Metabolic Dysfunction-Associated Fatty Liver Disease: From Pathogenesis to Treatment

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most prevalent chronic liver disease worldwide and represents a major hepatic manifestation of systemic metabolic dysfunction. The disease is closely linked to obesity and insulin resistance and progresses from simple hepatic steatosis to metabolic dysfunction-associated steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Increasing evidence indicates that MAFLD pathogenesis involves complex interactions among dysregulated lipid metabolism, mitochondrial dysfunction, oxidative stress, inflammatory signaling, bile acid imbalance, and gut microbiota-derived metabolites, reflecting the systemic and multifactorial nature of the disease. However, despite substantial progress in understanding these mechanisms, the integrated regulatory networks driving MAFLD progression and their translational therapeutic implications remain incompletely characterized. In this review, we comprehensively summarize recent advances in the molecular mechanisms underlying MAFLD, focusing on metabolic dysregulation, cellular stress responses, inflammatory pathways, and regulated cell death processes. We further highlight the critical role of interorgan communication particularly the adipose-liver and gut-liver axes and discuss emerging evidence on extracellular vesicles (EVs) as mediators of metabolic and inflammatory signaling. Finally, we evaluate current and potential therapeutic strategies, emphasizing the diagnostic and therapeutic promise of EV-based approaches in MAFLD management, and identifying emerging molecular targets for improved intervention and future clinical translation opportunities.