Malic Enzyme 1 as a Novel Anti‐Ferroptotic Regulator in Hepatic Ischemia/Reperfusion Injury

• DOI: 10.1002/advs.202205436
• Publication Date: 2023-02-25T13:20:30Z
• Authors: Xuexian Fang; Jiawei Zhang; You Li; Yijing Song; Yingying Yu; Zhaoxian Cai; Fuzhi Lian; Jun Yang; Junxia Min; Fudi Wang
• Keywords: Malic acid; Malic enzyme

Abstract Ferroptosis has been linked to the pathogenesis of hepatic injury induced by ischemia/reperfusion (I/R). However, mechanistic basis remains unclear. In this study, using a mouse model I/R injury, it is observed that glutathione (GSH) and cysteine depletion are associated with deficiency reducing power nicotinamide adenine dinucleotide phosphate (NADPH). Genes involved in maintaining NADPH homeostasis screened, identified I/R‐induced ferroptosis significantly reduced expression activity NADP + ‐dependent malic enzyme 1 (Me1). Mice hepatocyte‐specific Me1 gene deletion exhibit aggravated liver under treatment; while supplementation L‐malate, substrate ME1, restores GSH levels eventually inhibits injury. A study further reveals downregulation largely mediated phosphatase tensin homologue (PTEN)‐dependent suppression target rapamycin/sterol regulatory element‐binding protein (mTOR/SREBP1) signaling pathway model. Finally, PTEN inhibitor, mTOR activator, or SREBP1 over‐expression all increase NADPH, block ferroptosis, protect against Taken together, findings suggest targeting ME1 may provide new therapeutic opportunities for other ferroptosis‐related conditions.