Autophagy in MASLD: A Metabolic and Precision Medicine Perspective

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver condition worldwide and a major contributor to cirrhosis and hepatocellular carcinoma (HCC). While metabolic triggers such as obesity and insulin resistance are key drivers of MASLD, growing evidence has identified defects in intracellular quality control-namely impaired autophagy-as central mechanisms governing disease progression. Autophagy, including selective lipophagy and mitophagy, plays a crucial role in hepatic lipid turnover and mitochondrial homeostasis. In MASLD, disruption of these processes contributes to lipid accumulation and oxidative stress, leading to hepatocellular damage (ballooning), fibrogenesis, and HCC. Experimental studies linked impaired autophagic flux to liver injury, and emerging evidence from human genetics suggests that inter-individual inherited variation influences MASLD susceptibility by impairing autophagy. Specifically, main genetic MASLD modifiers such as the p.I148M variant of Patatin-like phospholipase domain-containing protein 3 (PNPLA3) and loss-of-function and hypomorphic variants in autophagy-related gene 7 (ATG7), a core autophagy gene, predispose to ballooning, fibrosis, and HCC. By outlining emerging therapies that restore autophagic flux and reduce steatosis, lipotoxicity, and fibrosis, we propose an integrated precision-medicine model based on genetics and autophagy dynamics biomarkers, offering a new framework for personalized therapeutics.