Downregulation of ubiquitous microRNA-320 in hepatocytes triggers RFX1-mediated FGF1 suppression to accelerate MASH progression.
10.1016/j.apsb.2025.06.007
- Author:
Liu YANG
1
;
Wenjun LI
2
;
Yingfen CHEN
1
;
Ru YA
1
;
Shengying QIAN
1
;
Li LIU
2
;
Yawen HAO
1
;
Qiuhong ZAI
1
;
Peng XIAO
3
;
Seonghwan HWANG
4
;
Yong HE
1
Author Information
1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
2. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
3. Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun 130021, China.
4. College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea.
- Publication Type:Journal Article
- Keywords:
AMPK;
FGF1;
MASLD;
RFX1;
miR-320
- From:
Acta Pharmaceutica Sinica B
2025;15(8):4096-4114
- CountryChina
- Language:English
-
Abstract:
Metabolic dysfunction-associated steatohepatitis (MASH), a severe type of metabolic dysfunction-associated steatotic liver disease (MASLD), is a leading etiology of end-stage liver disease worldwide, posing significant health and economic burdens. microRNA-320 (miR-320), a ubiquitously expressed and evolutionarily conserved miRNA, has been reported to regulate lipid metabolism; however, whether and how miR-320 affects MASH development remains unclear. By performing miR-320 in situ hybridization with RNAscope, we observed a notable downregulation of miR-320 in hepatocytes during MASH, correlating with disease severity. Most importantly, miR-320 downregulation in hepatocytes exacerbated MASH progression as demonstrated that hepatocyte-specific miR-320 deficient mice were more susceptible to high-fat, high-fructose, high-cholesterol diet (HFHC) or choline-deficient, amino acid-defined, high-fat diet (CDAHFD)-induced MASH compared with control littermates. Conversely, restoration of miR-320 in hepatocytes ameliorated MASH-related steatosis and fibrosis by injection of adeno-associated virus 8 (AAV8) carrying miR-320 in different types of diet-induced MASH models. Mechanistic studies revealed that miR-320 specifically regulated fibroblast growth factor 1 (FGF1) production in hepatocytes by inhibiting regulator factor X1 (RFX1) expression. Notably, knockdown of Rfx1 in hepatocytes mitigated MASH by enhancing FGF1-mediated AMPK activation. Our findings underscore the therapeutic potential of hepatic miR-320 supplementation in MASH treatment by inhibiting RFX1-mediated FGF1 suppression.
