bims-simsho 2025-10-05 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–10–05
28 papers selected by
Chun-Chi Chang, Lunds universitet

Molecular mechanisms of sex hormones in Hepatocellular Carcinoma: a systematic review.
Steroid hormone regulation of immunometabolism and inflammation.
Sex Disparities in Obesity: A Comprehensive Review of Hormonal and Genetic Influences on Obesity-Related Phenotypes.
The future of androgen receptor targeting in prostate cancer: third-generation inhibitors and beyond.
Natural Products Targeting the Androgen Receptor Signaling Pathway: Therapeutic Potential and Mechanisms.
Steroid anabolic and catabolic hormones in highly and recreationally trained female athletes across the menstrual cycle.
How FSH and LH analogs affect fertility hormone results?
Discovering a new paradigm: Gut microbiota as a central modulator of sexual health.
Androgen receptor antagonist flutamide modulates estrogen receptor alpha expression in distinct regions of the hypospadiac rat penis.
Multi-omics protein signaling networks identify sex-specific therapeutic candidates in lung adenocarcinoma.
Characterization of vaginal prokaryotes and eukaryotes microbiota and its link to sexually transmitted infections.
Estradiol and dihydrotestosterone exert sex-specific effects on human fibroblast and endothelial proliferation, bioenergetics, and vasculogenesis.
Pan-tissue transcriptome analysis reveals sex-dimorphic human aging.
Role of progestogens in hormone therapy.
Spatial transcriptomics reveals distinct role of monocytes/macrophages with high FCGR3A expression in kidney transplant rejections.
TRPV4 is involved in progesterone-mediated sexual dimorphism in mesenchymal stem cell functions and bio-mineralization.
Comprehensive analysis of androgen receptor splice variant target gene expression in prostate cancer.
Testosterone as a mediator of APOE4-linked sex differences in Alzheimer's disease.
Reproductive aging in biological females: mechanisms and immediate consequences.
Sex chromosomes/hormones and the tumor microenvironment of non-reproductive cancers.
Unraveling the links between estrogen and gut microbiota in sex-hormone driven cancers.
Trained immunity in pregnancy: Impact on maternal-fetal outcomes and mechanistic insights.
Epigenetic modification of hypothalamic neuropeptides and metabolic hormone receptors in metabolic health.
Single-cell analysis uncovers preserved prostate cancer lineages and universally altered pathways in Matrigel-free patient-derived organoids.
Treatment options in hormone-sensitive prostate cancer: targeting the androgen-sensitive pathway.
Comparative single-cell immune responses in peripheral blood and lymph node of immunized SARS-CoV-2 challenged infant rhesus macaques.
AMICI: Attention Mechanism Interpretation of Cell-cell Interactions.
Leveraging the role of the microbiome in endometriosis: novel non-invasive and therapeutic approaches.

Mol Biol Rep. 2025 Oct 03. 52(1): 975

Molecular mechanisms of sex hormones in Hepatocellular Carcinoma: a systematic review.

Marwa Zahra, Marwa Saady, Hassan Mohamed El-Said Azzazy.

  Sex hormones have a prominent role in the gender disparity that is apparent in hepatocellular carcinoma (HCC). This systematic review investigates the molecular mechanisms of sex hormones-androgens, estrogens, and testosterone-in HCC, addressing the gender disparities observed in HCC prevalence and progression. Relevant search terms were used to retrieve pertinent studies found in PubMed, Web of Science, and Scopus which investigated the molecular mechanism of sex hormones in developing HCC. A quality assessment using a tailored checklist was performed. This study is registered with PROSPERO (CRD42025635841). Out of the 3,076 retrieved articles, 34 met the inclusion criteria, with six focusing on androgens, fifteen on estrogens, and thirteen examining multiple sex hormones. Studies utilized in vitro and in vivo models to understand the complex interplay between sex hormones and HCC. Estrogens were found to exert protective effects through anti-inflammatory, anti-proliferative, and mitochondrial integrity mechanisms, while androgens promoted tumorigenesis via cell cycle regulation and immune checkpoint modulation. The review highlights the contrasting roles of estrogens and androgens, emphasizing the necessity for a thorough understanding of their molecular interactions and signaling pathways, such as JAK-STAT, Wnt/β-catenin, and PI3K-AKT. This review underscores the potential for sex hormone pathway targeting in HCC therapy. Further research is warranted to explore therapeutic interventions, such as estrogen receptor antagonists and androgen receptor modulators, and to address gaps in understanding hormonal influences on HCC progression.

Keywords:  Androgens; Estrogens; Hepatocellular carcinoma; Molecular mechanisms; Molecular pathways; Pathways; Sex difference; Sex hormones; “Androgen receptor”; “Estrogen receptor”

DOI:  https://doi.org/10.1007/s11033-025-11065-2
Front Immunol. 2025 ;16 1654034

Steroid hormone regulation of immunometabolism and inflammation.

Ley Cody Smith, Mohankumar Ramar, Gregory L Riley, Clinton B Mathias, Ji-Young Lee.

  The metabolism of immune cells adapts to support the energy demands for their activation, differentiation, and effector functions through a process known as metabolic reprogramming. This metabolic plasticity is influenced by both extrinsic and intrinsic factors, including steroid hormones such as glucocorticoids, androgens, progestogens, and estrogens. These critical mediators modulate immune function and inflammatory responses through genomic and non-genomic regulation of intracellular metabolic pathways, including glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation. Interestingly, these effects appear to be dependent on cell type, hormonal concentration, and microenvironmental context. Herein, we discuss how steroid hormones regulate inflammation and immunometabolism and summarize recent studies highlighting immunometabolic regulation by steroid hormones as the key driver of their immunomodulatory effects. We also address potential mechanisms contributing to their seemingly dichotomous and context-specific regulation. Understanding the link between steroid hormone signaling, immunometabolism, host defense, chronic inflammation, and immunity will expand our understanding about how biological sex and stress influence the immune system and facilitate more precise therapeutic targeting of immune cell activity to mitigate inflammation- and immune-mediated diseases.

