It remains unclear whether breastfeeding in infancy is associated with risk of metabolic dysfunction-associated steatohepatitis (MASH) and adverse liver outcomes in adulthood. We analyzed data from the prospective UK Biobank. Breastfeeding in infancy was ascertained via self-report. In a cross‑sectional analysis involving 26,850 participants with liver MRI data, metabolic dysfunction-associated steatotic liver disease (MASLD) was defined as PDFF > 5.5%, and MASH as PDFF > 5.5% combined with cT1 > 800 ms. Additionally, a longitudinal analysis of 378,702 participants assessed associations with incident cirrhosis, hepatocellular carcinoma (HCC), and liver‑related mortality. In MRI-based analysis, breastfeeding in infancy was associated with lower odds of MASLD (OR 0.89, 95% CI 0.80-0.99) and MASH (OR 0.79, 95% CI 0.65-0.97) in females but not males, with a significant sex interaction for MASH (P for interaction = 0.023) but not for MASLD (P for interaction = 0.301). Over a median follow‑up of 14.9 years, breastfeeding was associated with reduced risks of cirrhosis (HR 0.71, 95% CI 0.60-0.83), HCC (HR 0.52, 95% CI 0.33-0.82), and liver‑related mortality (HR 0.63, 95% CI 0.46-0.86) in females. No such associations were observed in males (P for interaction = 0.047, 0.030, and 0.008, respectively). Mediation analysis revealed that circulating insulin-like growth factor-1 (IGF-1) mediated the association specifically in females, with a sex difference in the indirect effect (FDR < 0.001). Breastfeeding in infancy confers a long-term protective effect against MASH and adverse liver outcomes in women, but not in men. This sex-specific protective association was mediated by circulating IGF-1, suggesting a potential underlying mechanism.

This study aimed to systematically map the sex-specific clinical and proteomic risk profiles of aortic aneurysm (AA), elucidate its molecular mechanisms, and develop a sex-specific protein risk prediction score. Based on the UK Biobank, we adopted a sex-stratified strategy to assess associations between traditional clinical factors and AA in 471,660 participants, and performed proteomics analysis on 49,887 participants with plasma protein data. Mediation analysis was used to explore the molecular mechanisms by which clinical risks drive AA. Finally, sex-specific protein risk scores were developed via LASSO regression, and their predictive performance was evaluated in an independent validation cohort. Smoking (HR: Male: 2.82; Female: 4.42) and valvular disease (HR: Male: 2.01; Female: 4.62) were the strongest shared risk factors, with women exhibiting significantly higher susceptibility. Incident AA was primarily attributed to smoking (Male: 15.3%; Female: 19.8%) and hypertension (Male: 11.2%; Female: 10.2%). Smoking was associated with AA potentially through the ECM degradation pathway in both sexes. Hypertension may also influence AA risk through this pathway in men, whereas in women, it may primarily operate through metabolic and growth factor regulation pathways. Among LASSO-selected proteins, 4 were shared, 10 were male-specific, and 9 were female-specific. Ultimately, the model integrating traditional risk factors and sex-specific protein scores demonstrated superior predictive performance in an independent cohort (C-statistic: Male: 0.809; Female: 0.832). Smoking and hypertension are primary risk factors for AA. Men may be predisposed to structural destruction potentially mediated by ECM degradation, whereas women may be predisposed to intrinsic failure potentially involving metabolic dysregulation and cell apoptosis. The model integrating age, clinical factors, and protein scores better captures residual risk, significantly improving AA prediction.

As an important interface between the peripheral environment and the central nervous system, the gut microbiota varies greatly between patients or animals with Alzheimer's disease (AD) and their respective non-AD counterparts; however, it remains unexplored whether the apolipoprotein E (APOE) genotype, age, and sex may interactively influence the characteristics of gut microbiota in AD animals. APOE genotype, age, and sex were enrolled as independent variables, with genotype distinguished into APOE3 and APOE4, age into 3 and 10 months, and sex into female and male. The composition, structure, and potential functions of gut microbiota were systematically analyzed by 16S rRNA gene amplicon sequencing to evaluate the individual and interactive effects of APOE genotype, age and sex. Significant interactions were observed among APOE genotypes, ages, and sexes, with different factor combinations exhibiting distinct effect on microbiotic composition and functional potential. APOE genotype exerted the most significant influence on gut microbiota, followed by age and sex with a relatively minor effect, highlighting the dominant role of host genetic background. Functional prediction analysis indicated that the functional profiles were mainly concentrated in basic metabolic pathways, including the biosynthesis of secondary metabolites and amino acids, and carbon metabolism. APOE genotype, age, and sex are jointly associated with the structure and potential function of the gut microbiota in AD model mice. These findings provide a perspective of multi-factor interaction into the alterations in gut microbiota in AD and offer new microecological evidence for understanding APOE4-related AD susceptibility, as well as a conceptual basis for future stratified microecological intervention studies.

