific ERα phosphorylation determines sex-dependent metabolic, reproductive, and body-compositional phenotypes in mice.
The mechanism study of targeting DPP4 in regulating ferroptosis and its influence on endometrial receptivity in PCOS.
Intestinal Microbiome in Response to Air Pollutant Exposure in Pregestational and Gestational Murine Females and their Male and Female Offspring.
X chromosome dosage in respiratory stem cells is critical for post-embryonic development and survival.
Sex Hormones and Effects on Kidney Health: Piecing Together the Science.
Interaction between ZMIZ2 and AR promotes prostate cancer proliferation in vitro and in vivo.
Sex-specific placental transcriptome alterations in late-onset preeclampsia reveal male-biased immune and metabolic dysregulation.
Correction to: "Growth and Adult Height Attainment in Danish Transgender Adolescents Treated With GnRH Analog and Sex Hormones".
Inter- and intra-individual differences in brain sex map to neuroendocrine profiles.
Diet-derived microbial metabolites as regulators of immune function.
Sex Differences in Thyroid Function: From Central Regulation to Hormone Metabolism and Disease Susceptibility.
Gut hormone signaling drives sex differences in metabolism and behavior.
Sex differences in the neural circuitry of aggression.
Effects of high basal luteinizing hormone levels on in vitro fertilization/intra-cytoplasmic injection outcomes in polycystic ovarian syndrome: a retrospective study.
Immunometabolism and male reproductive function: linking inflammation, oxidative stress, and declining fertility.
Skin Microbiome in Health and Disease: Mechanisms and Emerging Therapeutic Strategies.
Glycan Profile Alterations in Vaginitis and Their Role in Pathogen-Host Interactions.
MicroRNA Crossroads in PCOS and Endometriosis.
Single-cell transcriptomics reveals systemic immune dysregulation in non-segmental vitiligo.
2-Deoxy-D-glucose attenuates lipopolysaccharide-induced inflammation and restricts Zika, Chikungunya, and Mayaro virus replication in monocyte-derived macrophages.
Prolonged Loss of Oxidative Phosphorylation and Mitochondrial Mass Characterize CD66b + Leukocytes from Patients with Sepsis.
Forced vaginal sex and genital immune correlates of HIV risk: a prospective study of female sex workers in Kenya.
Sex Bias in IL-10 Production by Type I Regulatory T Cells Regulated by PI3K/mTOR Signaling.
BMI is associated with sperm quality and sex hormones in men: a meta-analysis.

Folia Microbiol (Praha). 2025 Dec 26.

The interplay of microbiome, molecular mechanisms, and fertility -an integrated review.

Xiaoyu Zhang, Chaofan Li, Xiaoling Feng, Xingxing Yuan.

  The human microbiome, particularly the gut and reproductive tract microbiota, plays a critical role in regulating fertility through complex molecular and immunological mechanisms. This review synthesizes emerging evidence on the bidirectional communication along the gut-reproductive axis, emphasizing how microbial-derived metabolites, such as short-chain fatty acids (butyrate), bile acids, and indoles, modulate systemic inflammation, immune tolerance, hormone metabolism, and energy homeostasis. Dysbiosis, or microbial imbalance, is strongly associated with a range of reproductive pathologies, including polycystic ovary syndrome, endometriosis, premature ovarian insufficiency, impaired spermatogenesis, and recurrent implantation failure. Furthermore, site-specific microbiomes, such as Lactobacillus-dominated vaginal and uterine communities, are vital for successful implantation and pregnancy maintenance. External factors including diet, environmental toxins, and antibiotic use can disrupt these microbial ecosystems, whereas interventions like probiotics like Lactobacillus and Clostridium butyricum, prebiotics, postbiotics, and fecal microbiota transplantation offer promising avenues for restoring microbial and reproductive health. However, translational challenges remain, including methodological heterogeneity in microbiome research and the need to establish causal mechanisms beyond correlation. Future efforts should prioritize multi-omics integration, randomized controlled trials, and personalized microbiome-based diagnostics and therapeutics to effectively address infertility.

Keywords:  Dysbiosis; Gut-reproductive axis; Infertility; Microbial metabolites; Microbiome therapeutics

DOI:  https://doi.org/10.1007/s12223-025-01404-y
Biochim Biophys Acta Rev Cancer. 2025 Nov;pii: S0304-419X(25)00228-8. [Epub ahead of print]1880(6): 189486

Targeting sex hormone signaling: A promising therapeutic alternative for glioblastoma.

Juan Carlos Quintero, Omar Rafael Alemán, Ignacio Camacho-Arroyo.

  Glioblastoma is the most common and malignant primary brain tumor of the central nervous system, with conventional therapy yielding very poor results in overall patient survival and quality of life. The low life expectancy at diagnosis of just 15 months, highlights the need for novel therapeutic alternatives. Glioblastoma has a higher incidence in men than in women, suggesting a critical role of sex hormone signaling in tumor maintenance and progression. There is now ample evidence that sex hormones impact glioblastoma malignancy. Testosterone, through the androgen receptor, promotes proliferation, migration, and invasion of tumor cells. Interestingly, estradiol and progesterone show both pro- and anti-tumor effects, depending on the dose and the specific receptors expressed in the cells. Sex hormones regulate gene activity by binding to intracellular receptors, which act as ligand-activated transcription factors. Additionally, the presence of membrane receptors for estrogens and progesterone can promote rapid cellular responses, activating signaling pathways such as PI3K/AKT and MAPK in tumor cells. Thus, the regulation of sex hormone activity and receptor function can directly affect tumor progression and survival. This article analyzes the impact of sex hormone signaling on the malignancy of glioblastomas.

Keywords:  Androgen receptor; Estrogen receptor; Glioblastoma; Progesterone receptor

DOI:  https://doi.org/10.1016/j.bbcan.2025.189486
Biol Sex Differ. 2025 Dec 24.

Sex-dependent immune activation shapes disease progression in a model of Parkinson's disease.

Leah C Beauchamp, Lily A Palumbo, Toby B Lanser, Mariam Baig, Laura M Cox.

   BACKGROUND: While it is clear that inflammation contributes to Parkinson's disease (PD) and prevalence is higher in males, sex remains an underexplored determinant of immune responses in PD.
METHODS: Using the 3KL transgenic mouse model, which expresses three E to K α-synuclein mutations, we investigated how sex and age shape peripheral and central immunity and behavior in synucleinopathy. Male and female 3KL mice were aged to 8- and 14-months. At these ages animals underwent motor and cognitive assessment, followed by assessment of the peripheral immune response using flow cytometry and analysis of microglial transcriptional profiles by bulk RNA sequencing.
RESULTS: Male 3KL mice exhibited earlier onset and greater severity of motor and cognitive impairments, which was linked to a pro-inflammatory peripheral immune profile marked by increased cytotoxic CD8⁺ T cells and IFNγ-producing CD4 Th1 cells. In contrast, female mice displayed delayed symptom onset, preserved cognition, along with early elevations in regulatory IL-10⁺ CD4 and γδ T cells. RNA sequencing of microglia revealed broad sex differences at 8 months. Males demonstrated early upregulation of microglia neurodegenerative signatures, MHC class I/II signaling, ceramide signaling, and pronounced lipid dysregulation, while females showed upregulation of microglial pathways related to protein, metabolic, and neuronal maintenance, including phagosome formation, docosahexaenoic acid signaling, and synaptogenesis pathways. Microglial transcriptional differences were nearly absent by 14 months, suggesting sex-specific trajectories converge during late-stage disease, which is concurrent with a decrease in estrogen in aged female mice.
CONCLUSIONS: Together, these findings reveal distinct immune signaling in male and female 3KL mice and identify coordinated changes in T cell and microglial responses that may contribute to sex differences in PD vulnerability and progression. This work underscores the importance of incorporating sex as a biological variable in neurodegeneration research and provides mechanistic insight into immune-mediated modulation of synucleinopathy.