Keywords:  glycolysis; immune; immunometabolism; inflammation; oxidative phosphorylation; steroid hormones

DOI:  https://doi.org/10.3389/fimmu.2025.1654034
Obes Rev. 2025 Sep 30. e70026

Sex Disparities in Obesity: A Comprehensive Review of Hormonal and Genetic Influences on Obesity-Related Phenotypes.

Yu-Gyeong Lee, Yoo-Ree Kang, Yoomee Chang, Jongmin Kim, Mi-Kyung Sung.

  The Worldwide Incidence of Obesity, which tripled in 2016 from 1975, is a leading risk factor for chronic diseases. The presence of sex-dependent disparities in obesity has spurred increased interest in understanding the diverse environmental and genetic factors influencing this condition. Typically, men tend to have more visceral adipose tissue (VAT), while women generally have higher amounts of subcutaneous adipose tissue (SAT). These differences have been largely attributed to the effects of sex hormones, particularly estrogen. However, large-scale genome-wide association studies (GWAS) have identified genetic factors associated with sex-dependent disparities in obesity-related traits, which revealed that the role of estrogen may have been overemphasized. This review aims to summarize sex-specific differences in adipose tissue distribution and adipose tissue type such as white adipose tissue (WAT) and brown adipose tissue (BAT). Additionally, the mechanisms underlying the development of sex-specific characteristics are explained, with a focus on estrogen and obesity-associated genes. Specifically, we propose a list of GWAS-derived genes that may be responsible for the observed sex differences in obesity, which could significantly contribute to the existing literature.

Keywords:  GWAS; autosomes; men; obesity; sex chromosomes; sex hormones; women

DOI:  https://doi.org/10.1111/obr.70026
Ther Adv Med Oncol. 2025 ;17 17588359251379416

The future of androgen receptor targeting in prostate cancer: third-generation inhibitors and beyond.

Alice Bernard-Tessier, Natacha Naoun, Solenn Barraud, Ronan Flippot, Cedric Pobel, Macarena Rey, Capucine Baldini, Christophe Massard, Anna Patrikidou, Alina Fuerea, Mario Di Palma, Laurence Albigès, Yohann Loriot, Karim Fizazi.

  The androgen receptor (AR) pathway plays a fundamental role in the treatment of prostate cancer, from the localized stage to metastatic disease, even in castration-resistant prostate cancer (CRPC). Despite the significant benefit for the earlier use of second-generation AR pathway inhibitors (ARPI), treatment resistance is still emerging. A deeper understanding of the biology of ARPI resistance is crucial for developing new therapeutic targets. In this review, we will explore the biology of second-generation ARPI resistance and discuss the evolving landscape of third-generation ARPI and steroid hormone inhibitors, which are shaping the future of prostate cancer therapeutics. Targeting the biosynthesis of steroid precursors with CYP11A1 inhibition, inducing AR degradation with proteolysis-targeting chimera degraders or restoring ARPI sensitivity with EZH2 inhibitors are among the most advanced strategies in development. Alongside these new drugs, AR genomic alterations and particularly AR mutations emerge as a promising biomarker for patient selection. These innovative therapeutics help bring more personalized approaches to patients with prostate cancer, aiming to overcome resistance and improve patient outcomes.

Keywords:  AR alterations; AR-targeted therapy; androgen receptor pathway inhibitor; castration-resistant prostate cancer; drug resistance

DOI:  https://doi.org/10.1177/17588359251379416
Curr Issues Mol Biol. 2025 Sep 19. pii: 780. [Epub ahead of print]47(9):

Natural Products Targeting the Androgen Receptor Signaling Pathway: Therapeutic Potential and Mechanisms.

Sitong Wu, Esveidy Isabel Oceguera Nava, Dennis Ashong, Guanglin Chen, Qiao-Hong Chen.

  The androgen receptor (AR) signaling pathway is the primary driver of prostate cancer initiation and progression, including the development of castration-resistant prostate cancer (CRPC). Because current AR-targeted therapies inevitably encounter drug resistance, novel strategies to suppress AR signaling are urgently needed. Natural products represent a rich and structurally diverse source of bioactive compounds capable of targeting AR at multiple regulatory levels. This review overviews the interactions between natural products and the AR signaling axis through distinct mechanisms, including inhibition of testosterone production and 5α-reductase activity, direct antagonism of AR, and induction of AR degradation. In addition, several compounds disrupt AR nuclear translocation, downregulate AR splice variants, or suppress AR signaling indirectly through epigenetic regulation, microRNA modulation, or interference with co-regulator networks. Preclinical studies provide compelling evidence that these agents can effectively interrupt AR signaling, thereby suppressing prostate cancer growth. However, challenges remain, particularly the limited pharmacokinetic characterization, lack of in vivo validation, and scarcity of clinical studies. Future research should focus on improving bioavailability, exploring synergistic combinations with existing therapies, and advancing well-designed in vivo and clinical investigations. Collectively, these efforts may establish natural products as lead compounds to modulate AR signaling for prostate cancer prevention and treatment.

Keywords:  androgen receptor; antagonism; degradation; natural product; testosterone

DOI:  https://doi.org/10.3390/cimb47090780
Physiol Rep. 2025 Oct;13(19): e70588

Steroid anabolic and catabolic hormones in highly and recreationally trained female athletes across the menstrual cycle.

Katia Collomp, Carole Castanier, Caroline Teulier, Agnès Olivier, Léane Blanchard, Juliette Bonnigal, Emmanuelle Duron, Eric Favory, Mathieu Zimmermann, Virgile Amiot, Valérie Carité, Marine Lefebvre, Cynthia Mongongu, Magnus Ericsson, Corinne Buisson.

