Drug Repurposing for Metabolic-Associated Fatty Liver Disease: Current Evidence, Challenges, and Future Perspectives.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent chronic liver condition with limited approved pharmacotherapies. Drug repurposing offers a time-efficient alternative to de novo development, yet existing reviews often compile candidate compounds without critically appraising the methodological robustness, evidence quality, or translational barriers. In this review, we evaluated current repurposing strategies, including real-world data analyses, computational screening, and experimental validations. As a preliminary search for this review, we searched PubMed and clinical trial registries up to October 2025 using predefined search terms related to MAFLD, drug repurposing, and clinical trials. Despite numerous computational predictions and preclinical candidates, only a small fraction have advanced to late-stage trials. To date, regulatory approvals for MAFLD remain limited, with only a few agents approved and even fewer through repurposing. We examine key obstacles to clinical success, including patient heterogeneity, lack of validated biomarkers, inconsistent endpoint selection, and limited mechanistic target validation. In addition, we discuss the integration of multi-omics and AI-driven approaches with phenotypic screening as a promising avenue for target identification and validation. Our findings suggest that successful repurposing in MAFLD may benefit from a shift toward evidence-based, mechanism-informed frameworks, supported by real-world evidence and adaptive trial designs. This review summarizes current evidence and identifies open questions that may guide future research and clinical development.