New Definition, New Point of View: Sex and Gender Interpretation of MASLD—Interpretation of Guidelines and Review of the Literature

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum from simple steatosis to steatohepatitis (MASH), including liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The 2023 EASL–EASD–EASO guidelines provide updated definitions and emphasize personalized management, yet do not explicitly address sex- and gender-related differences. This review highlights the impact of biological sex and gender on MASLD epidemiology, pathogenesis, clinical presentation, and therapeutic response. Men show earlier peak prevalence, greater visceral obesity, higher insulin resistance, and increased risk of fibrosis, HCC, and cardiovascular mortality. Women of childbearing age benefit from estrogen-mediated protection, which diminishes after menopause, leading to disease risk similar to men. Genetic variants (PNPLA3, TM6SF2), hormonal factors, platelet parameters, liver biomarkers, and environmental exposures contribute to sex-specific susceptibility and disease progression. Lifestyle interventions and pharmacological therapies exhibit differential efficacy across sexes, influenced by hormonal status. Integrating biological sex, gender identity, and sociocultural factors into diagnostic and therapeutic strategies is essential to optimize MASLD management and reduce its global burden.