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  3. Ferroportin-dependent ferroptosis induced by ellagic acid retards liver fibrosis by impairing the SNARE complexes formation

Ferroportin-dependent ferroptosis induced by ellagic acid retards liver fibrosis by impairing the SNARE complexes formation

  • Redox Biol. 2022 Oct;56:102435. doi: 10.1016/j.redox.2022.102435.
Lihua Li 1,  Kunpeng Wang 2,  Rongjun Jia 3,  Jing Xie 4,  Liman Ma 5,  Zhiqing Hao 6,  Weiwei Zhang 7,  Jinggang Mo 8,  Fu Ren 9
Affiliations

Affiliations

  • 1 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, 318001, PR China. Electronic address: lilihua1018@sina.com.
  • 2 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, 318001, PR China. Electronic address: wkpeng101@126.com.
  • 3 Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, Zhejiang Province, 318001, PR China. Electronic address: 1085881994@qq.com.
  • 4 Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, Zhejiang Province, 318001, PR China. Electronic address: 347584368@qq.com.
  • 5 Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, Zhejiang Province, 318001, PR China. Electronic address: limanma1986@163.com.
  • 6 Department of Pathophysiology, School of Basic Medicine, Shenyang Medical College, Shenyang, Liaoning Province, 110000, PR China. Electronic address: 546573578@qq.com.
  • 7 Department of Pathophysiology, School of Basic Medicine, Shenyang Medical College, Shenyang, Liaoning Province, 110000, PR China. Electronic address: 2793353146@qq.com.
  • 8 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, 318001, PR China. Electronic address: mojg@tzzxyy.com.
  • 9 Department of Anatomy, School of Basic Medicine, Shenyang Medical College, Shenyang, Liaoning Province, 110000, PR China. Electronic address: rf@symc.edu.cn.
PMID: 36029649 DOI: 10.1016/j.redox.2022.102435
Abstract

Chronic liver injury causing liver fibrosis is a major cause of morbidity and mortality worldwide. Targeting the suppression of hepatic stellate cell (HSC) activation is recognized as an effective strategy for the treatment of liver fibrosis. Ellagic acid (EA), a natural polyphenol product isolated from fruits and vegetables, possesses many biological functions. Here, EA exerts its antifibrotic activity by inducing ferroptotic cell death of activated HSCs, which is accompanied by redox-active iron accumulation, lipid peroxidation, and GSH depletion in CCl4 mice and human LX-2 cells. The specific Ferroptosis inhibitor ferrostatin-1 prevented EA-induced ferroptotic cell death. Mechanistically, EA impairs the formation of vesicle-associated membrane protein 2 (VAMP2)/syntaxin 4 and VAMP2/synaptosome-associated protein 23 complexes by suppressing VAMP2 expression by enhancing its degradation in a proteasome-dependent pathway. This leads to the impairment of Ferroportin (FPN, an iron exporter) translocation and intracellular iron extrusion. Interestingly, VAMP2 overexpression inhibits the role of EA in blocking FPN translocation and increasing intracellular ferritin content (an iron storage marker). In contrast, VAMP2 knockdown shows a synergistic effect on EA-mediated ferroptotic events in both HSCs. Additionally, HSC-specific overexpression of VAMP2 impaired EA-induced HSC Ferroptosis in mouse liver fibrosis, and HSC-specific VAMP2 knockdown increased the inhibitory effect of EA on fibrosis. Taken together, our data suggest that the natural product EA exerts its antifibrotic effects by inducing FPN-dependent Ferroptosis of HSCs by disrupting the formation of SNARE complexes, and EA will hopefully serve as a prospective compound for liver fibrosis treatment.

Keywords

Ellagic acid; Ferroportin translocation; Ferroptosis; Liver fibrosis; SNARE complexes formation.

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