Keywords:  3KL; Aging; Alpha synuclein; Cognition; Microglia; Parkinson’s disease; Sex; T cells

DOI:  https://doi.org/10.1186/s13293-025-00809-1
Int J Biol Macromol. 2025 Dec 19. pii: S0141-8130(25)10367-X. [Epub ahead of print]338(Pt 2): 149810

Restraining SRD5A1 combined with BRD4 inhibitor delaying prostate cancer progression by decreasing AR expression.

Yifan Liu, Duocheng Qian, Yifan Ding, Denglong Wu, Chenye Tang, Chengdang Xu, Xi Chen.

  With increasing life expectancy, prostate cancer (PCa) has exhibited rising incidence and mortality rates. Although therapies such as androgen deprivation therapy (ADT) effectively extend patient survival, the development of drug resistance remains a major obstacle. Previous studies identified a key enzyme in the androgen metabolic pathway as essential to PCa progression, regulated by the epigenetic reader BRD4. Bioinformatic analysis revealed that SRD5A1, a critical enzyme in androgen metabolism, is downregulated by the BRD4 inhibitor JQ1. This finding was validated using I-BET151, another BRD4 inhibitor, which also suppressed SRD5A1 expression in PCa cell lines. Furthermore, treatment with dutasteride (Duta), an SRD5A family inhibitor, significantly reduced both cell proliferation and invasion. Mechanistic investigations demonstrated that SRD5A1 promotes androgen receptor (AR) activity by elevating intracellular dihydrotestosterone (DHT) levels, thereby enhancing AR expression and facilitating tumorigenesis. Notably, both BRD4 and SRD5A1 were shown to modulate AR expression in PCa cells. Co-administration of BRD4 and SRD5A1 inhibitors yielded a more pronounced suppression of AR expression. These findings highlight the pivotal role of SRD5A1 in PCa progression and suggest that combinatorial inhibition of BRD4 and SRD5A1 may provide a more effective strategy for attenuating AR expression and halting disease development.

Keywords:  Androgen receptor; BRD4; Prostate cancer; SRD5A1

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149810
Front Cell Infect Microbiol. 2025 ;15 1617187

The composition of lower genital tract microbiota correlates with in vitro fertilization and frozen embryo transfer outcomes in women with polycystic ovarian syndrome.

Yaoyao Tu, Zhiyang Zhou, Ye Lu, Bin Wei, Yingzhou Ge, Guolian Ding, Xi Dong, Jianzhong Sheng, Yixiang Zhang, Li Jin, Hefeng Huang.

  Adverse reproductive outcomes remain a significant concern for women of reproductive age with polycystic ovary syndrome (PCOS), yet the role of the lower genital tract (LGT) microenvironment has been largely overlooked. This study aimed to investigate the association between the LGT microbiome and the outcomes of in vitro fertilization and frozen embryo transfer (IVF-FET) in women with PCOS. A total of 191 reproductive-aged women undergoing assisted reproductive technology (ART) treatment between December 2018 and October 2021 were recruited. The LGT microbiota was profiled using 16S rRNA sequencing and analyzed in relation to ART outcomes and clinical parameters. Furthermore, cervical transcriptome sequencing was performed in a subset of PCOS patients to investigate whether LGT microbiota alterations were associated with functional changes in mucosal epithelial cells. The results demonstrate significant dysbiosis of the LGT microbiome in patients with PCOS, characterized by a reduction in Lactobacillus abundance. Among 72 PCOS patients undergoing IVF-FET, those with a relative Lactobacillus abundance of ≥50% (n = 57) exhibited significantly improved reproductive outcomes compared to those with Lactobacillus abundance <50% (n = 15). Elevated testosterone levels were identified as the most significant factor associated with a reduced abundance of Lactobacillus in PCOS patients. Transcriptomic analysis further revealed that the LGT microbiota was associated with maintaining mucosal epithelial barrier integrity and immune homeostasis in PCOS. In conclusion, the findings highlight that dysbiosis of the LGT microbiota may significantly influence reproductive outcomes in PCOS patients, emphasizing the importance of targeting the LGT microenvironment to improve ART success rates.

Keywords:  in vitro fertilization and frozen embryo transfer; lactobacillus; lower genital tract; microbiota; polycystic ovary syndrome

DOI:  https://doi.org/10.3389/fcimb.2025.1617187
bioRxiv. 2025 Dec 11. pii: 2025.12.08.693050. [Epub ahead of print]

Relative contribution of gonads and sex chromosomes to sex differences in cell-type gene expression in the mouse medial septum and sex-biased disease risk.

Juliana Shin, Montgomery Blencowe, Caden McQuillen, Haley Hrncir, Xuqi Chen, Graciel Diamante, In Sook Ahn, Guanglin Zhang, Arthur P Arnold, Allan Mackenzie-Graham, Jason Lerch, Armin Raznahan, Xia Yang.

Background: While sex differences in the brain have traditionally been attributed to gonadal hormones, emerging evidence points to regulation by sex chromosomes. This study aims to differentiate the influence of gonads versus sex chromosomes on cellular gene expression in the mouse medial septum (MS), a critically understudied brain region.
Methods: Using single nucleus RNA-sequencing and the Sex Chromosome Trisomy mouse model, we (1) quantified sex differences in cellular gene expression and (2) isolated sex-biasing effects by identifying perturbed cell types, differentially expressed genes, biological pathways, and gene networks, which were integrated with GWAS data to explore links with sex-biased human phenotypes.
Results: Our analysis revealed that volumetric sex differences in the MS are mirrored by widespread transcriptomic changes across cell types. Critically, genetic effects displayed elevated relevance compared to sex hormones in driving sex-biased gene expression. These effects converge to regulate synaptic/neuronal development, transcriptional regulation, and cellular metabolism. Sex chromosome-associated DEGs were enriched for various human disorders, suggesting a cellular and mechanistic basis for their sex-biased patterns.
Conclusions: Our findings challenge the classical gonad-centric views of sexual differentiation, as the MS displays sex-biased transcriptional regulation driven by sex chromosome-associated effects that are highly relevant for human health.

DOI: https://doi.org/10.64898/2025.12.08.693050
bioRxiv. 2025 Dec 21. pii: 2025.12.18.695200. [Epub ahead of print]

Asymmetric Cross-Reactivity of Nuclear Receptors Reveals an Evolutionary Buffer Between Estrogen and Androgen Signaling.

Shintaro Yamazaki, Akhilesh B Reddy.

A comprehensive all-by-all receptor ligand affinity screen using Boltz-2, a deep learning framework for protein-ligand interaction prediction, reveals a previously unrecognized asymmetry in steroid hormone receptor binding. Using systematic in silico affinity prediction, we show that estradiol binds the androgen receptor with higher predicted affinity than testosterone and also displays strong affinity for multiple related steroid hormone receptors, whereas the reciprocal interaction, binding of non-aromatized steroids to estrogen receptors, is not observed. Structural modeling demonstrates that estradiol and testosterone occupy the same canonical ligand-binding pocket within the androgen receptor, indicating a conserved steroid-recognition architecture rather than a specialized binding mode. Analysis of a clinically relevant androgen receptor mutation shows modest and broadly distributed stabilization of ligand engagement, consistent with tuning of a pre-existing estradiol-compatible interaction rather than generation of a novel binding mechanism. Reconstruction of ancestral steroid receptors indicates that estradiol maintains high predicted affinity across both ancestral and modern receptors, while other steroids progressively diversify in their receptor preferences following lineage expansion. Together, these results support an evolutionary model in which estradiol represents an early steroid ligand, with younger receptors retaining ancestral estrogen compatibility while evolving specificity for upstream steroid hormones. Functionally, this asymmetric architecture provides a mechanism by which estradiol may modulate androgen receptor signaling under physiological conditions and may contribute to altered receptor activation in pathological contexts such as advanced prostate cancer. These findings define a coherent biochemical and evolutionary framework for estradiol cross-reactivity and highlight the estradiol-androgen receptor interface as a potential therapeutic target.

DOI: https://doi.org/10.64898/2025.12.18.695200
Front Immunol. 2025 ;16 1704203

Inflammaging: triggers, molecular mechanisms, immunological consequences, sex differences, and cutaneous manifestations.

Ebru Karpuzoglu, Steven D Holladay, Robert M Gogal.

