MASLD vs. MetALD: mechanistic insights, diagnostic advances, and therapeutic horizons

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its inflammatory subtype, metabolic dysfunction-associated steatohepatitis (MASH), have become the most prevalent forms of chronic liver disease worldwide, representing leading causes of liver cirrhosis and hepatocellular carcinoma (HCC). In clinical practice, a substantial proportion of patients with metabolic disorders also present with clinically significant alcohol consumption. Metabolic risk factors and alcohol exposure act synergistically to exacerbate hepatocellular injury, inflammation, and fibrosis, giving rise to the overlapping clinical phenotype termed metabolic dysfunction and alcohol-related liver disease (MetALD). The introduction of the MetALD concept addresses key limitations of traditional exclusion-based diagnostic frameworks; however, operational alcohol-consumption ranges for classification remain consensus-based rather than evidence-derived, and fundamental challenges persist regarding synergistic pathogenic mechanisms, diagnostic accuracy of standard tools, and optimal personalized treatment strategies. This review provides a critical head-to-head comparison of MASLD and MetALD across mechanistic, diagnostic, and therapeutic domains. We quantitatively synthesize evidence on synergistic injury pathways, explicitly distinguishing preclinical findings from human clinical data; evaluate the performance of non-invasive diagnostic modalities in MetALD relative to MASLD, with standardized evidence grading; and critically appraise the evidence base for current and emerging therapies, delineating consensus-based recommendations from randomized trial evidence. We further identify key unresolved challenges and propose a prioritized research roadmap to advance precision diagnosis and management of steatotic liver disease across the metabolic-alcohol spectrum.