Hepatocellular Carcinoma in Metabolic Dysfunction-Associated Steatotic Liver Disease Beyond Fibrosis: Metabolic, Microbial, and Immune Determinants​.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly important cause of hepatocellular carcinoma (HCC). Fibrosis and cirrhosis remain the best-validated predictors of HCC, yet a substantial minority of MASLD-related tumors are diagnosed without cirrhosis. This narrative review evaluates what 'beyond fibrosis' should mean for risk assessment rather than treating fibrosis as dispensable. We first separate the proportion of HCC cases that are noncirrhotic from the much lower absolute incidence of HCC in the noncirrhotic MASLD population. We then synthesize human, animal, and in vitro evidence for lipotoxic and oxidative injury, insulin and insulin-like growth factor signaling, gut-liver communication, and immune remodeling. We distinguish plausible mechanistic drivers from clinical risk modifiers, future-risk biomarkers, early detection tests, and disease-modifying interventions. Current evidence supports fibrosis-centered, layered risk stratification using clinical factors and noninvasive fibrosis measures, whereas genetic, proteomic, microbial, and immune markers remain investigational. Resmetirom and semaglutide improve MASH histology in selected noncirrhotic patients with F2-F3 fibrosis; evidence for direct HCC prevention by metabolic drugs or bariatric surgery remains observational or absent. Routine surveillance is not justified for MASLD without advanced fibrosis, but individualized evaluation in F3 disease and prospective validation of multivariable risk models are priorities.