  Sex hormone fluctuations across the normal menstrual cycle (NMC) may affect women's performance and health, but literature is sparse on the estradiol (E2) impact on anabolic and catabolic hormones and well-being in female athletes. We therefore measured in 21 NMC anaerobically trained female athletes: 12 highly (HT) and nine recreationally (RT) during late luteal/early follicular (Low E2) and late follicular/peri-ovulatory (High E2) phases: DHEAS, DHEA, androstenedione (A4), testosterone (T), sex hormone-binding globulin (SHBG), cortisol, free androgen index (FAI = T/SHBG), and their relative ratios. Body composition and well-being, assessed by positive and negative affects (PANAS), were determined in parallel. In High versus Low E2, subjects showed a significant percentage increase in T, A4 (p < 0.001) and FAI (p < 0.05), with high A4/T correlation (r = 0.78), without any change in the other parameters. While no group difference was detected in hormone concentrations, HT versus RT subjects presented higher muscle mass and positive affects and lower FAI (p < 0.05). In conclusion, T and A4 were modulated across NMC, probably resulting from a variable ovarian contribution, but without inducing any change in the anabolic/catabolic balance, regardless of the physical training level. However, high anaerobic training may enhance T sensitivity in view of the FAI, body composition and well-being outcomes.

Keywords:  PANAS; androstenedione; cortisol; estradiol; testosterone; training status

DOI:  https://doi.org/10.14814/phy2.70588
Medicine (Baltimore). 2025 Sep 26. 104(39): e44413

How FSH and LH analogs affect fertility hormone results?

Ebru Ersoy, Ataman Gonel.

  Infertility is defined as the inability of a couple to achieve pregnancy within a certain period despite regular sexual intercourse. With technological advances, infertility treatments have also advanced, and assisted reproductive technologies have become increasingly widespread. In this study, the potential interference effects of different gonadotropin preparations used during controlled ovarian stimulation in in vitro fertilization treatment on hormone levels were experimentally investigated. The effects of urine-derived (menotropin and urofollitropin) and recombinant (folitropin and folitropin + lutropin) gonadotropin preparations on the hormone levels were evaluated. Interference effects on follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, prolactin, testosterone, thyroid-stimulating hormone, free T3, and free T4 hormone levels were analyzed using immunoassay techniques. The results showed significant deviations, especially in the FSH and LH tests, whereas the interference levels varied among the different preparations. The highest interference was observed in the FSH assays, with deviations reaching up to 292,138%. Significant differences were also observed in estradiol and thyroid hormones (free T3 and free T4). These findings suggest that gonadotropin drugs containing high concentrations of FSH and LH may interfere with routine immunoassay-based hormone tests, leading to errors in clinical interpretation. This study emphasizes the need for careful interpretation of hormone assays in patients undergoing in vitro fertilization treatment, and the importance of considering possible interference effects.

Keywords:  IVF; controlled ovarian stimulation; false results; gonadotropin; hormone; infertility

DOI:  https://doi.org/10.1097/MD.0000000000044413
World J Gastrointest Pathophysiol. 2025 Sep 22. 16(3): 107823

Discovering a new paradigm: Gut microbiota as a central modulator of sexual health.

Giuseppe Marano, Maria B Anesini, Miriam Milintenda, Mariateresa Acanfora, Claudia d'Abate, Francesco M Lisci, Ilaria Pirona, Gianandrea Traversi, Roberto Pola, Eleonora Gaetani, Marianna Mazza.

  The gut microbiota plays a pivotal role in human health, influencing diverse physiological processes, including those related to sexual health. Emerging evidence suggests a bidirectional relationship between the gut microbiota and sexual health, mediated by its impact on systemic inflammation, hormonal regulation, and immune function. A balanced gut microbiota supports optimal levels of sex hormones, such as estrogen and testosterone, which are critical for sexual function and reproductive health. Additionally, gut-derived metabolites such as short-chain fatty acids contribute to maintaining mucosal barrier integrity and regulating immune responses, which are essential for protecting against infections that may impair sexual health. Conversely, dysbiosis, an imbalance in gut microbial composition, has been linked to conditions such as erectile dysfunction, polycystic ovary syndrome, and reduced libido, emphasizing its role in sexual dysfunction. Lifestyle factors, including diet, stress, and antibiotic use, can modulate the gut microbiota and, consequently, sexual health outcomes. Recent therapeutic approaches, such as probiotics, prebiotics, and fecal microbiota transplantation, offer potential for restoring gut balance and improving sexual health. This review highlights the central role of the gut microbiota in sexual health, emphasizing its importance as a target for therapeutic interventions to enhance overall well-being.

Keywords:  Diet; Dysbiosis; Gut brain axis; Gut microbiota; Hormonal regulation; Mental health; Neurotransmitters; Psychobiotics; Psychological therapies; Sexual health; Sexual performance anxiety; Short-chain fatty acids

DOI:  https://doi.org/10.4291/wjgp.v16.i3.107823
Front Endocrinol (Lausanne). 2025 ;16 1654965

Androgen receptor antagonist flutamide modulates estrogen receptor alpha expression in distinct regions of the hypospadiac rat penis.

Emilie Elmelund, Monica K Draskau, Marie Berg, Ida W Strand, Jay R Black, Marta Axelstad, Andrew J Pask, Terje Svingen.

   Introduction: Intrauterine exposure to endocrine disrupting chemicals (EDCs), particularly anti-androgens, has been implicated in hypospadias by disrupting fetal masculinization of the genital tubercle (GT). Other pathways, including estrogen signaling, may also contribute but remain poorly characterized, especially in rats - a key model in chemical toxicity testing. Estrogen signaling has also been linked to hypospadias in mice, raising questions about androgen-estrogen interactions in guiding GT differentiation.
Methods: We induced hypospadias in male rat offspring via intrauterine exposure to the antiandrogenic drug flutamide and characterized androgen and estrogen receptor expression.
Results: We observed key structural and transcriptional changes in the developing penis, including altered estrogen receptor a (ERa, Esr1) expression. Notably, beyond this established androgen-estrogen relationship in hormone-sensitive tissues, anti-androgenic exposure also induced spatial changes in Esr1 expression in specific regions of the GT.
Discussion: Future toxicological testing using new approach methodologies (NAMs) should consider androgen-estrogen balance and crosstalk in reproductive tissues as a mechanism of action.

