PDF(Pubmed)
Abstract：
Ferroptosis has been linked to the pathogenesis of hepatic injury induced by ischemia/reperfusion (I/R). However, the mechanistic basis remains unclear. In this study, by using a mouse model of hepatic I/R injury, it is observed that glutathione (GSH) and cysteine depletion are associated with deficiency of the reducing power of nicotinamide adenine dinucleotide phosphate (NADPH). Genes involved in maintaining NADPH homeostasis are screened, and it is identified that I/R-induced hepatic ferroptosis is significantly associated with reduced expression and activity of NADP+ -dependent malic enzyme 1 (Me1). Mice with hepatocyte-specific Me1 gene deletion exhibit aggravated ferroptosis and liver injury under I/R treatment; while supplementation with L-malate, the substrate of ME1, restores NADPH and GSH levels and eventually inhibits I/R-induced hepatic ferroptosis and injury. A mechanistic study further reveals that downregulation of hepatic Me1 expression is largely mediated by the phosphatase and tensin homologue (PTEN)-dependent suppression of the mechanistic target of rapamycin/sterol regulatory element-binding protein 1 (mTOR/SREBP1) signaling pathway in hepatic I/R model. Finally, PTEN inhibitor, mTOR activator, or SREBP1 over-expression all increase hepatic NADPH, block ferroptosis, and protect liver against I/R injury. Taken together, the findings suggest that targeting ME1 may provide new therapeutic opportunities for I/R injury and other ferroptosis-related hepatic conditions.
摘要：
铁凋亡与缺血/再灌注（I/R）引起的肝损伤的发病机理有关。然而,机制基础尚不清楚。在这项研究中,通过使用小鼠肝I/R损伤模型，据观察，谷胱甘肽（GSH）和半胱氨酸的消耗与烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的还原能力不足有关。筛选参与维持NADPH体内平衡的基因，并且确定I/R诱导的肝铁死亡与NADP依赖性苹果酸酶1（Me1）的表达和活性降低显着相关。肝细胞特异性Me1基因缺失的小鼠在I/R治疗下表现出加重的铁细胞凋亡和肝损伤；而补充L-苹果酸，ME1的底物，恢复NADPH和GSH水平，并最终抑制I/R诱导的肝铁凋亡和损伤。一项机制研究进一步表明，肝脏Me1表达的下调主要是由磷酸酶和张力蛋白同源物（PTEN）依赖性抑制肝I/R模型中雷帕霉素/固醇调节元件结合蛋白1（mTOR/SREBP1）信号通路的机制靶标介导的。最后,PTEN抑制剂,mTOR活化剂,或SREBP1过度表达都会增加肝脏NADPH，阻断铁性凋亡，保护肝脏免受I/R损伤。一起来看,研究结果表明,靶向ME1可能为I/R损伤和其他铁死亡相关的肝脏疾病提供新的治疗机会.
