Extracellular Vesicle‐Based miRNA Profiling in Metabolic Dysfunction‐Associated Steatotic Liver Disease: A Secondary Analysis of the MULTISITE Clinical Trial

ABSTRACT

Metabolic dysfunction‐associated steatotic liver disease (MASLD) is the worldwide leading cause of liver‐related mortality with a prevalence of 75% among individuals with obesity and lacking screenings tools. Extracellular vesicles (EVs)‐based microRNAs (miRNAs) have emerged as promising biomarkers with important roles in the pathogenesis of MASLD. This study aimed to characterize EV‐based miRNA profiles in individuals with obesity and MASLD before and during weight loss intervention. Small RNA sequencing was used to profile EV‐miRNAs from plasma across three groups: individuals with obesity and MASLD ( n  = 35), individuals with obesity without hepatic steatosis ( n  = 24) and lean controls without hepatic steatosis ( n  = 26). Further, the MASLD group underwent a personalized weight‐loss intervention. The liver and MASLD‐related miR‐122‐5p and three other miRNAs were differentially expressed in the MASLD group compared with the obesity control group at baseline. Moreover, miR‐122‐5p correlated with liver fat and liver enzymes (ALT, AST and GGT) at baseline, revealed solid predictability for MASLD in a combined panel (AUC = 0.8), and lastly demonstrated the highest accuracy in identifying individuals with high liver fat among all individuals with obesity. Finally, several MASLD‐ and hepatocellular carcinoma‐related miRNAs decreased significantly following weight loss and liver fat reduction in the MASLD group.