Keywords:  androgen receptor; endocrine disrupting chemicals; estrogen receptor; genital tubercle; hypospadias; penis development

DOI:  https://doi.org/10.3389/fendo.2025.1654965
Biol Sex Differ. 2025 Sep 29. 16(1): 71

Multi-omics protein signaling networks identify sex-specific therapeutic candidates in lung adenocarcinoma.

Chen Chen, Enakshi Saha, Jonas Fischer, Marouen Ben Guebila, Viola Fanfani, Katherine H Shutta, Megha Padi, Kimberly Glass, Dawn L DeMeo, Camila M Lopes-Ramos, John Quackenbush.

   BACKGROUND: Lung adenocarcinoma shows distinct differences between males and females in incidence, prognosis, and treatment response, suggesting unique molecular mechanisms that remain underexplored. This study aims to identify sex-specific molecular signatures and therapeutic targets in lung adenocarcinoma using multi-omics approaches to inform personalized treatment strategies.
METHODS: We conducted an integrative analysis of transcriptomic and proteomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) datasets, comparing male and female lung adenocarcinoma profiles. Transcription factor activity was assessed using TIGER on gene expression data, while kinase activity was evaluated with PTM-SEA on proteomic data. These results were combined to build a kinase-transcription factor signaling network. Potential sex-specific drugs were identified using the PRISM drug screening database.
RESULTS: The analysis revealed significant sex-based differences in transcription factor and kinase activity. Notably, NR3C1, AR, and AURKA exhibited sex-biased expression and activity. The constructed signaling network highlighted druggable pathways linked to cancer-related processes, with distinct profiles in males and females. PRISM screening identified glucocorticoid receptor agonists and aurora kinase inhibitors as promising sex-specific therapeutic candidates.
CONCLUSIONS: Our findings underscore the importance of considering sex differences in lung adenocarcinoma molecular profiles. The integration of transcriptomic and proteomic data reveals sex-specific pathways and potential therapies, paving the way for personalized treatment approaches tailored to male and female patients.

Keywords:  APOLLO; CPTAC; Drug repurposing; Lung adenocarcinoma; Multi-omics; PRISM; Post-translational modifications; Protein signaling network; Sex differences; TCGA

DOI:  https://doi.org/10.1186/s13293-025-00752-1
Sci Rep. 2025 Sep 30. 15(1): 34073

Characterization of vaginal prokaryotes and eukaryotes microbiota and its link to sexually transmitted infections.

Ana Moya-Beltrán, Carolina Sánchez, Celia Bórquez B, Teresa Reyes T, Hilda Villanueva D, Carlos Soto S, Mariana León G, Pamela Mieres-Amigo, Mauricio A Saez, Raquel Quatrini, Alberto J M Martin, Claudio Alburquenque.

The vaginal microbiota plays a critical role in maintaining reproductive health. Although Lactobacillus species often dominate the vaginal environment in healthy individuals, recent studies have shown that healthy microbiota compositions can also include Lactobacillus-depleted states, as described by the Community State Types (CSTs) framework. However, disruptions in the microbiota composition, such as those caused by sexually transmitted infections (STIs), can lead to increased diversity and instability, compromising host protection. This study investigates the association between vaginal microbiota composition and the prevalence of STIs in a cohort of incarcerated women in Chile. Using metataxonomic approaches targeting 16S and 18S rRNA genes, we characterized prokaryotic and eukaryotic components of the vaginal microbiota across healthy, dysbiotic, and pathogen-dominated subjects. Alpha diversity analysis using the Shannon index indicated that Lactobacillus-dominant communities were associated with lower microbial diversity correlates with reduced variability. Whereas communities dominated by pathogens including Trichomonas vaginalis, Gardnerella vaginalis, Treponema pallidum, and HIV, tended to exhibit higher diversity. The pathogen-dominated group displayed an increased prevalence of opportunistic microorganisms and reduced Lactobacillus abundance, which may reflect an imbalance in the microbial ecosystem, often interpreted as reduced stability. This study provides novel insights into the intricate dynamics between normal and altered vaginal microbiomes and their association with STIs. Understanding these community-level patterns and associations is crucial for designing targeted interventions aimed at restoring microbial balance and preventing infections.

DOI: https://doi.org/10.1038/s41598-025-14573-0
Commun Biol. 2025 Oct 03. 8(1): 1422

Estradiol and dihydrotestosterone exert sex-specific effects on human fibroblast and endothelial proliferation, bioenergetics, and vasculogenesis.

Ashley T Martier, Yasmin V Maurice, K Michael Conrad, Delia A Carlino, Franck Mauvais-Jarvis, Mark J Mondrinos.

Sex-specific cell culture methods and microphysiological systems can enhance our understanding of how biological sex influences health and disease. Here, we investigated the effects of estradiol and dihydrotestosterone on primary human lung and ocular fibroblasts as well as in human umbilical vein and retinal microvascular endothelial cells from both female and male donors. Treatment of female cells with estradiol and male cells with dihydrotestosterone in 2D culture significantly enhanced proliferation, mitochondrial membrane potential, and upregulated genes associated with bioenergetics and stress responses. Conversely, treatment of female cells with dihydrotestosterone and of male cells with estradiol decreased bioenergetic potential and inhibited cell proliferation. A microphysiological model of bulk tissue vasculogenesis revealed that estradiol enhances vasculogenesis in female tissues and inhibits vasculogenesis in male tissues. Collectively, these findings demonstrate that the sex hormone composition of culture medium significantly influences bioassay readouts in a sex-specific manner.

DOI: https://doi.org/10.1038/s42003-025-08822-1
Elife. 2025 Oct 03. pii: RP102449. [Epub ahead of print]13

Pan-tissue transcriptome analysis reveals sex-dimorphic human aging.

Siqi Wang, Danyue Dong, Xin Li, Zefeng Wang.

