Eva Kočar

The liver is a central metabolic organ with pronounced sex-specific differences shaped by sex hormones, sex chromosome-linked gene expression, ageing, and circadian rhythm. These factors influence disease susceptibility, progression, and treatment response, with notable differences between females and males in the prevalence, severity, and clinical outcomes of metabolic dysfunction-associated steatotic liver disease. This condition represents a growing global health burden that can progress to hepatocellular carcinoma, the second leading cause of cancer-related death worldwide. Despite this impact, sex remains an underexplored variable in liver research, and the molecular mechanisms by which sex influences disease development remain poorly understood. In this review, we examine the key determinants of sex differences in liver pathogenesis. We highlight the protective role of estrogen signaling in female liver metabolism, the increased vulnerability to disease progression after menopause, and the contribution of circadian regulation to sex-specific outcomes. We further discuss how the lack of systematic inclusion of both sexes in preclinical and clinical studies limits the identification of biomarkers and the development of effective therapeutic interventions. Incorporating sex as a biological variable is therefore essential to improve mechanistic understanding, translational relevance, and the personalization of treatment approaches. Particular emphasis is placed on animal models that reflect sex-specific liver physiology and pathophysiology, as these provide valuable frameworks for studying disease progression and testing targeted interventions. In summary, recognizing and integrating sexual dimorphism in liver metabolism is crucial to advancing prevention, diagnosis, and treatment strategies. Addressing sex differences is critical for developing accurate diagnostic tools and personalized therapeutic approaches, ultimately improving outcomes for both women and men with liver disease.