GPX4
程序性细胞死亡
基因敲除
癌症研究
免疫学
下调和上调
细胞生物学
生物
谷胱甘肽
生物化学
谷胱甘肽过氧化物酶
细胞凋亡
基因
酶
作者
Huimian Jiang,Fang Yan,Yuxin Wang,Ting Li,Hongwei Lin,Lin Jia,Tongtong Pan,Qingxiu Liu,Jiaojian Lv,Runsheng Chen,Yongping Chen
标识
DOI:10.1016/j.intimp.2023.109762
摘要
Autoimmune hepatitis (AIH) is increasingly affecting human health but pharmacotherapies remain to be identified. Growing evidence reveals that ferroptosis, a newly recognized form of programmed cell death, is critical for AIH. However, the exact mechanisms of the ferroptotic cascade remain elusive. Data in this study showed that ferroptosis aggravation was associated with protectively-elevated fibroblast growth factor 4 (FGF4) expression in Concanavalin A (ConA)-induced AIH liver injury, with these effects being effectively reversed by Ferrostatin-1 (Fer-1). Moreover, hepatic Fgf4 depletion was more susceptible to lipid peroxidation and iron accumulation, as well as hepatic lesion and inflammation caused by ConA administration. Conversely, treatment with non-mitogenic recombinant FGF4 (rFGF4) mitigated liver damage and hepatocellular ferroptosis while being accompanied by the upregulation of CDGSH iron-sulfur domain-containing protein 3 (CISD3) in vivo and in vitro. Furthermore, CISD3 overexpression exhibited stronger resistance to ferroptosis while CISD3 knockdown reduced ferroptotic biomarkers cystine/glutamate transporter (xCT) and glutathione peroxidase 4(GPX4) in rFGF4-treated Erastin-induced AML12 cells. In addition, rFGF4 significantly enhanced the levels of heme oxygenase 1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) in ConA-induced AIH mice. Overall, this study showed that FGF4 can act as a phylactic role in AIH progression, with rFGF4 treatment inhibiting ferroptosis of hepatocytes by increasing CISD3 levels and activating Nrf2/HO-1 signaling.
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