1. Academic Validation
  2. Dimethyl fumarate protects against hepatic ischemia-reperfusion injury by alleviating ferroptosis via the NRF2/SLC7A11/HO-1 axis

Dimethyl fumarate protects against hepatic ischemia-reperfusion injury by alleviating ferroptosis via the NRF2/SLC7A11/HO-1 axis

  • Cell Cycle. 2022 Dec 8;1-11. doi: 10.1080/15384101.2022.2155016.
Debin Qi 1 Peng Chen 1 Haili Bao 1 Lei Zhang 1 Keyan Sun 1 Shaohua Song 1 Tao Li 1
Affiliations

Affiliation

  • 1 Department of General Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Abstract

Dimethyl fumarate (DMF), a therapeutic agent for relapsing-remitting multiple sclerosis, has cytoprotective and antioxidant effects. Ferroptosis, a pathological cell death process, is recently shown to play a vital part in ischemia-reperfusion injury (IRI). This study aimed to unveil the suppressive role of DMF on Ferroptosis in liver IRI. The anti-ferroptosis effect of DMF on hepatic IRI was investigated using a liver IRI mouse model and a hypoxia-reoxygenation injury (HRI) model in alpha mouse liver (AML12) cells. Serum transaminase concentrations reflected liver function. Hematoxylin and eosin staining was used to assess liver damage. Cell viability was evaluated utilizing the CCK-8 assay. Malondialdehyde (MDA), the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, and BODIPY 581/591C11 were measured to estimate the injury caused by lipid peroxidation. Western blotting and real-time polymerase chain reaction (RT-PCR) were performed to explore the underlying molecular mechanisms. We demonstrated the anti-ferroptosis effects of DMF both in vivo and in vitro. DMF treatment ameliorated hepatic IRI. KEGG enrichment analysis and transmission electron microscopy revealed a close relationship between Ferroptosis and liver IRI. Furthermore, DMF protected against HRI by inhibiting Ferroptosis via activating the nuclear factor E2-related factor 2 (NRF2) pathway. Interestingly, NRF2 knockdown notably decreased the expression of SLC7A11 and HO-1 and blocked the anti-ferroptosis effects of DMF. DMF inhibits Ferroptosis by activating the NRF2/SLC7A11/HO-1 axis and exerts a protective effect against hepatic IRI.

Keywords

Dimethyl fumarate; NRF2; SLC7A11; ferroptosis; ischemia-reperfusion injury.

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