A Global Perspective on Metabolic Dysfunction-Associated Steatotic Liver Disease: From Molecular Mechanisms to Therapeutic Strategy Innovation.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a prevalent global health issue driven by metabolic syndrome, with cardiovascular disease being the leading cause of mortality. This review synthesizes current knowledge on its multifactorial pathogenesis, the impact of sexual dimorphism, and key experimental models. The progression of MASLD involves interconnected pathways including dysregulated de novo lipogenesis, insulin resistance, mitochondrial dysfunction, gut dysbiosis, ferroptosis, and genetic and epigenetic predispositions. These mechanisms not only promote hepatic injury but also accelerate atherosclerosis. Notably, MASLD exhibits significant sexual dimorphism, influenced by physiological differences, sex hormones, genetic factors, and the microbiome. The study of these complex processes relies mostly on dietary-induced animal models, particularly in rats, which effectively recapitulate features of the human disease. Given the multifaceted nature of MASLD, the therapeutic focus is shifting from monotherapies to combination or dual-target strategies. To enable this transition, refinement of preclinical models is essential to better understand and target this complex disorder.