Beyond cardiovascular protection: a conceptual and translational review of the hepato-specific mechanisms of statins in metabolic dysfunction-associated steatotic liver disease (MASLD)

Carolina Jiménez-González, Paula Iruzubieta, Marta Alonso-Peña, Lorena Cayon, Javier Crespo

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, and cardiovascular disease remains the leading cause of death in this population. Statins are therefore a cornerstone of therapy in MASLD because of their antiatherosclerotic efficacy. Less attention has been paid to the possibility that part of the hepatic benefit observed in MASLD cohorts—including lower aminotransferase levels, slower fibrosis progression, reduced decompensation and lower hepatocellular carcinoma incidence—may reflect direct hepatic effects beyond LDL reduction. Although the evidence is predominantly observational, the direction and magnitude of the association have remained broadly consistent across independent cohorts. Recent studies have strengthened this signal, including a post hoc analysis of the PROSPER trial showing attenuation of excess mortality in individuals with elevated FIB-4, and a large Veterans Affairs cohort demonstrating a dose-dependent association between cumulative statin exposure and lower primary liver cancer risk in MASLD. This review integrates the preclinical, observational and indirect randomized evidence supporting the biological plausibility of liver-directed effects of statins. Mechanistically, the argument centres on inhibition of the mevalonate pathway as a molecular hub linking lipotoxicity, NLRP3-dependent inflammation, fibrogenesis and carcinogenesis through impaired prenylation of small GTPases. A fifth axis, intrahepatic hemodynamics mediated through KLF2/eNOS signaling, is supported by randomized evidence in compensated cirrhosis. In contrast, the LIVERHOPE-EFFICACY trial showed no benefit in decompensated cirrhosis, helping define the therapeutic window. Within the limitations of the available evidence, we propose a conceptual reframing: in MASLD, statins may act not only as cardiovascular drugs, but also as agents with potentially relevant hepatic effects mediated through a shared molecular substrate.