MASLD beyond the liver: decoding the gut–genetic–metabolic nexus

Abstract

Metabolic dysfunction–associated steatotic liver disease (MASLD), formerly non-alcoholic fatty liver disease, is the most prevalent chronic liver disorder globally and is tightly linked to obesity, diabetes, dyslipidemia, and metabolic syndrome. MASLD spans a continuum from simple steatosis to metabolic dysfunction–associated steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Its pathogenesis is driven by complex interactions among host genetics, metabolic stress, dietary factors, gut microbiota dysbiosis, immune dysregulation, and oxidative injury. The gut–liver axis plays a central role, with microbial metabolites and altered intestinal permeability driving hepatic inflammation and fibrogenesis. Genetic variants, including PNPLA3, TM6SF2, and MBOAT7, modulate disease susceptibility and metabolic pathways. Emerging therapies target interconnected mechanisms through lifestyle interventions, microbiome-directed strategies, bile acid signaling, incretin-based treatments, and antifibrotic approaches. Advances in omics technologies and biomarkers support precision medicine frameworks. Despite major advances in mechanistic understanding, resmetirom has recently become the first FDA-approved therapy for adults with non-cirrhotic MASH and moderate-to-advanced fibrosis. Nevertheless, effective treatment options remain limited, emphasizing the need for additional mechanism-based and personalized therapeutic strategies.