Hepatic microRNA-320 restrains ferroptosis to mitigate acute-on-chronic alcohol-induced liver injury

  • Biochim Biophys Acta Mol Basis Dis. 2025 Apr;1871(4):167748. doi: 10.1016/j.bbadis.2025.167748.
Wenjun Li  1 ,  Li Liu  1 ,  Shengying Qian  2 ,  Yingfen Chen  2 ,  Ru Ya  2 ,  Ningning Ma  2 ,  Yawen Hao  2 ,  Shujun Ge  1 ,  Xiaoxiao Zhang  1 ,  Liu Yang  3 ,  Yong He  4
Affiliations
  • 1. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
  • 3. Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
  • 4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China. Electronic address: [email protected].
PMID: 40015214 DOI: 10.1016/j.bbadis.2025.167748
Abstract

Alcohol-associated Liver Disease (ALD) is one of the major chronic liver diseases worldwide and has high mortality and high incidence rate. microRNA-320 (miR-320), a highly conserved and widely expressed miRNA, has been reported to be involved in lipid metabolism; however, whether miR-320 affects the progression of ALD remains unclear. In this study, we demonstrated that hepatic miR-320 was significantly downregulated in chronic-plus-binge alcohol-fed mice. Interestingly, such downregulation might accelerate ALD progression as evidenced that hepatocyte-specific miR-320 deficient mice displayed higher susceptibility to acute-on-chronic alcohol feeding-induced steatosis and inflammation. Moreover, restoration of hepatic miR-320 ameliorated acute-on-chronic alcohol-induced hepatocyte damage and steatosis. Mechanistically, miR-320 inhibited alcohol-induced Ferroptosis by targeting Transferrin Receptor 1 (TFRC) to suppress iron accumulation. Moreover, silencing of Tfrc in hepatocytes attenuated ethanol-induced iron accumulation, thus inhibiting Ferroptosis and ultimately mitigating ALD. Taken together, these findings suggest that miR-320 plays an important role in limiting ALD progression via inhibiting Ferroptosis, providing a therapeutic target for the treatment of ALD.

Keywords
ALD; Ferroptosis; TFRC; miR-320.
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