  Complex diseases often exhibit sex dimorphism in morbidity and prognosis, many of which are age-related. However, the underlying mechanisms of sex-dimorphic aging remain foggy, with limited studies across multiple tissues. We systematically analyzed ~17,000 transcriptomes from 35 human tissues to quantitatively evaluate the individual and combined contributions of sex and age to transcriptomic variations. We discovered extensive sex dimorphisms during aging with distinct patterns of change in gene expression and alternative splicing (AS). Intriguingly, the male-biased age-associated AS events have a stronger association with Alzheimer's disease, and the female-biased events are often regulated by several sex-biased splicing factors that may be controlled by estrogen receptors. Breakpoint analysis showed that sex-dimorphic aging rates are significantly associated with decline of sex hormones, with males having a larger and earlier transcriptome change. Collectively, this study uncovered an essential role of sex during aging at the molecular and multi-tissue levels, providing insight into sex-dimorphic regulatory patterns.

Keywords:  AS regulatory network; aging; alternative splicing; chromosomes; computational biology; gene expression; human; sex dimorphism; systems biology; time series

DOI:  https://doi.org/10.7554/eLife.102449
Menopause. 2025 Oct 01. 32(10): 975-977

Role of progestogens in hormone therapy.

James H Liu.

DOI: https://doi.org/10.1097/GME.0000000000002649
Front Immunol. 2025 ;16 1654741

Spatial transcriptomics reveals distinct role of monocytes/macrophages with high FCGR3A expression in kidney transplant rejections.

Yan Chen Wongworawat, Chirag Nepal, Mark Duhon, Wanqiu Chen, Minh-Tri Nguyen, Adam Godzik, Xinru Qiu, Wei Vivian Li, Gary Yu, Rafael Villicana, Craig Zuppan, Michael De Vera, Michael T Eadon, Mark Haas, Charles Wang.

   Introduction: Kidney transplant rejections are classified as active antibody mediated rejection (AMR) and cell mediated rejection (TCMR), with AMR primarily driven by antibodies produced by B cells, whereas TCMR is mediated by T lymphocytes that orchestrate cellular immune responses against the graft. Emerging evidence highlights the essential roles of innate immune cells in rejections, especially monocytes/macrophages and natural killer (NK) cells. However, the roles of specific innate immune cell subpopulations in kidney allograft rejection remain incompletely understood.
Methods: We performed the spatial transcriptomics using the formalin-fixed paraffin-embedded (FFPE) core needle biopsies from human kidney allografts.
Results: We demonstrated that non-rejection, AMR, acute TCMR and chronic active AMR have distinct transcriptomic features. Subclusters of monocytes/macrophages with high Fc gamma receptor IIIA (FCGR3A) expression were identified in C4d-positive active AMR and acute TCMR, and the spatial distribution of these cells corresponded to the characteristic histopathological features. Key markers related to monocyte/macrophage activation and innate alloantigen recognition were upregulated, along with metabolic pathways associated with trained immunity in AMR and TCMR.
Discussion: Taking together, these findings revealed that intragraft monocytes/macrophages with high FCGR3A expression play a critical role in kidney transplant rejections.

Keywords:  Fc gamma receptor IIIA (FCGR3A); cell mediated rejection; innate immunity; kidney allograft antibody mediated rejection; macrophages; monocytes; spatial transcriptomic; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1654741
Biochim Biophys Acta Mol Cell Res. 2025 Sep 27. pii: S0167-4889(25)00171-5. [Epub ahead of print] 120066

TRPV4 is involved in progesterone-mediated sexual dimorphism in mesenchymal stem cell functions and bio-mineralization.

Nishant Kumar Dubey, Satish Kumar, Shamit Kumar, Subham Mishra, Nilesh Kumar Das, Chandan Goswami.

  The prevalence of bone disorders in female has been linked with imbalances in sex hormones, especially during pregnancy and menopause. Apart from regulation of transcription, recent reports suggest the involvement of various ion channels which can also be the molecular targets of an array of steroids (and steroid-like molecules). The differences in steroid responses between males and females also impose the need to understand the complexity of steroid actions. This current in vitro study has been carried out during the osteoblast differentiation (day 1 and day 12, early and late time points respectively) using MSCs-derived from male and female animals and in the presence of progesterone (P4) and/or TRPV4 modulators to explore the existence of sexual dimorphism at the cellular level if any and possible involvement of TRPV4 and P4 in it. Different subcellular parameters such as cytosolic Ca2+, mitochondrial potential, cytosolic- and mitochondrial-ROS and functional assays such as bio-mineralization (BM) were performed. All these results point out that P4 modulates TRPV4 both in the short-term and long-term, but differently in male and female-derived primary cells. It is observed that P4 can modulate TRPV4 in a long-term, both transcription-dependent and transcription-independent manner. Thus, the observed sexual dimorphism at the cultured cellular system is more prominent in the early time point which seems to be dampened, but still exists in the later time points. These findings may be relevant for bone disorders due to hormonal imbalance.

Keywords:  Bone mineralization; Cellular dimorphism; Osteoblast differentiation; Progesterone; TRPV4

DOI:  https://doi.org/10.1016/j.bbamcr.2025.120066
Biochim Biophys Acta Mol Cell Res. 2025 Sep 30. pii: S0167-4889(25)00167-3. [Epub ahead of print] 120062

Comprehensive analysis of androgen receptor splice variant target gene expression in prostate cancer.

Neele Wüstmann, Julissa Reimann, Julia Vieler, Verena Humberg, Katrin Schlack, Martin Bögemann, Andres Jan Schrader, Christof Bernemann.

