Consolidating Clinical Insights and Uncovering Novel Regulatory Mechanisms of Exosomal MicroRNAs in Obesity and Metabolic Dysfunction Associated Steatotic Liver Disease: A Systematic Review and Bioinformatics Analysis.

Obesity and metabolic dysfunction associated steatotic liver disease (MASLD) are interrelated metabolic disorders characterized by chronic inflammation, insulin resistance, and dyslipidemia. While both conditions are well recognized clinically, the molecular mechanisms underlying their frequent coexistence remain poorly understood. Growing evidence indicates that circulatory exosomal microRNAs (miRNAs) act as critical mediators of inter-organ communication. In this PROSPERO-registered systematic review (CRD420251017335), we integrated clinical evidence with bioinformatics analyses to clarify shared miRNA-mediated regulatory networks between obesity and MASLD. Literature was retrieved from MEDLINE, ISI Web of Science, and Embase. Bioinformatics analysis using miRWalk also revealed shared miRNAs, predicted target genes, and elucidated enriched pathways using Gene Ontology and KEGG. Clinical studies identified 93 obesity-associated and 24 MASLD-associated exosomal miRNAs, with let-7b and miR-335-5p emerging as common nodes. Bioinformatics analysis using miRWalk revealed extensive overlap at the functional level, including 40,410 shared miRNA-mRNA interactions and 42 common target genes. Several circulating exosomal miRNAs from obese individuals, including miR-122, miR-192, miR-128, and miR-9-5p, were consistently associated with liver histopathology, inflammatory markers, and liver enzyme levels. Importantly, obesity-derived miR-298, miR-342, and let-7d-5p showed strong diagnostic performance (AUC ≥ 0.85), exceeding that of alanine aminotransferase (ALT). Furthermore, ADIPOQ emerged as a central therapeutic target within the shared miRNA network, regulated by both let-7b and miR-335-5p, providing a molecular link between adipose tissue dysfunction and hepatic metabolic regulation. This integrative analysis supports a unified model in which exosomal miRNAs serve as key molecular intermediaries connecting obesity and MASLD.