BackgroundFamilial hypercholesterolemia (FH) is a genetic disorder of cholesterol metabolism caused by loss-of-function variants in the low-density lipoprotein receptor (LDLR), resulting in persistently elevated LDL-cholesterol levels in plasma. Although hypercholesterolemia, especially the high levels of LDL, has been linked to an increased risk of dementia, the underlying mechanisms remain unclear. Here, we investigated the effects of sexual dimorphism and aging on metabolic and cognitive functions in a murine model of FH.MethodsAdult and middle-aged, male and female, C57BL/6 and LDLr-/- mice were used in this study. Behavioral assessments included locomotor activity, spatial memory, and anxiety-like behavior. Plasma lipid profiles were measured, and mitochondrial function in the hippocampus and brown adipose tissue (BAT) was assessed using high-resolution respirometry.ResultsLDLr-/- mice of both sexes exhibited increased cholesterol and triglycerides levels. Male LDLr-/- mice displayed hyperlocomotion in the Open Field (OF) and Elevated Plus Maze (EPM) at both ages, whereas this phenotype emerged in middle-aged female LDLr-/- mice only in OF. Spatial memory impairments were observed in LDLr-/- mice regardless of sex or age. Hippocampal oxygen consumption was reduced in adult males and middle-aged female mice, whereas BAT respiration was impaired in both sexes at middle-aged animals, affecting distinct respiratory parameters. Correlation analyses revealed that elevated cholesterol levels were associated with memory deficits and hyperlocomotion, along with positive correlations between hippocampal and BAT mitochondrial function.ConclusionsCollectively, these findings demonstrate that FH induces sex- and age-dependent alterations in behavior and mitochondrial metabolism, providing mechanistic insights into the link between FH and neurodegenerative disease risk.Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s13293-026-00893-x.

Extreme low temperatures impose severe physiological stress on aquatic crustaceans. Understanding the molecular mechanisms of cold adaptation is critical for improving stress resilience in key aquaculture species. This study employed integrated transcriptomic and metabolomic analyses to decipher sex-divergent neuroendocrine strategies in Cherax quadricarinatus under cold stress. Males rely on high basal antioxidant capacity for rapid JAK-STAT pathway activation to combat acute cold stress, whereas females maintain metabolic homeostasis through sustained pathway activation. This sexually dimorphic strategy is negatively regulated by C16-ceramide. Females relied on sustained JAK-STAT activation for transcriptional reprogramming, while males exhibited rapid metabolic remodeling and transient antioxidant mobilization. Crucially, the sphingolipid hub molecule C16-ceramide was coordinately downregulated in both sexes. Exogenous supplementation revealed C16-ceramide potently suppressed JAK-STAT genes and disrupted hepatopancreatic redox homeostasis in females, while triggering antioxidant collapse in males. This study provides the first evidence of sexual dimorphism in JAK-STAT mediated cold adaptation in invertebrates, identifies C16-ceramide as a regulator of sex-specific defense strategies, and confirms the penetration of sexual dimorphism into conserved molecular stress response networks.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition characterized by hepatic fat accumulation and systemic metabolic dysfunction. MASLD exhibits clear sex differences, yet the mechanisms underlying these disparities remain poorly defined. To investigate the early temporal dynamics of MASLD, male and female mice were fed a choline-deficient, methionine-restricted (0.1%) high-fat (61%) diet (CDAHFD; characterized by impaired hepatic lipid export and enhanced lipotoxic stress) for two weeks, enabling assessment of initial metabolic responses. Despite their presumed protection, females developed an exacerbated hepatic phenotype accompanied by intestinal remodeling and compromised barrier integrity. In contrast, males displayed early weight loss and improved glucose tolerance, alongside reduced hepatic transcriptional changes indicative of adaptive metabolism. Additionally, sex-specific hypothalamic responses were observed, with males showing reduced expression of microglial homeostatic markers, increased inflammation, and alterations in energy balance-related signaling, consistent with neuroimmune modulation. These responses were paralleled by sex-dependent alterations in adipose tissue, including early adipocyte remodeling and distinct transcriptional changes, which were predominantly consistent with baseline sex differences and therefore suggest a limited contribution of this tissue to the early diet-induced metabolic divergence. Importantly, these early sex-dependent adaptations were not sustained over time, as prolonged CDAHFD (14weeks) resulted in a shift towards a more sever inflammatory and fibrotic hepatic phenotype in males, while females exhibited relative preservation of hepatic metabolic function and attenuation of intestinal alterations. These findings demonstrate that sexual dimorphism in MASLD arises early and evolves dynamically, with females mounting an acute metabolic and intestinal stress response, whereas males activate compensatory pathways that preserve metabolic homeostasis. These results highlight sex-specific trajectory in MASLD progression and emphasize the need for integrative approaches to unravel its pathophysiology.

