New Genetic Factor Identified In Worsening Of MASLD, With FDA-Approved Vitamin B3 As Most Effective Therapeutic Agent

Abstract

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. 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. 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. 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.

Approximately 30% of the global population is affected by metabolic-associated fatty liver disease (MASLD), a condition that previously lacked targeted treatments. In a groundbreaking discovery, researchers have identified a genetic factor that exacerbates the disease, and remarkably, the FDA-approved drug that most effectively targets this factor is vitamin B3.

A collaborative research team led by Professor Jang Hyun Choi from the Department of Life Sciences at UNIST, in partnership with Professor Hwayoung Yun from the College of Pharmacy and Research Institute for Drug Development at Pusan National University (PNU), and Professor Neung Hwa Park from Ulsan University Hospital (UUH), has, for the first time globally, elucidated the role of microRNA-93 (miR-93), which is expressed in the liver, as a key genetic regulator in the development and progression of MASLD.

MiR-93 is a specialized RNA molecule expressed in hepatocytes that functions to suppress the expression of specific target genes. The team observed abnormally elevated levels of miR-93 in both patients with fatty liver disease and animal models. Through molecular analysis, they demonstrated that miR-93 promotes lipid accumulation, inflammation, and fibrosis by inhibiting the expression of SIRT1, a gene involved in lipid metabolism within liver cells.

In experiments utilizing gene editing techniques to eliminate miR-93 production in mice, researchers observed a marked reduction in hepatic fat accumulation, along with significant improvements in insulin sensitivity and liver function indicators. Conversely, mice with overexpressed miR-93 exhibited worsened hepatic metabolic function.

Furthermore, screening 150 FDA-approved drugs revealed that niacin (vitamin B3) most effectively suppresses miR-93. Mice treated with niacin showed a significant decrease in hepatic miR-93 levels and a notable increase in SIRT1 activity. The activated SIRT1 restored disrupted lipid metabolism pathways, thereby normalizing liver lipid homeostasis.

The research team explained, "This study precisely elucidates the molecular origin of MASLD and demonstrates the potential for repurposing an already approved vitamin compound to modulate this pathway, which has high translational clinical relevance."

They added, "Given that niacin is a well-established and safe medication used to treat hyperlipidemia, it holds promise as a candidate for combination therapies targeting miRNA pathways in MASLD."

This research was supported by various including the National Research Foundation of Korea (NRF) and the Korea Research Institute of Bioscience and Biotechnology (KRIBB). The findings were published online in the prestigious biomedical journal, Metabolism: Clinical and Experimental on April 12, 2025. It has been participated by Dr. Yo Han Lee and Kieun Park from UNIST, along with Professor Joonho Jeong from Ulsan University Hospital and Jinyoung Lee from Pusan National University, as co-first authors.

Journal Reference

Yo Han Lee, Jinyoung Lee, Joonho Jeong, et al., "Hepatic miR-93 promotes the pathogenesis of metabolic dysfunction-associated steatotic liver disease by suppressing SIRT1," (2025).