2. Academic Validation
  3. m6A methylation is required for dihydroartemisinin to alleviate liver fibrosis by inducing ferroptosis in hepatic stellate cells

m6A methylation is required for dihydroartemisinin to alleviate liver fibrosis by inducing ferroptosis in hepatic stellate cells

  • Free Radic Biol Med. 2022 Mar;182:246-259. doi: 10.1016/j.freeradbiomed.2022.02.028.
Min Shen 1,  Mei Guo 1,  Yujia Li 1,  Yingqian Wang 1,  Yangling Qiu 1,  Jiangjuan Shao 1,  Feng Zhang 2,  Xuefen Xu 1,  Guoping Yin 3,  Shijun Wang 4,  Anping Chen 5,  Zili Zhang 6,  Shizhong Zheng 7
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 2 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 3 Department of Anesthesiology, Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.
  • 4 College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250035, China.
  • 5 Department of Pathology, School of Medicine, Saint Louis University, St Louis, MO, 63104, USA.
  • 6 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: zilizhang@njucm.edu.cn.
  • 7 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: nytws@163.com.
PMID: 35248719 DOI: 10.1016/j.freeradbiomed.2022.02.028
Abstract

Activation of hepatic stellate cells (HSCs) is a central event in the development of liver fibrosis, and the elimination of activated HSCs is considered to be an effective anti-fibrotic strategy. Here, we report that dihydroartemisinin (DHA) prevented the activation of HSCs via Ferroptosis pathway. Importantly, DHA treatment increased the level of Autophagy in HSCs. The inhibition of Autophagy by 3-MA dramatically abolished the DHA-induced Ferroptosis in HSCs. Mechanistically, the up-regulated m6A modification is essential for the activation of Autophagy by DHA through the reduction of fat mass and obesity-associated gene (FTO). Down-regulation of m6A modification by FTO overexpression could impair Autophagy and the classical ferroptotic events. Interestingly, the m6A modification of BECN1 mRNA was evidently up-regulated compared with other autophagy-related genes. More importantly, YTHDF1 was identified as a key m6A reader protein for BECN1 mRNA stability, and knockdown of YTHDF1 could prevent DHA-induced HSC Ferroptosis. Noteworthy, YTH domain was essential for YTHDF1 to prolong the half-life of BECN1 mRNA in DHA-induced HSC Ferroptosis. In mice, DHA treatment alleviated liver fibrosis by triggering HSC Ferroptosis. HSC-specific inhibition of m6A modification and Autophagy could impair DHA-induced HSC Ferroptosis in murine liver fibrosis. Overall, these results provided novel implications to reveal the molecular mechanism of DHA-induced Ferroptosis, by which pointed to m6A modification-dependent Ferroptosis as a potential target for the treatment of liver fibrosis.

Keywords

Autophagy; Dihydroartemisinin; Ferroptosis; Hepatic stellate cell; Liver fibrosis; m(6)A modification.

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