Both brain-derived neurotrophic factor (BDNF) and ovarian hormones are powerful neuromodulators, yet evidence of their impact on human cognition remains mixed. As prior work has studied them in isolation, examining their interacting effects presents a key empirical opportunity for explicating their effects on cognition. We genotyped participants for the BDNF Val66Met single nucleotide polymorphism, which is associated with less efficient activity-dependent BDNF secretion and altered hippocampal function, and examined their performance on a complex learning task at two points in the menstrual cycle: early follicular (characterized by low levels of ovarian hormones) and late follicular (characterized by high estradiol). While met carriers showed advantages during the early follicular timepoint, val homozygotes outperformed them at the late follicular timepoint. Furthermore, effects in met carriers were largely driven by increased sensitivity to both absolute levels and changes in levels of estradiol. The current findings provide the first evidence of BDNF Val66Met interacting with the menstrual cycle to predict cognition, demonstrate nuanced genotype- and hormone-specific outcomes, and underscore the importance of studying effects of interacting biological systems on human cognition.

Sexual dimorphism in skeletal muscle is a well-recognized biological phenomenon of adaptive evolution, yet its developmental genetic basis remains poorly understood. In many anurans, males develop hypertrophied forelimb muscles to facilitate amplexus (mating embrace) during breeding season, offering an ideal model to dissect the ontogeny of sex-specific muscle growth. The aim of this study was to determine the developmental onset of sexual dimorphism in the flexor carpi radialis (FCR) muscle and to characterize the transcriptional landscape driving this phenotypic divergence. We first established the developmental timeline of sexual dimorphism in the FCRmuscle of Bufo gargarizans through morphological analysis. Based on the identified onset time, we performed comparative RNA sequencing at three critical post-metamorphic stages: pre-dimorphism (PD; 2 months post-metamorphosis), onset of dimorphism (OD; 4 months post-metamorphosis), and adult (AD; 24 months post-metamorphosis), to capture transcriptional dynamics associated with phenotype emergence. The results showed that males exhibited significantly greater FCR mass than females beginning at the OD stage and this difference persisted into adulthood. Transcriptomic profiling revealed a marked increase in sex‑biased differentially expressed genes (DEGs) at OD, coinciding with the emergence of morphological divergence. Time‑series analysis identified two major expression trajectories: 415 genes showed a sharp increase in male-biased expression from PD to OD, followed by a decline in AD, whereas 177 genes increased continuously from PD through AD. Integrated analysis highlighted eight candidate genes, comprising seven collagen isoforms (COL1A1, COL2A1, COL4A1, COL6A1, COL6A2, COL6A3, COL6A6) and an integrin β subunit (ITGB6), which showed coordinated male‑biased expression at OD stage. Protein-protein interaction network predicted ITGB6 as a critical hub linking extracellular matrix (ECM) remodeling to intracellular focal adhesion and FAK signaling pathways. These findings support a developmental model in which collagen-integrin-mediated ECM remodeling at a critical post-metamorphic stage, well before sexual maturation. This process establishes and stabilizes a sexually dimorphic muscle phenotype optimized for the mechanical demands of amplexus. Male-biased hypertrophy of the flexor carpi radialis (FCR) muscle in male B. gargarizans emerges within a specific post-metamorphic pre-maturation window, accompanied by a surge in male-biased transcription. A sex-biased co-expressed gene set comprising seven collagen isoforms and the integrin subunit ITGB6 shows coordinated upregulation specifically at the onset of sexually dimorphic muscle development. Network analysis positions ITGB6 as a mechanotransduction hub that links extracellular collagen matrix remodeling (ECM) to intracellular focal adhesion and FAK signaling pathways, providing a molecular basis for sex-specific muscle growth. In many animals, males and females differ in their physical traits known as sexual dimorphism. In frogs and toads, for example, males often have stronger forelimb muscles that help them clasp females during mating. However, it was unclear when these muscle differences first appear during development and what genetic instructions make them grow differently. We investigated these questions in Asiatic toads (B. gargarizans). Our study clarifies that males begin to exhibit significant hypertrophy of the flexor carpi radialis muscle at four months after metamorphosis, well before sexual maturation. We found that this growth is accompanied by an increase in the activity of specific genes. We identified eight candidate genes involved in extracellular matrix remodeling-a process that reorganizes the muscle microenvironment and influences its architecture. Among these, a protein called ITGB6 acts as a molecular bridge, connecting the extracellular matrix to internal signaling pathways within muscle cells that help regulate muscle growth. Our study highlights that sex-biased transcriptional changes during early development coincide with lasting differences between males and females, providing insight into the potential biological basis of sexually dimorphic traits in vertebrates.