  This study aimed to comprehensively analyze AR-V specific target gene expression using a physiological system that simulates the actual situation of AR-FL and AR-V co-appearance in prostate cancer patients. Clinically described AR splice variants AR-V3, AR-V7 and AR-V9 were transfected along with AR-FL in AR-negative prostate cancer PC-3 cells. RNA sequencing analysis showed only slight differences in differentially expressed genes between AR-FL and AR-V co-expressing cells compared to solely AR-FL expressing cells. Immunofluorescence analysis and luciferase assays revealed hormonal dependency of AR-FL, constitutive activity of AR-V7, and ambivalent activity of AR-V9, while AR-V3 showed no activity. Analysis of a set of published target genes showed steady upregulation of EDN2 and FKBP5. Yet, clinical analysis revealed no significant differences in overall survival data in prostate cancer patients. The study challenges the existence of an AR-V specific transcriptome responsible for treatment resistance and tumor progression and highlights the need for further investigation into the molecular mechanism by which AR-V proteins route resistance to ARTA treatment.

Keywords:  Androgen receptor; Androgen receptor splice variants; Androgen receptor targeted agents; Biomarker; Liquid biopsy; Metastatic castration resistant prostate cancer; Predictive; Prognostic; Target genes

DOI:  https://doi.org/10.1016/j.bbamcr.2025.120062
Int Immunopharmacol. 2025 Sep 28. pii: S1567-5769(25)01579-6. [Epub ahead of print]166 115588

Testosterone as a mediator of APOE4-linked sex differences in Alzheimer's disease.

Zhidan Shi, Lingzhi Wu, Chu Zhang, Xiaoqian Zeng, Guangzhe Yao, Xinqi He, Jiayi Hu, Tian Xie, Ling He.

  The pathological mechanisms and clinical manifestations of Alzheimer's disease (AD) exhibit significant gender differences, with a higher proportion of female AD patients. Women carrying the apolipoprotein E4 (APOE4) genotype face a markedly higher risk of developing the disease compared to men. APOE4 plays a crucial role in shaping these gender disparities by influencing the characteristic pathologies of AD. As the primary androgen, testosterone and its metabolites play a vital role in maintaining central nervous system homeostasis by interacting with steroid hormone receptors. Testosterone may mediate these effects through the androgen receptor (AR), participate in immune regulation, influence lipid metabolism, and interfere with the cholinergic system, thereby contributing to gender differences among APOE4 carriers. Key regulatory nodes include IL-17 and TGF-β. Furthermore, we synthesized clinical evidence linking testosterone replacement therapy to cognitive impairment, analyzed current research limitations and gaps in the field, and provided theoretical guidance for developing future targeted interventions and gender-specific therapeutic strategies.

Keywords:  AD; APOE4; Gender dimorphism; Testosterone

DOI:  https://doi.org/10.1016/j.intimp.2025.115588
Front Endocrinol (Lausanne). 2025 ;16 1658592

Reproductive aging in biological females: mechanisms and immediate consequences.

Yasin Ali Muhammad.

  Reproductive aging is a dynamic, systemic process that encompasses more than the decline in ovarian function. It involves coordinated changes across neuroendocrine, immune, metabolic, and mitochondrial systems. Central to this transition is the depletion of ovarian follicles, leading to reduced estradiol and progesterone production and subsequent disruption of the hypothalamic-pituitary-gonadal (HPG) axis. This hormonal shift remodels hypothalamic signaling networks - particularly those involving kisspeptin, neurokinin B (NKB), and GABA - driving alterations in gonadotropin-releasing hormone (GnRH) pulsatility, vasomotor symptoms (VMS), and loss of reproductive cycling. Simultaneously, chronic inflammation, oxidative stress, and mitochondrial dysfunction further accelerate both ovarian and neural aging. Estrogen receptor subtypes (ERα and ERβ) play critical and region-specific roles in mediating tissue responses to hormonal withdrawal, contributing to variability in symptom expression and therapeutic outcomes. Genetic, cultural, and environmental factors - such as diet, endocrine disruptors, and APOE genotype - further influence the trajectory and severity of menopause-related changes. Emerging treatments, including neurokinin receptor antagonists and ERβ-selective modulators, offer targeted alternatives to conventional hormone therapy. This review frames menopause not as a singular endocrine endpoint but as a neuroimmune transition, highlighting the need for mechanistic insight and personalized therapeutic approaches to improve health outcomes during reproductive aging.

Keywords:  aging; endocrine system; hypothalamas; menopause (estrogen withdrawal); ovarian follicle cells

DOI:  https://doi.org/10.3389/fendo.2025.1658592
Front Immunol. 2025 ;16 1642956

Sex chromosomes/hormones and the tumor microenvironment of non-reproductive cancers.

Chun-Miao Zhang, Zhong-Bo Ge, Hai-Hong Zhou, Meng-Xiao Wei, Xin-Yuan Ding, Zhe-Zheng Lin, Ming-Yu Wang, Cai-Juan Bai.

  Cancer exhibits profound sexual dimorphism in incidence and therapeutic outcomes, driven by the interplay between biological sex determinants and immune regulation. Besides established environmental risk factors (e.g., male-predominant smoking/alcohol consumption), emerging evidence identifies the tumor immune microenvironment (TIME) as a pivotal mediator of sex disparities in carcinogenesis and immunotherapy response. This review synthesizes recent advances in two fundamental mechanisms: (1) Sex chromosome biology: Recent studies delineate the Ubiquitous loss of chromosome Y (LOY) of male cancers that promotes immunosuppressive TIME remodeling, while X-chromosome inactivation escape in females enhances antitumor immunity; (2) Endocrine regulation: Androgen receptor signaling induces T-cell exhaustion via PD-1 transcriptional activation in males. Estrogen-ERα boosts cancer progression via PD-L1 high expression, whereas ERβ inhibits cancer progression via CD8+ T cell activation in females. This mechanistic synthesis provides actionable strategies for precision immuno-oncology trials targeting sex-based immunological divergence.

Keywords:  X-chromosome inactivation escape; antitumor immunity; loss of Y chromosome; non-reproductive cancer; sex hormone; sexual dimorphism; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1642956
World J Clin Oncol. 2025 Sep 24. 16(9): 108819

Unraveling the links between estrogen and gut microbiota in sex-hormone driven cancers.

Amal Tahri, Amedeo Amedei.

