Lee Yo Han, Lee Jinyoung, Jeong Joonho, Park Kieun, Baik Bukyung, Kwon Yuseong, Kim Kimyeong, Khim Keon Woo, Ji Haneul, Lee Ji Young, Kim Kwangho, Kim Ji Won, Dao Tam, Kim Misung, Lee Tae Young, Yang Yong Ryoul, Yoon Haejin, Ryu Dongryeol, Hwang Seonghwan, Lee Haeseung, Nam Dougu, Kim Won Kon, Park Neung Hwa, Yun Hwayoung, Choi Jang Hyun
Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
College of Pharmacy and Research Institute for Drug Development, Pusan National University (PNU), Busan 46241, Republic of Korea.
Metabolism. 2025 Apr 12;169:156266. doi: 10.1016/j.metabol.2025.156266.
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.
代谢功能障碍相关脂肪性肝病（MASLD）潜在的分子机制仍不清楚；然而，新出现的证据表明，微小RNA（miRNA）在调节参与MASLD的靶基因转录调控中起关键作用。本研究旨在阐明miR-93在脂质代谢和MASLD进展中的作用。
我们全面分析了MASLD患者和饮食诱导肥胖小鼠肝脏组织中的miRNA表达谱。给miR-93基因敲除（KO）小鼠喂食高脂肪高果糖（HFHFr）饮食，以评估miR-93缺乏对MASLD的影响。进行转录组分析以阐明miR-93在MASLD中的分子机制和作用。此外，我们采用高通量筛选系统来鉴定能够调节miR-93表达的药物。
miR-93在MASLD患者和饮食诱导肥胖小鼠的肝脏中显著上调。miR-93 KO小鼠肝脂肪变性减轻。具体而言，miR-93缺乏上调了参与脂肪酸氧化的基因，并下调了与胆固醇生物合成相关的基因。沉默调节蛋白1（SIRT1）被鉴定为miR-93的直接靶标，miR-93 KO增强了SIRT1表达并激活了LKB1-AMPK信号通路。烟酸治疗下调miR-93，通过增强SIRT1活性改善肝脂肪变性。
这些发现表明miR-93是MASLD的一个新的治疗靶点。该研究证明了烟酸在调节miR-93/SIRT1轴方面的治疗潜力，为目前治疗选择有限的MASLD提供了一种新的潜在治疗方法。