  Inflammaging, defined as chronic, low-grade, systemic inflammation that increases with age in the absence of overt infection, is a phenomenon that was first described in 2000 as a member of a growing number of age-related processes that had pleiotropic effects on immune function and disease susceptibility. Although many pathological consequences have been attributed to inflammaging, it remains distinct from immunosenescence and not completely understood. A resurgence of interest in inflammaging has been spurred by recent work demonstrating roles for senescent cells in driving chronic inflammatory signaling and defining the cellular and molecular triggers that sustain cytokine production during aging. Alongside elevations in pro-inflammatory mediators (e.g., IL-6, TNF-α, IL-1β), attention to anti-inflammatory mediators (e.g., IL-10, IL-1Ra) and composite ratios (e.g., IL-6:IL-10) can better index inflammatory balance in older adults. In this review, we summarize the characterization of inflammaging mechanisms, highlight roles for chronic inflammation that are clearly defined in immune system remodeling, and outline questions regarding inflammaging functions in sex differences, hormonal regulation, autoimmunity, and skin biology that still require further exploration.

Keywords:  estrogen; immunosenescence; inflammaging; inflammation; sex differences; skin aging

DOI:  https://doi.org/10.3389/fimmu.2025.1704203
iScience. 2025 Dec 19. 28(12): 114112

Site-specific ERα phosphorylation determines sex-dependent metabolic, reproductive, and body-compositional phenotypes in mice.

Binghao Zou, Jarvis Williams, Madeleine B Landau, Weiqiang Lin, Sallie Fell, Ziqi Yang, MaryJane Jones, Robert Blair, Chad H Steele, Pratik Khare, Cissy Zhang, Anne Le, Muralidharan Anbalagan, Brian G Rowan.

  Estrogen receptor alpha (ERα) phosphorylation regulates receptor activity and tissue-specific gene expression. We generated serine (S) to alanine (A) phosphorylation-deficient knock-in mice targeting two conserved ERα sites, S171 and S216, to examine their physiological roles. ERα S216A females were subfertile, with ∼30% smaller litters and diminished uterine growth in response to estradiol (E2). Single-cell spatial transcriptomics revealed a disrupted E2-regulated transcriptome in the myometrium. Metabolic profiling revealed the suppression of glycolytic and redox pathways in ERα S216A mice, with males exhibiting reduced adiposity and increased lean mass. Skeletal analysis revealed opposing effects: ERα S216A females exhibited reduced femoral bone density, while ERα S171A females showed an increase. These data demonstrate critical roles for site-specific ERα phosphorylation in modulating receptor levels and activity, as well as gene expression, which have a profound impact on murine body composition, fertility, and metabolism.

Keywords:  cell biology; metabolomics; transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2025.114112
Biol Sex Differ. 2025 Dec 23. 16(1): 107

The mechanism study of targeting DPP4 in regulating ferroptosis and its influence on endometrial receptivity in PCOS.

Jian Zhang, Ruifang Wang, Xiuli Tian, Nan Ding, Yajun He, Kexin Wang, Chengbin Tao, Jiao Cai, Qiliang Jian, Fang Wang.

   BACKGROUND: Polycystic ovary syndrome (PCOS) impairs endometrial receptivity, contributing to reproductive dysfunction. Our previous work identified ferroptosis-related dipeptidyl Peptidase 4 (DPP4) as a key regulator of endometrial receptivity in PCOS, though its mechanism remained unclear.
OBJECTIVE: We aimed to explore the regulatory mechanism of DPP4 in the occurrence and tolerance of endometrial ferroptosis in PCOS.
METHODS: Using high dose (HD) DHEA-induced rats and hormone-treated (E2 and HD DHEA) telomerase-immortalized human endometrial stromal cells (T-HESCs), we investigated DPP4's role in endometrial ferroptosis and receptivity. We evaluated the correlation of specific endometrial marker expression levels with reproductive outcomes.
RESULTS: Phenotypic assessments revealed elevated endometrial Fe2+ accumulation, antioxidant dysfunction, mitochondrial damage, and enhanced estrogen/androgen receptor expression in PCOS models. DPP4 inhibition via sitagliptin improved decidualization responses and receptivity markers in rats prior to pregnancy. In T-HESCs, downregulated DPP4 could suppress hormone receptor expression and ferroptosis markers. Functional validation using BeWo spheroid implantation assays demonstrated restored endometrial receptivity following DPP4 intervention. Mechanistically, DPP4-driven ferroptosis exacerbated PCOS-associated endometrial dysfunction, while its suppression would enhance stromal cell decidualization capacity and implantation potential. Consistent with these findings, evaluation of endometrial specimens from PCOS patients confirmed a marked reversal of ferroptosis-related markers following sitagliptin intervention, which was further associated with significantly improved reproductive outcomes, including higher clinical pregnancy and live birth rates.
CONCLUSION: Reducing DPP4 expression not only inhibited ferroptosis but also improved the PCOS phenotype of the endometrium, ultimately influencing changes in endometrial receptivity, and indicating the ferroptosis-related protein DPP4 as a promising therapeutic target.

Keywords:  Dipeptidyl Peptidase 4; Endometrial receptivity; Endometrial stromal cells; Ferroptosis; Polycystic ovary syndrome

DOI:  https://doi.org/10.1186/s13293-025-00786-5
Reprod Toxicol. 2025 Dec 23. pii: S0890-6238(25)00321-1. [Epub ahead of print] 109150

Intestinal Microbiome in Response to Air Pollutant Exposure in Pregestational and Gestational Murine Females and their Male and Female Offspring.

Shubhamoy Ghosh, Amit Ganguly, Tien S Dong, Venu Lagishetty, Jonathan P Jacobs, Sherin U Devaskar.

  We investigated the impact of chronic air pollutant (AP) exposure upon intestinal microbial diversity, composition, and metagenomic inferred functional pathways in murine pregestational and late gestational adult females, and male and female postnatal offspring (P21), compared to age- and sex- matched controls (CON). Intestinal microbiome analysis was undertaken with certain phenotypic characteristics in adult non-pregnant and pregnant females and the male and female offspring. In response to AP, pooled male and female offspring displayed no difference in E19 fetal and P1 postnatal body weights. At P21, females exposed in-utero to AP were heavier with increased fat and muscle mass at one month versus CON. Males were no different at P21 and 1 month revealing decreased fat mass and hyperglycemia. In pregestational/gestational females, AP did not change microbial α- or β-diversity from the respective CON. Gestational females showed AP induced changes in taxonomic composition such as reduced Bacteroides and increased Firmicutes, Verrucomicrobia, and Akkermansia, among others. In response to intra-uterine AP exposure, the offspring intestinal microbiome revealed more compelling differences in α- and β- diversity than adult females. While certain microbial changes were common in both sexes, sex-specific differences also emerged with reduced α-diversity, decreased Bacteroides and increased Akkermansia in males only. The metagenomic inferred pathways revealed perturbations in multiple pathways. We conclude that the offspring exposed in-utero to AP revealed sex-specific changes in microbial diversity, composition and function, displaying certain similarities with distinct differences from mothers. These early life changes were associated with the subsequent emergence of pre-diabetes and adiposity.

Keywords:  air pollutants; chronic disorders; intestinal microbial diversity; intrauterine exposure; obesity

DOI:  https://doi.org/10.1016/j.reprotox.2025.109150
Curr Biol. 2025 Dec 22. pii: S0960-9822(25)01607-0. [Epub ahead of print]

X chromosome dosage in respiratory stem cells is critical for post-embryonic development and survival.

Océane Tournière, Lucie Goy, Irene Miguel-Aliaga, Bruno Hudry.