  Estrogens are a group of steroid hormones produced by ovary, placenta, and other organs. They have historically been associated with female reproduction, but according to current evidence estrogens regulate also male reproductive and nonreproductive organs. Estrogens play a crucial role in female reproductive development and maintenance either directly by increasing glycogen levels, epithelial thickness and mucus secretion or indirectly, by decreasing vaginal pH through the maintenance of lactobacilli dominance and lactic acid production. Several studies demonstrated that dysbiosis and/or specific bacteria could have impact on the development of sex-hormone driven cancers such as endometrial, cervical, ovarian, breast and prostate cancers, through mechanisms involving modulation of estrogen metabolism. This modulation is realized through secretion of β-glucuronidase which deconjugates estrogens into their active forms. When gut dysbiosis occurs, microbial diversity decreases and so the deconjugation diminishes leading to a decrease of circulating estrogens. Low levels of circulating estrogen may adversely affect a wide range of physiological factors, with clinical implications especially for gut health. In this review, we discuss the different aspects of the critical interplay between gut microbiome and estrogens in sex-hormone driven cancers and the potential outcomes on their clinical management.

Keywords:  Breast; Cancer; Diet; Estrobolome; Estrogen; Gut microbiome; Prostate

DOI:  https://doi.org/10.5306/wjco.v16.i9.108819
Placenta. 2025 Sep 22. pii: S0143-4004(25)00700-3. [Epub ahead of print]

Trained immunity in pregnancy: Impact on maternal-fetal outcomes and mechanistic insights.

Sirui Liu, Jia Liang, Dongyong Yang, Lingtao Yang, Songchen Cai, Linlin Wang, Tailang Yin, Lianghui Diao.

  Trained immunity, defined as the epigenetic and metabolic reprogramming of innate immune cells that shapes their subsequent responses, has emerged as a key paradigm in reproductive immunology. In pregnancy, trained immunity can act as a "double-edged sword." Beneficial training of decidual NK cells and macrophages promotes vascular remodeling, tissue repair, and host defense, thereby supporting implantation and placental development. Conversely, dysregulated training triggered by hypoxia, metabolic stress, or infection may sustain chronic inflammation and contribute to preeclampsia, fetal growth restriction, and recurrent pregnancy loss. In this review, we summarize current evidence for both protective and pathogenic roles of trained immunity during pregnancy, highlight the underlying molecular mechanisms, and discuss key research gaps. Considering pregnancy complications from the perspective of trained immunity may provide new insights into pathogenesis and suggest opportunities for biomarker discovery and targeted interventions.

Keywords:  Decidual NK cells; Epigenetic reprogramming; Gestational diabetes mellitus; Metabolic adaptation; Preeclampsia; Trained immunity

DOI:  https://doi.org/10.1016/j.placenta.2025.09.015
Front Endocrinol (Lausanne). 2025 ;16 1645474

Epigenetic modification of hypothalamic neuropeptides and metabolic hormone receptors in metabolic health.

Busayo Oladun, Smita Mall, Min-Hyun Kim.

  The hypothalamus plays a central role in regulating metabolism by integrating neuropeptide signaling with environmental cues to maintain energy homeostasis. Adverse environmental factors, such as obesogenic diet, undernutrition, stress, and sedentary lifestyles, can disrupt the normal regulation of key hypothalamic neuropeptides and metabolic hormone receptors through epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA regulation. These epigenetic alterations are not merely transient; they can be heritable and may influence metabolic health across generations, highlighting the critical need to understand the underlying epigenetic mechanisms. In this review, we provide a comprehensive overview of how environmental factors shape the epigenetic landscape of hypothalamic neuropeptides (pre-opiomelanocortin, neuropeptide Y, and agouti-related peptide) and metabolic hormone receptors (leptin receptor and insulin receptor), thereby modulating their expression and contributing to long-term metabolic outcomes. A better understanding of environment-epigenome interactions holds promise for the development of innovative therapeutic strategies to combat obesity and metabolic disorders.

Keywords:  energy homeostasis; epigenetics; hypothalamus; metabolic hormone receptors; metabolism; neuropeptides; obesity

DOI:  https://doi.org/10.3389/fendo.2025.1645474
Cell Rep. 2025 Sep 30. pii: S2211-1247(25)01123-4. [Epub ahead of print]44(10): 116352

Single-cell analysis uncovers preserved prostate cancer lineages and universally altered pathways in Matrigel-free patient-derived organoids.

Robin Dolgos, Romuald Parmentier, Jing Wang, Raphaëlle Servant, Arnoud J Templeton, Tobias Zellweger, Alastair D Lamb, Kirsten D Mertz, Svetozar Subotic, Tatjana Vlajnic, Helge Seifert, Ashkan Mortezavi, Cyrill A Rentsch, Lukas Bubendorf, Clémentine Le Magnen.

  The application of patient-derived organoids (PDOs) in prostate cancer (PCa) research has been hampered by poor take rates and benign overgrowth. We highlight the limitations of existing culture conditions and identify extracellular matrix composition as a determinant of organoid outcome. Single-cell RNA sequencing reveals that Matrigel-free PDOs exhibit cellular heterogeneity, preserve patient-specific PCa cells with active androgen receptor signaling, and enrich in intermediate cells. In contrast, Matrigel fails to maintain primary PCa cells and produces in vitro basal-like features divergent from patient samples. Furthermore, we redefine cell-type signatures, identify biomarkers discriminating tumor versus other cell types, and show that expression of laminin-binding integrins is a hallmark of Matrigel-derived organoids. Finally, integrating previously published datasets with our data, we generate a prostate PDO single-cell atlas (PPScA), which captures a spectrum of cellular identities while revealing pathways altered in vitro. Our study provides methodological improvements for short-term culture and cellular biology insights.

Keywords:  CP: Cancer; CP: Stem cell research; PDOs; cancer models; cellular heterogeneity; culture conditions; ex vivo; extracellular matrix; patient-derived organoids; prostate cancer; single-cell RNA sequencing; single-cell atlas

DOI:  https://doi.org/10.1016/j.celrep.2025.116352
Future Oncol. 2025 Oct 03. 1-9

Treatment options in hormone-sensitive prostate cancer: targeting the androgen-sensitive pathway.

