Pathophysiology of metabolic dysfunction associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent liver pathology worldwide, affecting more than one-third of the general population. Its pathophysiology is complex and multifactorial, involving metabolic, immunological, genetic, and environmental alterations that interact synergistically to determine the patient’s phenotype. This review provides an in-depth analysis of the main mechanisms involved in the development and progression of MASLD, including energy excess and de novo lipogenesis, insulin resistance, lipid metabolism disturbances, oxidative stress and mitochondrial dysfunction, inflammation mediated by the inflammasome, genetic factors, and intestinal dysbiosis with increased gut permeability. These alterations converge in hepatic microcirculatory dysfunction, which promotes hepatic stellate cell activation and progression toward fibrosis, advanced chronic liver disease, and hepatocellular carcinoma. Moreover, MASLD is associated with a significant increase in cardiovascular, metabolic, and neoplastic risk, reinforcing its multisystemic nature and the need for a comprehensive clinical approach. In this context, personalized medicine emerges as a key tool for risk stratification and therapeutic optimization, using biomarkers, genetic profiling, and microbiome analysis. A detailed understanding of the pathophysiological mechanisms of MASLD is essential for the development of effective preventive and therapeutic strategies, and for improving the prognosis of patients affected by this silent yet clinically, economically, and socially impactful disease.