BackgroundNumerous sex differences has been described in aterosclerosis including in endothelial dysfunction. Oxidized low-density lipoproteins (ox-LDL) contribute to the formation of atherosclerotic plaque by binding to a membrane glycoprotein expressed by endothelial cells. Ox-LDL also play a key role in mediating endothelial dysfunction during pregnancy. Elevated maternal ox-LDL levels can lead to oxidative stress, inflammation and apoptosis in placental and fetal endothelial cells. The aim of this study was to investigate sex-related differences in the response to ox-LDL-induced damage in human umbilical vein endothelial cells (HUVECs) isolated from male and female newborns.MethodsIn our study, the effects of 100 µg/ml ox-LDL on HUVECs, obtained from umbilical cords of healthy newborns of both sexes, were analyzed. By flow cytometry, fluorescence microscopy, and Western blotting techniques, mitochondrial function, cell survival, and autophagy were studied.ResultsSex differences in cell motility and fate have been detected after ox-LDL treatment. Indeed, following ox-LDL treatment, male HUVECs (MHUVECs) exhibited reduced motility and a significant increase in adhesion molecules ICAM-1 and VCAM-1, in contrast to female HUVECs (FHUVECs). Furthermore, MHUVECs exhibited higher levels of fission proteins (DRP1 and Fis1), superoxide anion (O₂⁻), and earlier mitochondrial membrane (MM) hyperpolarization, while FHUVECs showed higher levels of fusion proteins (OPA1 and MFN2), hydrogen peroxide (H₂O₂), and delayed MM changes. These findings were consistent with a greater propensity for apoptosis in MHUVECs. In contrast, FHUVECs exhibited higher levels of Survivin, making them less susceptible to apoptosis and more susceptible to the autophagy process.ConclusionsOur findings reveal significant sex-related variations in endothelial responses to oxidative stress. The enhanced survival and repair capacity of FHUVECs suggests that female cells are more resilient to ox-LDL-induced damage.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13293-026-00845-5.

Sex differences play a crucial role in determining tumor incidence, treatment sensitivity, and prognosis among men and women. However, current clinical cancer treatment strategies fail to account for these differences. Furthermore, the underlying mechanisms of tumor disparities between sexes remain elusive. Sex differences in sex chromosomes, hormone levels, metabolism, and immunity synergistically contribute to tumor-related disparities. As the demand for precision medicine escalates, there is an urgent need to conduct further exploration and research to address the tumor differences between sexes. In this review, we discuss the impact of biological sex differences on tumor cells and the tumor microenvironment, aiming to identify more effective strategies for tumor prevention and treatment.