Cora N Sternberg, Alicia K Morgans.

  This podcast examines how hormone-sensitive prostate cancer (HSPC) is treated, specifically looking at therapies that target the androgen-sensitive pathway. Identification of patients and the clinical rationale for following different treatment pathways is reviewed, including examination of the current treatment options for both metastatic HSPC (mHSPC) and nonmetastatic HSPC, and consideration of barriers that might exist for optimal treatment. The importance of selecting a treatment strategy that offers control of the disease but allows the patient to maintain their functionality and quality of life is discussed, with an emphasis that, for patients with high-risk biochemical recurrence or mHSPC, combination treatment with androgen deprivation therapy and an androgen receptor pathway inhibitor is the standard of care that should be considered unless contraindicated.

Keywords:  Androgen receptor pathway inhibitors; PSMA PET imaging; hormone-sensitive prostate cancer; prostate neoplasms; quality of life; therapeutics

DOI:  https://doi.org/10.1080/14796694.2025.2561320
Front Immunol. 2025 ;16 1599408

Comparative single-cell immune responses in peripheral blood and lymph node of immunized SARS-CoV-2 challenged infant rhesus macaques.

Sasha Anronikov, Cameron Meikle, Emma C Milligan, Han Chen, Nilanjan Mukherjee, Zach Bjornson, Brice Gaudillière, Sizun Jiang, Sallie R Permar, Koen K A Van Rompay, Garry P Nolan, Kristina De Paris, David R McIlwain.

   Introduction: A better understanding of post-exposure immune responses in vaccinated individuals, particularly infants, is needed.
Methods: Using a rhesus macaque model, we compared recipients of mRNA- or protein-based SARS-CoV-2 vaccines administered in infancy with unvaccinated controls 7 days post-SARS-CoV-2 virus challenge. Mass cytometry profiling of peripheral blood mononuclear cells and dissociated mediastinal lymph node cells at 7 days post-challenge revealed tissue-specific differences between groups, representing a snapshot of immune activity at this point.
Results: Vaccinated animals showed lower frequencies of activated CD8+ T cells in blood and lower levels of monocyte and B cell subsets in lymph nodes, aligning with lower viral loads and milder pathology. Plasmacytoid dendritic cells-commonly depleted in circulation during severe human COVID-19-were preserved in the blood of vaccinated groups. Ex vivo stimulation demonstrated heightened inflammatory cell signaling from unvaccinated rhesus macaques, correlating with worse clinical outcomes.
Discussion: These findings enhance our understanding of a critical nonhuman primate model and underscore the utility of single-cell, tissue-level analyses in evaluating next-generation pediatric SARS-CoV-2 vaccine strategies.

Keywords:  COVID-19; CyTOF; SARS-CoV-2; delta variant; lymph node; peripheral blood mononuclear cells; rhesus macaques; vaccine

DOI:  https://doi.org/10.3389/fimmu.2025.1599408
bioRxiv. 2025 Sep 24. pii: 2025.09.22.677860. [Epub ahead of print]

AMICI: Attention Mechanism Interpretation of Cell-cell Interactions.

Justin Hong, Khushi Desai, Tu Duyen Nguyen, Achille Nazaret, Nathan Levy, Can Ergen, George Plitas, Elham Azizi.

Spatial transcriptomic data enable study of cell-cell communication, yet current analysis tools often fail to provide dynamic, interpretable estimates of interactions and their spatial range across tissue. We present AMICI, an interpretable attention framework that jointly estimates interaction length scales, adaptively resolves sender-receiver subpopulations, and links communication to downstream gene programs. AMICI recovers ground-truth interactions in semi-synthetic data, uncovers gene programs linked to cell communication in the mouse cortex, and reveals length-scale-dependent tumor-immune signaling that reinforces estrogen receptor (ER) programs in breast cancer.

DOI: https://doi.org/10.1101/2025.09.22.677860
Front Immunol. 2025 ;16 1631522

Leveraging the role of the microbiome in endometriosis: novel non-invasive and therapeutic approaches.

Eleni Andria Kalopedis, Amine Zorgani, Dmitry A Zinovkin, Muruj Barri, C David Wood, Md Zahidul I Pranjol.

  Endometriosis (EMS) is an oestrogen-dependent condition characterised by ectopic endometrial-like tissue growth with a chronic and inflammatory nature leading to severe symptoms and reduced quality of life. Emerging evidence implicates gut microbiome dysbiosis in EMS pathogenesis, driving chronic inflammation, immune dysfunction, and altered bacterial taxa within patient gut microbiome. This review examines the intricate relationship between gut dysbiosis and EMS, with a focus on immunomodulatory mechanisms and the downstream consequences of the bacterial contamination theory. It evaluates recent findings regarding microbial imbalances and microbial diversity, pinpointing gaps in current research that mandate further understanding. For example, while microbial markers like Lactobacillus depletion and elevated Escherichia coli have been observed in patients, their diagnostic potential remains poorly defined. Additionally, it addresses the broader implications of EMS, including its physical, mental and healthcare burdens. Simultaneously, critiquing current drawbacks in diagnostic and therapeutic strategies such as their invasiveness and limited efficacy. The review further evaluates novel microbiome-based strategies namely Lactobacillus-based probiotics and faecal microbiota transplantation (FMT), assessing their potential in modulating immune responses and alleviating EMS symptoms while considering associated challenges. Lastly, it highlights the emerging role of metabolomics in identifying non-invasive and diagnostic biomarkers like short-chain fatty acids (SCFAs), implicated in the interplay between microbial metabolites and immune signalling pathways in EMS.

Keywords:  biomarkers; dysbiosis; endometriosis; estroblome; gut microbiome; immunomodulation; microbiota-based therapy; probiotics

DOI:  https://doi.org/10.3389/fimmu.2025.1631522