Camilla Venturin, Massimiliano Cadamuro, Romina Fiorotto, Mario Strazzabosco, Paolo Simioni, Luca Fabris

Abstract. Liver fibrosis is a stereotyped repair response to chronic liver damage marked by overproduction of extracellular matrix, and it is a major cause of morbidity and mortality worldwide. Liver fibrosis can lead to cirrhosis, portal hypertension and its severe complications, and it is associated with primary liver cancers. Current evidence indicates that the establishment and progression of liver fibrosis varies significantly between males and females, suggesting that gender differences play a crucial role in determining susceptibility to damage, rate of progression, and response to treatment. These differences are the result of a complex interaction between hormonal, metabolic, immunological, genetic, epigenetic, and environmental factors. Oestrogens generally exert a protective effect by modulating hepatic stellate cell activation, lipid metabolism, and immune response, while androgens tend to promote pro-fibrogenic processes. Furthermore, the distribution of risk factors and major aetiologies of liver fibrosis, such as metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/ MASH), hepatitis viruses B and C, autoimmune diseases, and alcohol abuse, shows marked gender differences. In this review, we discuss gender differences in the prevalence, pathogenic mechanisms, and therapeutic responses of liver fibrosis, highlighting the clinical implications of a personalized, gender-based approach to optimize the management of chronic liver diseases.