Hepatic miR-93 promotes the pathogenesis of metabolic dysfunction-associated steatotic liver disease by suppressing SIRT1

Abstract

Background and aims: The molecular mechanisms underlying metabolic dysfunction-associated steatotic liver disease (MASLD) remain largely unclear; however, emerging evidence suggests that microRNAs (miRNAs) play a critical role in modulating transcriptional regulation of target genes involved in MASLD. This study aims to elucidate the role of miR-93 in lipid metabolism and MASLD progression. Methods: We comprehensively analyzed miRNA expression profiles in liver tissues from patients with MASLD and diet-induced obese mice. miR-93 knockout (KO) mice were fed a high-fat？high-fructose (HFHFr) diet to assess the impact of miR-93 deficiency on MASLD. Transcriptome analysis was performed to elucidate the molecular mechanisms and role of miR-93 in MASLD. Additionally, we employed a high-throughput screening system to identify drugs capable of modulating miR-93 expression. Results: miR-93 was significantly upregulated in the livers of patients with MASLD and diet-induced obese mice. miR-93 KO mice exhibited reduced hepatic steatosis. Specifically, miR-93 deficiency upregulated genes involved in fatty acid oxidation and downregulated genes associated with cholesterol biosynthesis. Sirtuin 1 (SIRT1) was identified as a direct target of miR-93, and miR-93 KO enhanced SIRT1 expression and activated the LKB1-AMPK signaling pathway. Niacin treatment downregulated miR-93, ameliorating hepatic steatosis by enhancing SIRT1 activity. Conclusions: These findings implicate miR-93 as a novel therapeutic target for MASLD. The study demonstrates the therapeutic potential of niacin in modulating the miR-93/SIRT1 axis, providing a new potential treatment for MASLD, a disease with limited current treatment options.