The convergent roles of metabolic dysfunction, alcohol, and iron in steatotic liver disease: a review

Abstract Steatotic liver disease (SLD) encompasses a broad spectrum of disorders influenced by metabolic dysfunction, alcohol use, and other cofactors. The updated classification of metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD), along with the recognition of the overlapping entity MetALD, allows for better identification of patients at increased risk of progressive liver injury. While iron dysregulation is known to worsen both MASLD and ALD, its role within MetALD remains poorly defined. Understanding how iron contributes to this combined phenotype may provide new insight into why these patients experience more severe disease outcomes. This review synthesises current evidence linking iron to MASLD, ALD, and their intersection in MetALD. It introduces the concept of Fe-MetALD, a “triple-hit” phenotype where metabolic dysfunction, alcohol, and iron overload act together to accelerate liver injury. Mechanistically, these insults share common pathways involving oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, and hepatic stellate cell activation, collectively promoting fibrosis progression and potentially increasing the risk of cirrhosis and hepatocellular carcinoma. Experimental studies suggest that the combination of these insults produces more severe liver injury than any individual factor alone. Emerging therapies that target iron pathways, including hepcidin mimetics, ferroportin inhibitors, and iron-reduction strategies like venesection or chelation, may offer therapeutic potential, although current evidence remains largely preclinical. Recognising Fe-MetALD as a high-risk phenotype supports incorporating iron markers into diagnosis and developing therapies targeting metabolic, alcohol-related, and iron-mediated injury. Understanding this triple-hit interaction may improve risk stratification and guide future therapies for SLD.