  Sex chromosome pairs, while carrying sex-determining genes, often exhibit marked structural heteromorphism due to extensive gene loss on the sex-specific chromosome. This heteromorphism generates a fundamental dosage imbalance in sex-linked gene expression, with one sex having one copy and the other two. To address this imbalance and equalize gene expression between the sexes, many species have evolved epigenetic-based, chromosome-wide dosage compensation (DC) mechanisms. While the molecular machinery governing such processes is well characterized in model organisms, the cause of sex-specific lethality due to compensation failure or naturally occurring X monosomy remains unknown. Here, we innovated Drosophila melanogaster genetic tools to investigate X chromosome DC in somatic organs. By implementing ∼150 cell-type-specific perturbations across developmental stages, we uncover cell populations requiring X chromosome DC for sex-specific survival to adulthood. Unexpectedly, DC is largely dispensable across many tissues and developmental stages, with the exception, among others, of the respiratory system during metamorphosis, where X chromosome DC determines adult stem cell viability. Furthermore, we demonstrate that cellular polyploidy confers insensitivity to X-dosage perturbations, providing a mechanistic explanation for cell-type-specific dispensability of DC. These findings reveal how X aneuploidy impairs development and highlight the initial cellular events leading to organismal death.

Keywords:  Drososphila; Turner syndrome; X monosomy; chromosome; dosage compensation; polyploidy; respiratory stem cells; sex chromosomes; sex differences; sexual dimorphism

DOI:  https://doi.org/10.1016/j.cub.2025.11.066
Am J Kidney Dis. 2025 Dec 23. pii: S0272-6386(25)01216-8. [Epub ahead of print]

Sex Hormones and Effects on Kidney Health: Piecing Together the Science.

Michelle M Estrella.

DOI: https://doi.org/10.1053/j.ajkd.2025.11.004
Cancer Biol Ther. 2026 Dec 31. 27(1): 2604936

Interaction between ZMIZ2 and AR promotes prostate cancer proliferation in vitro and in vivo.

Jing-Ze Yu, Xiao-Pan Zou, Xiao-Bei Wu, Yang-Yang Cui, Tan Wei, Jun Di, Xue-Chao Feng, Xiao-Meng Li.

   BACKGROUND: ZMIZ2, an androgen receptor (AR) transcriptional co-regulator, promotes prostate cancer (PCa) cell proliferation by interacting with AR to upregulate genes associated with cell proliferation; however, its specific cooperative mechanisms remain unclear. This study aims to elucidate these mechanisms.
MATERIALS AND METHODS: We analyzed the expression level and prognostic significance of ZMIZ2 in PCa using bioinformatics methods. ZMIZ2 expression and its correlation with the Gleason score were analyzed using clinical samples. LNCaP cells with ZMIZ2 overexpression or AR knockdown were employed to evaluate cell proliferation. RNA-seq, qPCR, Western blot, and co-immunoprecipitation were used to explore the molecular mechanisms. In vivo xenograft models were utilized to validate the effects.
RESULTS: ZMIZ2 expression was significantly higher in PCa tissues and positively correlated with the Gleason score. Overexpressing ZMIZ2 robustly promoted LNCaP cell growth, but this promoting effect was dramatically lessened in the absence of AR expression. Mechanistically, ZMIZ2 recruited multiple acetyltransferases and formed a transcriptional complex with the N-terminal domain of AR, which bound to the promoters of cell cycle-related genes CDK1, CCNA2, and CCNE2, leading to upregulated transcription. Both in vitro cell culture experiments and in vivo models supported ZMIZ2's role in promoting proliferation.
CONCLUSION: ZMIZ2 promotes PCa cell proliferation through the AR signaling pathway by regulating key cell-cycle genes, highlighting it as a potential therapeutic target.

Keywords:  Prostate cancer; ZMIZ2; acetyltransferase; androgen receptor (AR); cell cycle

DOI:  https://doi.org/10.1080/15384047.2025.2604936
Biol Sex Differ. 2025 Dec 24.

Sex-specific placental transcriptome alterations in late-onset preeclampsia reveal male-biased immune and metabolic dysregulation.

Melanie D Smith, Seema Plaisier, James Breen, K Justinian Bogias, Tanja Jankovic-Karasoulos, Dylan McCullough, Dale McAninch, Anya L Arthurs, Melissa A Wilson, Katherine A Pillman, Claire T Roberts.

   BACKGROUND: Preeclampsia is a hypertensive disorder of pregnancy with major maternal and fetal consequences. While the molecular basis of early-onset preeclampsia is well studied, the mechanisms underlying late-onset disease-and how they differ by fetal sex-remain poorly understood. Placental transcriptomic profiling at term can reveal persistent molecular alterations reflecting cumulative disease processes.
METHODS: We conducted a cross-sectional observational analysis of placental gene expression using RNA sequencing in a subset of 58 term placentas (21 male-bearing and 37 female-bearing pregnancies) drawn from two large prospective birth cohorts. Pregnancies were classified based on a clinical diagnosis of late-onset preeclampsia (diagnosed ≥ 20 weeks' gestation according to ISSHP criteria) or as uncomplicated pregnancies. We then assessed for differential gene expression. Cell type proportions were estimated using CIBERSORTx from a placenta-specific reference single-cell dataset. Weighted gene co-expression network analysis identified modules of co-expressed genes associated with late-onset preeclampsia and fetal sex.
RESULTS: Differential gene expression analysis identified 150 genes with altered expression in male-bearing placentas from pregnancies with late-onset preeclampsia compared to those from uncomplicated pregnancies. No differentially expressed genes were identified in female-bearing placentas. Cell type deconvolution revealed increased abundance of CD14 + monocytes and CD8 + activated T cells (log odds of 1.42 and 1.44 respectively) and reduced fetal GZMK natural killer cells (log odds of 0.60) in male-bearing placentas from affected pregnancies. In female-bearing placentas, late-onset preeclampsia was associated with increased fetal nucleated red blood cells and maternal plasma cells (log odds of 1.33 and 1.40 respectively). Male-specific co-expression analysis identified gene modules enriched for biological processes including RNA processing, immune regulation, and metabolism.
CONCLUSIONS: Placental transcription and cellular responses to late-onset preeclampsia differ by fetal sex. Evidence of altered immune cell composition and gene co-expression in male-bearing placentas suggests a sex-specific vulnerability. These findings highlight the importance of considering fetal sex in molecular investigation and clinical management of preeclampsia. Preeclampsia is a common pregnancy complication marked by high blood pressure, but how it affects the placenta, especially in later pregnancy and depending on the baby's sex, is not well understood. In this study, we analysed placental tissue from pregnancies with and without late-onset preeclampsia using RNA sequencing. By separating the data based on whether the neonate was male or female, we found striking differences in gene expression. Only placentas from male-bearing pregnancies showed significant changes in gene expression linked to preeclampsia. These changes involved genes related to immune response, metabolism and vascular function. We also used computational tools to estimate what types of cells were present in each placental sample. In male-bearing pregnancies affected by late-onset preeclampsia, there was a notable increase in certain immune cells, suggesting an altered immune response and increased inflammation. In contrast, female-bearing pregnancies affected by late-onset preeclampsia showed an increase in cell composition for two blood related cell types, but no significant gene expression differences. By grouping genes that worked together into networks, we identified several groups, especially in placentas from male-bearing pregnancies, that were strongly associated with biological processes known to be disrupted in preeclampsia, such as blood vessel formation, extracellular matrix remodelling, and hormone regulation. These findings emphasise the importance of considering fetal sex in pregnancy research and could help guide future sex-specific diagnostic or treatment strategies.

Keywords:  Cell type deconvolution; Extra-cellular matrix; Late-onset preeclampsia; Placenta; Pregnancy; Transcriptomics

DOI:  https://doi.org/10.1186/s13293-025-00781-w
J Clin Endocrinol Metab. 2025 Dec 24. pii: dgaf683. [Epub ahead of print]

Correction to: "Growth and Adult Height Attainment in Danish Transgender Adolescents Treated With GnRH Analog and Sex Hormones".

DOI: https://doi.org/10.1210/clinem/dgaf683
bioRxiv. 2025 Dec 11. pii: 2025.12.09.693141. [Epub ahead of print]

Inter- and intra-individual differences in brain sex map to neuroendocrine profiles.

Gloria Matte Bon, Ann-Christin S Kimmig, Erika Comasco, Birgit Derntl, Tobias Kaufmann.

