Molecular mechanisms and pathogenesis of MASH

Metabolic dysfunction-associated steatotic liver disease (MASLD), including its progressive form metabolic dysfunction-associated steatohepatitis (MASH), represents the hepatic manifestation of metabolic syndrome and is increasingly recognized as a multi-organ disease. MASLD is now the most prevalent chronic liver disease worldwide and a rising indication for liver transplantation. MASLD incidence continues to increase, driven by sedentary lifestyles, the obesity epidemic and associated pathologies such as type 2 diabetes. MASH is a significant risk factor for fibrosis, cirrhosis and hepatocellular carcinoma (HCC)-a leading cause of cancer-related death. Over the past decade, substantial progress has been made in elucidating the molecular and cellular mechanisms driving MASLD initiation and progression. Key pathogenic processes include insulin resistance, genetic drivers, dysregulated hepatic lipid metabolism, lipotoxicity, adipose tissue dysfunction, immune-mediated inflammation, fibrogenesis and perturbations of the gut-liver axis. Increasingly, these mechanistic insights are informing clinical translation. Genetic risk variants and polygenic risk scores are beginning to enable improved risk stratification for disease progression and HCC. Furthermore, therapeutic strategies targeting defined metabolic pathways are emerging, including approaches that reduce hepatic lipogenesis or modulate mitochondrial metabolism. Here we highlight the state of the art of molecular and cellular mechanisms underlying MASH pathogenesis and its transition to HCC.