Alcohol-Related Liver Disease and Metabolic Dysfunction-Associated Steatotic Liver Disease: Molecular Pathogenesis...

Alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD) are among the most prevalent chronic liver conditions globally, placing a substantial burden on global healthcare systems. Although significant progress has been made in their study, the pathogenic mechanisms remain incompletely defined, and effective treatments are still limited. This review aims to provide a comprehensive analysis of the shared and divergent molecular pathogenic mechanisms underlying these two diseases and to systematically summarize the latest therapeutic intervention strategies. Although ALD and MASLD have distinct etiologies, they share multiple pathophysiological pathways, such as dysregulated lipid metabolism, programmed cell death, cellular senescence, gut dysbiosis, and immune activation. We focus on key molecular events within these shared pathways, such as impaired fatty acid oxidation, increased lipogenesis, activation of pyroptotic and necroptotic signaling pathways, engagement of the p53-p21 senescence axis, and gut microbiota-driven immune signaling pathways via microbial metabolites and microbe-associated molecular patterns. Building upon these mechanistic insights, the review further outlines therapeutic strategies targeting lipid metabolism, cell death, cellular senescence, microbiota modulation, and immunomodulation, while also discussing the specific challenges and opportunities. Ultimately, this review proposes a mechanistic framework to guide the development of precision therapies for ALD and MASLD.