Sex hormone fluctuations modulate structural and functional brain dynamics, yet little is known how sex steroid levels map onto the expression of sex differences in the brain. Here, we trained machine learning models for brain sex classification based on anatomical structures in cross-sectional data of N = 1090 individuals (50% females, age matched). Applied to dense sampled data of one male and two females in different hormonal states (naturally cycling, oral contraceptive user, pregnancy), we linked inter- and intra-individual fluctuations in brain sex to neuroendocrine modulation. We found lower variation in brain sex across time in the male compared to the female subjects. Oral contraceptive use was associated with a more female-like brain, while (inverted) U-shaped brain sex trajectories emerged across menstrual cycle phases and pregnancy trimesters. Overall, our findings suggest that changes in brain sex capture hormone-related plasticity over time in dense sampled individuals.

DOI: https://doi.org/10.64898/2025.12.09.693141
Curr Opin Immunol. 2025 Dec 22. pii: S0952-7915(25)00189-X. [Epub ahead of print]98 102713

Diet-derived microbial metabolites as regulators of immune function.

Francesco Siracusa, Andres Machicote, Samuel Huber, Nicola Gagliani.

The intestinal microbiota transforms dietary components into bioactive metabolites that profoundly influence mucosal and systemic immunity. Short-chain fatty acids, secondary bile acids and tryptophan-derived indoles are among the most studied microbial metabolites shaping T, B and innate immune cell functions through a variety of mechanisms, including receptor signaling, epigenetic modification and metabolic reprogramming. Dietary habits strongly affect the composition of the intestinal microbiota and thus, the production and availability of these microbial metabolites, with consequences that range from protective immune regulation to detrimental inflammatory responses. Here, we review recent findings from mouse and human studies, highlighting how the microbiota-immunity axis can be modulated by diets and discuss implications for tissue homeostasis, infection and chronic inflammatory diseases. Understanding this complex interplay may guide the development of ad hoc dietary and microbial interventions to restore tolerance and improve therapeutic outcomes.

DOI: https://doi.org/10.1016/j.coi.2025.102713
J Endocrinol. 2025 Dec 23. pii: JOE-25-0346. [Epub ahead of print]

Sex Differences in Thyroid Function: From Central Regulation to Hormone Metabolism and Disease Susceptibility.

Caroline C Faria, Vania Maria Correa da Costa, Andrea Claudia Freitas Ferreira, Rodrigo S Fortunato, Denise P Carvalho.

Sexual dimorphism in endocrinology refers to the biological differences between males and females in hormone production, secretion, metabolism, and action, shaped by genetic, epigenetic, and hormonal influences. These differences are fundamental to thyroid physiology and disease, affecting regulatory pathways from central hypothalamic-pituitary control to peripheral hormone metabolism. Clinically, women have a higher prevalence of autoimmune thyroid diseases, nodules, and differentiated thyroid cancer, while men more often present with advanced and aggressive disease. In this review, we integrate current evidence on sexual dimorphism in thyroid function, spanning from central regulation through the hypothalamic-pituitary-thyroid axis to thyroid hormones biosynthesis and peripheral metabolism, and discuss how these differences influence disease susceptibility and progression.

DOI: https://doi.org/10.1530/JOE-25-0346
Mol Metab. 2025 Dec 19. pii: S2212-8778(25)00219-4. [Epub ahead of print] 102312

Gut hormone signaling drives sex differences in metabolism and behavior.

Olga Kubrak, Alina Malita, Nadja Ahrentløv, Stanislav Nagy, Michael J Texada, Kim Rewitz.

Males and females have different physiological and reproductive demands and consequently exhibit widespread differences in metabolism and behavior. One of the most consistent differences across animals is that females store more body fat than males, a metabolic trait conserved from flies to humans. Given the central role of gut hormones in energy balance, we asked whether gut endocrine signaling underlies these sex differences. We therefore performed a multidimensional screen of enteroendocrine cell (EEC)-derived signaling across a broad panel of metabolic and behavioral traits in male and female Drosophila. Here, we uncover extensive sex-biased roles for EEC-derived signals - many of which are conserved in mammals - in energy storage, stress resistance, feeding, and sleep. We find that EEC-derived amidated peptide hormones sustain female-typical states, including elevated fat reserves, enhanced stress resilience, and protein-biased food choice. In contrast, the non-amidated peptide Allatostatin C (AstC) promotes male-like traits by stimulating energy mobilization, thereby antagonizing amidated-peptide function. Female guts contain more AstC-positive EECs. Disruption of peptide amidation by eliminating peptidylglycine α-hydroxylating monooxygenase - the enzyme required for maturation of most gut peptide hormones - abolished female-typical physiology and behavior, shifting females toward a male-like state. Among individual amidated peptides, Diuretic hormone 31 (DH31) and Neuropeptide F (NPF) emerged as key mediators of female physiology. These findings establish gut hormone signaling as a determinant of sex-specific metabolic and behavioral states.

DOI: https://doi.org/10.1016/j.molmet.2025.102312
bioRxiv. 2025 Dec 19. pii: 2025.12.18.695285. [Epub ahead of print]

Sex differences in the neural circuitry of aggression.

Susan D Lee, Dario Aspesi, Kim L Huhman, H Elliott Albers.

The social behavior neural network (SBNN) is a circuit composed of reciprocally connected limbic structures that regulate a range of social behaviors, including aggression. Although both males and females of many species display aggressive behavior, studies of the neural circuitry underlying aggression have focused almost exclusively on males. In the present study, we investigated sex differences in neuronal activation of the neural circuitry controlling aggression in Syrian hamsters (Mesocricetus auratus). We employed c-Fos immunohistochemistry to quantify neuronal activation following aggressive encounters between same-sex male and female dyads. Animals were tested in their home cage either alone (n=7 per sex) or with a same-sex, non-aggressive intruder (n=7 per sex) for 10 minutes. Our data revealed substantial sex differences in the neuronal activation of the SBNN following aggression. In some regions, neuronal activity changed in opposite directions in males and females compared to controls (e.g., posterior lateral septum), while in others, there was a change in neuronal activation in only one sex (e.g., medial amygdala). These findings support the hypothesis that the neural circuitry regulating aggression exhibits marked sexual differentiation.

DOI: https://doi.org/10.64898/2025.12.18.695285
J Ovarian Res. 2025 Dec 24. 18(1): 302

Effects of high basal luteinizing hormone levels on in vitro fertilization/intra-cytoplasmic injection outcomes in polycystic ovarian syndrome: a retrospective study.

Hongfa Peng, Lu Wang, Jingjing Jiang, Ting Pan, Yang Yang, Na Cui, Yanan Sun, Guimin Hao, Wei Wang.

   BACKGROUND: The clinical implications of elevated luteinizing hormone (LH) levels in patients with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) fresh embryo transfer cycles remain unclear, particularly regarding oocyte maturation and pregnancy outcomes. We aimed to evaluate the impact of basal LH elevation on treatment outcomes and compare the efficacy of protocols involving gonadotropin-releasing hormone antagonist (GnRH-ant) and gonadotropin-releasing hormone agonist (GnRH-a) for ovarian stimulation in patients with PCOS undergoing in vivo IVF/ICSI.
METHODS: This single-center, retrospective cohort study included 1,269 patients with PCOS who underwent IVF/ICSI treatment following a flexible GnRH-ant or long GnRH-a protocol with a human chorionic gonadotropin trigger between January 2013 and December 2023. Primary outcomes included the number of retrieved oocytes, metaphase II (MII) oocytes, two pronuclear embryos, high-quality embryos, and the ovarian hyperstimulation syndrome (OHSS) rate. Secondary outcomes included clinical pregnancy, miscarriage, and live birth rates following fresh embryo transfer.
RESULTS: Among the participants, 492 (38.77%) exhibited basal LH levels of ≥ 10 mIU/mL, and 777 (61.23%) had LH levels of < 10 mIU/mL. Additionally, 465 (36.64%) and 804 (63.36%) participants underwent GnRH-ant and GnRH-a protocols, respectively. Elevated basal LH levels showed no significant associations with MII oocyte yield, fertilization rate, high-quality embryo count, or clinical pregnancy outcomes (all p > 0.05). However, patients with high LH levels demonstrated increased oocyte retrieval (p = 0.008), a high incidence of ovarian hyperstimulation syndrome (OHSS) (p < 0.001), and reduced fresh embryo transfer rates (p = 0.003). The GnRH-ant protocol required shorter stimulation duration (p < 0.001) and lower amounts of recombinant follicle-stimulating hormone (p < 0.001) than did the GnRH-a protocol. The GnRH-ant protocol also yielded significantly higher proportions of oocytes (p = 0.022), MII oocytes (p = 0.003), and high-quality embryos (p < 0.001); however, it exhibited lower fresh embryo transfer rates (p < 0.001). The two protocols showed no significant differences concerning clinical pregnancy success or OHSS risk.
CONCLUSIONS: Elevated basal LH levels did not impair the outcome of fresh embryo transfer in women with PCOS undergoing IVF/ICSI. However, the number of retrieved oocytes and the OHSS rate were significantly higher in patients with high basal LH levels. The GnRH-ant protocol is an efficient alternative for this subpopulation, particularly regarding stimulation efficiency.
CLINICAL TRIAL NUMBER: Not applicable.

Keywords:  GnRH-a; GnRH-ant; IVF/ICSI; Luteinizing hormone; Polycystic ovary syndrome

DOI:  https://doi.org/10.1186/s13048-025-01899-6
Front Immunol. 2025 ;16 1736492

Immunometabolism and male reproductive function: linking inflammation, oxidative stress, and declining fertility.

Jiedong Zhou, Shian Hu, Yong Ouyang, Yucheng Kong, Min Liu.

   Background: Male infertility accounts for approximately 50% of all infertility cases, and its pathogenesis is highly complex. Beyond traditional factors such as genetics, endocrine disorders, and infections, growing evidence indicates that dysregulation of immunometabolism plays a pivotal role in the onset and progression of male reproductive dysfunction.
Objective: This review aims to systematically elucidate the role of immunometabolism in male reproductive health, focusing on the complex interplay among inflammation, oxidative stress, and metabolic imbalance. Additionally, it seeks to summarize potential therapeutic targets and outline future research directions.
Methods: A narrative review was conducted in accordance with the SANRA (Scale for the Assessment of Narrative Review Articles) guidelines. Relevant studies published between January 2010 to March 2025 were retrieved from PubMed, Embase, and Web of Science using keywords such as "immunometabolism," "testis," "male infertility," and "oxidative stress."
Results: Testicular immune homeostasis depends on the metabolic coordination among Sertoli cells, Leydig cells, and local immune cells. Aberrant immunometabolism disrupts the blood-testis barrier and endocrine balance by enhancing glycolysis, suppressing oxidative phosphorylation, and promoting the accumulation of reactive oxygen species (ROS), thereby impairing spermatogenesis and testosterone synthesis. Systemic metabolic inflammation induced by obesity, diabetes, and gut microbiota dysbiosis further exacerbates testicular dysfunction through the mTOR/HIF-1α signaling axis and the "gut-immune-gonadal axis." Pharmacological modulation of key immunometabolic regulators, including AMPK, SIRT1, and PPARγ, has been shown to improve sperm quality and hormone levels in experimental models.
Conclusion: Immunometabolism serves as a crucial mechanistic bridge linking inflammation, oxidative stress, and the decline of male fertility. Future studies integrating multi-omics and spatial analysis technologies are expected to delineate immunometabolic phenotypes associated with male infertility, paving the way for precision diagnosis and personalized therapeutic interventions.

Keywords:  gut microbiota; immunometabolism, testicular immunity; male infertility; metabolic signaling; oxidative stress

DOI:  https://doi.org/10.3389/fimmu.2025.1736492
Clin Cosmet Investig Dermatol. 2025 ;18 3443-3455

Skin Microbiome in Health and Disease: Mechanisms and Emerging Therapeutic Strategies.

Zhouna Li, Jianqing Zhang, Ying Zhang, Hong Chen, Yanqiu Bao.

  The skin microbiome plays a vital role in maintaining skin homeostasis by regulating immune responses, preserving barrier integrity, and inhibiting pathogen colonization. This review systematically explores the mechanisms underlying its dysregulation in conditions such as acne, atopic dermatitis, psoriasis, and impaired wound healing, with a focus on key factors including microbial over colonization, diminished diversity, and host immune dysregulation. The influence of microbial metabolites, such as short-chain fatty acids and porphyrins, is also examined. We further evaluate emerging microbial-targeted therapeutic strategies, including live biotherapeutic products, skin microbiota transplantation, epigenetic and metabolic interventions, and precision antimicrobial polymers. These approaches aim to restore microbial balance rather than achieve broad-spectrum sterilization, representing a significant shift in the treatment paradigm for cutaneous diseases. In contrast to previous reviews, this article places special emphasis on the mechanisms of multi-organ interactions within the gut-skin axis and discusses the potential of integrating multi-omics technologies and artificial intelligence to advance the clinical translation of personalized microbial therapies, thereby providing a forward-looking perspective on the field.

Keywords:  dysbiosis; host-microbe interactions; skin diseases; skin microbiome; therapeutic interventions

DOI:  https://doi.org/10.2147/CCID.S571984
Pol J Microbiol. 2025 Dec 01. 74(4): 494-506

Glycan Profile Alterations in Vaginitis and Their Role in Pathogen-Host Interactions.

Małgorzata Bodaszewska-Lubaś.

  Glycosylation is one of the post-translational modifications that occur in the endoplasmic reticulum (ER)-Golgi pathway. During enzymatic glycosylation, glycosidic linkages form between saccharides, proteins and lipids. Cervicovaginal mucus (CVM), produced by epithelial cells in the female genital tract, is predominantly composed of water, mucins, and immunologically active factors. CVM is a viscoelastic natural hydrogel that lubricates the vagina and acts as a barrier against microorganisms. The glycan compounds of CVM function as cellular recognition, adherence and signaling molecules, as well as mediating host-microbe interactions. Additionally, the endocervical and vaginal epithelia secrete cervicovaginal fluid (CVF), which contains glycan compounds and various antimicrobial agents. The vaginal epithelium is mainly colonized by lactic acid bacteria (LAB) in a state of eubiosis. These bacteria produce immunomodulatory and antimicrobial compounds to prevent vaginitis. Disturbing vaginal eubiosis can lead to changes in the microbial community and the development of inflammation. Pathogens possess various mechanisms and virulence factors that facilitate their virulence. A significant proportion of microbial mechanisms and pathogen-host interactions are linked to glycan structural functions. Changes in the glycan profile are associated with vaginitis and may result from bacterial glycosidase activity, which compromises vaginal mucus and epithelial integrity. The aim of this review is to describe the glycan composition of CVF in eubiosis and dysbiosis, the influence of pathogens on glycan profiles, immune system regulation, and glycan-dependent factors in pathogen-host interactions. Understanding glycan-dependent events during vaginitis could be crucial for identifying new glycan biomarkers and treatment targets for vaginitis.

Keywords:  glycan; lactic acid bacteria; molecular mimicry; sialidase; vaginosis

DOI:  https://doi.org/10.33073/pjm-2025-043
Reprod Sci. 2025 Dec 23.

MicroRNA Crossroads in PCOS and Endometriosis.

Girrijha Sambath, Januki Kalai, Usha Rani G, Jabez William Osborne, Ravindran Sumitha, Venkatachalam Deepa Parvathi.

  In the intricate landscape of health disorders in women, polycystic ovary syndrome and endometriosis stand out. Despite their complete etiology being unknown, their impact on women's health and link to hereditary factors have given them the spotlight in the world of gynaecology and endocrinology. These two conditions although vastly different, share common symptoms, clinical manifestations, pathways and genetic and epigenetic factors and regulators [10, 39]. Decoding the link between the two conditions can lead to enormous breakthroughs in the diagnostic and therapeutic aspects of gynaecological disorders and possibly aid in the unravelling of unknown mechanisms associated with the pathophysiology of PCOS and endometriosis. MicroRNAs being small and potent regulators of gene expression, are infamous for their role in regulation of mRNA expression and aiding in post transcriptional modifications and their association with gynaecological disorders and impact on the endocrine system, typically the Hypothalamic-Pituitary-Ovarian axis has garnered an enormous amount of attention. MicroRNAs are known to affect pathways linked to inflammation, immunity, neuroendocrine stress response, fertility, metabolism, environmental response and are actively associated with the clinical manifestations of a plethora of diseases and disorders [37, 49-51]. This comprehensive review showcases the multifaceted roles of microRNAs involved in gynaecological disorders, specifically PCOS and endometriosis, offering avenues for microRNAs as possible therapeutic and diagnostic markers in gynaecological disorders, harnessing their applications to the maximum extent, possibly aiding in betterment of overall health in women.

Keywords:  Endometriosis; Gene regulation; MicroRNAs; PCOS; Reproductive disorders; Women’s health

DOI:  https://doi.org/10.1007/s43032-025-02037-9
Front Immunol. 2025 ;16 1698566

Single-cell transcriptomics reveals systemic immune dysregulation in non-segmental vitiligo.

Jialing Xiao, Xiaojuan Guo, Lingxue Gong, Qinhui Li, Kai Dong, Xiaoxin Guo, Huan Li, Ting Wang, Liang Wang, Weijia Wu, Chengzi Gan, Mingze Li, Bo Gong, Yixuan Jiang, Yixiao Wu, Yifan Hu, Liang Han, Jianing Yang, Yujie Mao.

   Background: Non-segmental vitiligo (NSV) is an autoimmune disorder characterized by irregular depigmented skin patches due to melanocyte loss, which causes considerable psychosocial burden. Although localized mechanisms underlying vitiligo pathogenesis have been studied extensively, investigations into peripheral blood mononuclear cells (PBMCs), key mediators of autoimmune diseases, remain limited.
Methods: To address this gap, we performed single-cell RNA sequencing (scRNA-seq) on peripheral blood samples from 3 untreated patients with generalized, progressive non-segmental vitiligo (GP-NSV) and 3 healthy controls. Findings were validated using flow cytometry in an additional cohort of 7 GP-NSV patients and 30 controls. Computational analyses, including pseudotime trajectory reconstruction and pathway enrichment, were employed to characterize immune cell subsets and their functional states.
Results: Vitiligo patients exhibited striking heterogeneity in PBMC subsets. KLRC2+ NK cells were markedly reduced and enriched in tumor necrosis factor (TNF) and apoptotic signaling pathways, a finding further confirmed by flow cytometry. Pseudotime analysis indicated that NK cells underwent negative regulation of DNA metabolic processes alongside activation of granzyme-mediated programmed cell death. In addition, the frequency of FCGR3A+ Cytotoxic CD8+T cell was reduced, with enrichment in T cell activation and differentiation signatures. STAM+ regulatory T cells (Tregs) were increased, whereas EGR1+ B cells were decreased, both subsets showing enrichment in pathways linked to osteoclast differentiation and calcium ion metabolism, suggesting a potential role of calcium homeostasis dysregulation in disease pathogenesis.
Conclusions: This study provides the single-cell atlas of PBMCs in GP-NSV, uncovering profound transcriptional and compositional alterations across multiple immune cell subsets in active vitiligo. These findings offer novel insights into systemic immune dysregulation in GP-NSV and pave the way for novel targeted therapeutic strategies.

Keywords:  B cell; Cytotoxic CD8⁺ T cell; EGR1; FCGR3A; GP-NSV; KLRC2; NK cell; single-cell RNA sequencing

DOI:  https://doi.org/10.3389/fimmu.2025.1698566
Antiviral Res. 2025 Dec 24. pii: S0166-3542(25)00264-5. [Epub ahead of print] 106338

2-Deoxy-D-glucose attenuates lipopolysaccharide-induced inflammation and restricts Zika, Chikungunya, and Mayaro virus replication in monocyte-derived macrophages.

Y S Tamayo-Molina, Yisel García-Marin, Silvio Urcuqui-Inchima.

  Re-emerging arthropod-borne viruses such as Mayaro (MAYV), Chikungunya (CHIKV), and Zika (ZIKV) pose a growing global health concern as Aedes mosquito populations expand. These arboviruses infect innate immune cells, particularly monocyte-derived macrophages (MDMs), which support viral replication and serve as reservoirs that facilitate dissemination. Because no effective antiviral treatments are available, strategies that modulate macrophage responses and restrict viral replication are urgently needed. Here, we evaluated the immunomodulatory and antiviral effects of 2-deoxy-D-glucose (2-DG) in human MDMs. First, we assessed how 2-DG shapes transcriptional responses to lipopolysaccharide (LPS), a canonical TLR4 agonist. Co-treatment with 2-DG and LPS induced genes linked to inflammatory, antiviral, and endoplasmic reticulum (ER) stress pathways. Notably, IL10 mRNA and IL-10 protein displayed an inverse relationship with metabolic stress yet correlated positively with inflammatory and antiviral gene expression, whereas GADD34 was positively associated with both inflammatory and ER stress responses, suggesting an integrative regulatory role. We next investigated whether 2-DG pretreatment limits replication of MAYV, CHIKV, and ZIKV in infected MDMs. Antiviral assays demonstrated that 2-DG reduced replication of all three arboviruses by approximately one log10. Additional analyses revealed distinct temporal sensitivities: MAYV and CHIKV showed early and late susceptibility, whereas ZIKV exhibited a distinct kinetic profile. Mechanistic experiments confirmed that 2-DG acts post-entry primarily and reverses the antiviral phenotype observed in LPS-primed MDMs. Collectively, these findings reveal crosstalk among inflammatory, antiviral, and ER stress pathways and demonstrate that 2-DG modulates LPS-driven inflammation while reducing replication of pathogenic arboviruses in human MDMs.

Keywords:  2-deoxy-D-glucose; Antiviral; Arbovirus; ER stress; Inflammatory; Lipopolysaccharide

DOI:  https://doi.org/10.1016/j.antiviral.2025.106338
bioRxiv. 2025 Dec 18. pii: 2025.12.16.694726. [Epub ahead of print]

Prolonged Loss of Oxidative Phosphorylation and Mitochondrial Mass Characterize CD66b + Leukocytes from Patients with Sepsis.

Christine Rodhouse, Evan L Barrios, Leilani Zeumer-Spataro, Leandro Balzano-Nogueira, Ruoxuan Wu, Xuanxuan Yu, Guimei Tian, Jason O Brant, Marie-Pierre L Gauthier, Jing Chen, Miguel Hernandez-Rios, Valerie E Polcz, Whitman Wiggins, Angel M Charles, Marvin L Dirain, Ricardo Ungaro, Jaimar Rincon, Tyler Loftus, Feifei Xiao, Guoshuai Cai, Lyle L Moldawer, Robert Maile, Michael P Kladde, Philip A Efron, Clayton E Mathews.

Introduction: Sepsis leads to expansion of myeloid-derived suppressor cells (MDSC) and their subtypes. These normally transitory MDSCs suppress T cell activation and alter T cell cytokine production while simultaneously promulgating systemic low-grade inflammation. Immune metabolism can shape cell responses, regulate immune suppression, and enhance effector activity. Although MDSC metabolism has been extensively studied in cancer, the metabolic phenotype of this heterogeneous population in sepsis remains unclear. Our goal was to assess metabolic flux in blood MDSCs during and after sepsis and to stratify these patients' clinical features and outcome with differences in metabolic flux that may guide treatment decisions.
Methods: Peripheral blood mononuclear cells (PBMC) from healthy subjects and sepsis patients at 4 days, 2-3 weeks, and 6 months underwent CD66b + or CD3 + enrichment, followed by assessment of metabolic flux, flow cytometry, mRNA sequencing, and chromatin accessibility.
Results: Mitochondrial basal oxygen consumption rates (OCR) and maximal oxygen consumption rates (SRC, spare respiratory capacity) were decreased in MDSC from septic patients at 4 days after infection and persisted for up to 6 months after sepsis onset. Sepsis was not associated with differences in glycolysis. In contrast, oxidative metabolism in CD3 + T cells was similar between sepsis patients and healthy subjects. Reduced MDSC oxidative metabolism was linked to adverse clinical outcomes. The decline in oxygen consumption from MDSCs in septic patients was also associated with significant reductions in MDSC mitochondrial content. Transcriptomic analysis of CD66b + cells isolated from PBMC of healthy participants and patients with sepsis at 4 days, 2-3 weeks, and 6 months revealed 19 differentially expressed genes and three long non-coding RNAs as potentially responsible for this decline in mitochondrial mass. Specifically, NR4A3 , NR4A2, and TAMLIN/NR4A1 expression, all critical for mitochondrial biogenesis, were persistently decreased with reduced chromatin accessibility indicative of gene silencing.
Discussion: After sepsis, blood CD66b + cells present with reduced mitochondrial mass and oxidative metabolism that continue at least 6 months after sepsis. These changes in mitochondrial function result from a reduced content of these organelles. We have also identified gene silencing, reduced gene expression of key transcription factors that regulate mitochondrial biogenesis, as well as increased long non-coding RNA as potential drivers of this unique metabolic phenotype. These results highlight the potential benefit of targeting metabolism in sepsis to promote immune homeostasis and recovery.

DOI: https://doi.org/10.64898/2025.12.16.694726
BMJ Glob Health. 2025 Dec 21. pii: e018219. [Epub ahead of print]10(12):

Forced vaginal sex and genital immune correlates of HIV risk: a prospective study of female sex workers in Kenya.

Maisha Fiti Study Champions

   BACKGROUND: The likelihood of HIV acquisition is increased following forced vaginal sex. This relates in part to epidemiological and behavioural factors; however, the biological effects of forced vaginal sex, including impacts on immune parameters linked to HIV susceptibility, are poorly understood. Here, we examine biological mediators of HIV susceptibility among female sex workers (FSWs) in Nairobi, Kenya, who recently experienced forced vaginal sex.
METHODS: The Maisha Fiti study was a longitudinal cohort study of FSWs from Nairobi, Kenya. At up to three visits, HIV-uninfected participants completed a detailed sociodemographic survey in which they were asked if they had experienced forced vaginal sex in the past 7 days. Proinflammatory cytokines and soluble E-cadherin (sE-cad), a biomarker of epithelial barrier disruption, were quantified in cervico-vaginal secretions by multiplex immunoassay. Associations between recent forced sex and genital inflammation were assessed longitudinally in a mixed-effects regression model adjusted for potential confounders and within-participant correlation.
RESULTS: Of the 746 participants, 44 (6%) reported forced vaginal sex in the past 7 days at baseline, with strong evidence of associations with adverse childhood experiences (p<0.001), mental health issues (p<0.001) and poverty (p=0.02). Recent forced sex was associated with increased genital inflammation (adjusted OR (aOR)=2.74; 95% CI 1.33 to 5.68; p<0.01) independent of previously defined confounders but was not associated with altered levels of sE-cad (p=0.56). Neither recent consensual sex (aOR=0.94, 95% CI 0.63 to 1.40, p=0.76) nor forced sex within the past 6 months, excluding the past 7 days (aOR=0.93, 95% CI 1.21 to 5.42, p=0.70), was associated with genital inflammation.
CONCLUSIONS: Cervicovaginal inflammation is increased in FSWs for at least a week after forced vaginal sex. This has important implications for HIV prevention programmes that provide care to women experiencing gender-based violence. Further studies are needed to understand the specific timing of proinflammatory cytokine release following forced vaginal sex.

Keywords:  Gender-Based Violence; Global Health; HIV; Interdisciplinary Research; Kenya

DOI:  https://doi.org/10.1136/bmjgh-2024-018219
Neurol Neuroimmunol Neuroinflamm. 2026 Mar;13(2): e200532

Sex Bias in IL-10 Production by Type I Regulatory T Cells Regulated by PI3K/mTOR Signaling.

Aymeline Debonlier, Saniya Kari, Florence Bucciarelli, Thibault Angles, Amelia Perez-Pestel, Chanaëlle Fébrissy, Sophie Laffont, Roland Liblau, Françoise Lenfant, Shannon Elizabeth Dunn, Julie Guillermet-Guibert, Anne L Astier.

BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) is more prevalent in women, with a female-to-male ratio of 3:1. The molecular mechanisms driving this sex difference are still mostly unknown. MS results from immune dysfunction, with an imbalance in effector and regulatory T cells. Among the latter, Type I regulatory T cells (Tr1) are dysfunctional in people with MS (pwMS), secreting less IL-10, a potent anti-inflammatory cytokine, than in healthy donors. Our objectives were to explore the effect of biological sex on Tr1 cell differentiation in healthy donors and pwMS.
METHODS: CD4+ T cells were isolated from peripheral blood mononuclear cells, and Tr1 differentiation was induced by costimulation with the complement regulator CD46 or IL-27. The frequency of Tr1 cells and their production of IL-10 and IFN-γ were examined. The impact of the PI3K/mTOR pathway on male and female Tr1 cells was also studied.
RESULTS: We found that healthy female Tr1 cells produce less IL-10 than male cells (16 women and 16 men, 18-45 years old, p = 0.0053). This sex difference was only observed when Tr1 cells were differentiated by CD46 costimulation. Mechanistically, this sex difference in IL-10 expression by Tr1 cells was due to the differential activity of a negative feedback loop targeting PI3K signaling in male vs female Tr1 cells. In contrast to findings in healthy donors, no sex difference in IL-10 production was observed when CD4+ T cells from pwMS (12 women and 12 men, 18-48 years old) were differentiated to Tr1 cells via the CD46 pathway, further emphasizing the dysregulation of Tr1 generation in MS. However, PI3Kδ inhibition in MS cells also revealed a sex bias, as it reduced IL-10 production by IL-27-induced Tr1 cells only in men (7 men and 5 women, p = 0.0043), while increasing IL-10 levels in the CD46 pathway in both sexes (8 men and 11 women).
DISCUSSION: We demonstrate that sex influences IL-10 production by Tr1 cells via the PI3K pathway, potentially contributing to the greater susceptibility of women to MS. Furthermore, our data suggest that targeting PI3Kδ may represent a novel therapeutic strategy to boost IL-10 production in female pwMS.

DOI: https://doi.org/10.1212/NXI.0000000000200532
Front Endocrinol (Lausanne). 2025 ;16 1714019

BMI is associated with sperm quality and sex hormones in men: a meta-analysis.

Fengming Ji, Bing Yan, Chenghao Zhanghuang, Chengchuang Wu, Jinshuan Dai, Shengde Wu.

   Aim: To systematically evaluate the relationship between body mass index (BMI) and sperm quality parameters as well as sex hormones levels in males.
Method: A comprehensive literature search was conducted across Pubmed, Embase and the Cochrane Library for literature, China National Knowledge Infrastructure, and Wanfang database. Studies investigating the association between BMI and semen parameters or sex hormones in adult males (>18 years) were included. Two reviewers independently performed study selection, data extraction, and quality evaluation Meta-analysis was performed using RevMan 5.4 and Stata 18.0.
Results: Of the 275 studies identified, 14 met the inclusion criteria. A total of 14 studies involving 8443 patients were included, including 3467 cases of normal BMI, 3444 cases of overweight and 1532 cases were obesity. All 14 studies involved sperm quality analysis, and 4 studies addressed sex hormone analysis. The meta-analysis results indicate that there were statistically significant differences in normal morphology (NM), total motility (TM), sperm concentration (SC), progressive motility (PM), volume and total sperm count (TSC) among the three groups. In the analysis of sex hormones, total testosterone (TT), follicle stimulating hormone (FSH) and luteinizing hormone (LH) showed statistically significant difference among three groups.
Conclusion: Elevated BMI is significantly associated with impaired sperm quality and altered sex hormone levels. BMI should be considered a risk factor in male fertility assessments. Further longitudinal studies are needed to explore the reversibility of these effects through lifestyle interventions.

Keywords:  BMI; men; meta-analysis; sex hormones; sperm quality

DOI:  https://doi.org/10.3389/fendo.2025.1714019