Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, Fujian 350122, P.R. China.
Department of Obstetrics and Gynecology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China.
Mol Med Rep. 2023 Dec;28(6). doi: 10.3892/mmr.2023.13123. Epub 2023 Nov 8.
Ferroptosis is driven by iron‑dependent accumulation of lipid hydroperoxides, and hemolytic hyperbilirubinemia causes accumulation of unconjugated bilirubin and iron. The present study aimed to assess the role of ferroptosis in hemolytic hyperbilirubinemia‑induced brain damage (HHIBD). Rats were randomly divided into the control, phenylhydrazine (PHZ) and deferoxamine (DFO) + PHZ groups, with 12 rats in each group. Ferroptosis‑associated biochemical and protein indicators were measured in the brain tissue of rats. We also performed tandem mass tag‑labeled proteomic analysis. The levels of iron and malondialdehyde were significantly higher and levels of glutathione (GSH) and superoxide dismutase activity significantly lower in the brain tissues of the PHZ group compared with those in the control group. HHIBD also resulted in significant increases in the expression of the ferroptosis‑related proteins acyl‑CoA synthetase long‑chain family member 4, ferritin heavy chain 1 and transferrin receptor and divalent metal transporter 1, as well as a significant reduction in the expression of ferroptosis suppressor protein 1. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis demonstrated that the differentially expressed proteins of rat brain tissues between the control and PHZ groups were significantly involved in ferroptosis, GSH metabolism and fatty acid biosynthesis pathways. Pretreatment with DFO induced antioxidant activity and alleviated lipid peroxidation‑mediated HHIBD. In addition, PC12 cells treated with ferric ammonium citrate showed shrinking mitochondria, high mitochondrial membrane density, and increased lipid reactive oxygen species and intracellular ferrous iron, which were antagonized by pretreatment with ferrostatin‑1 or DFO, which was reversed by pretreatment with ferrostatin‑1 or DFO. The present study demonstrated that ferroptosis is involved in HHIBD and provided novel insights into candidate proteins that are potentially involved in ferroptosis in the brain during hemolytic hyperbilirubinemia.
铁死亡是由铁依赖性脂质过氧化物的积累驱动的，溶血性高胆红素血症会导致未结合胆红素和铁的积累。本研究旨在评估铁死亡在溶血性高胆红素血症诱导的脑损伤（HHIBD）中的作用。将大鼠随机分为对照组、苯肼（PHZ）组和去铁胺（DFO）+PHZ 组，每组 12 只大鼠。测量大鼠脑组织中铁死亡相关生化和蛋白质指标。我们还进行了串联质量标签标记的蛋白质组学分析。与对照组相比，PHZ 组大鼠脑组织中的铁和丙二醛水平明显升高，谷胱甘肽（GSH）水平和超氧化物歧化酶活性明显降低。HHIBD 还导致与铁死亡相关的蛋白质酰基辅酶 A 合成酶长链家族成员 4、铁蛋白重链 1 和转铁蛋白受体和二价金属转运蛋白 1 的表达显著增加，铁死亡抑制剂蛋白 1 的表达显著降低。京都基因与基因组百科全书途径富集分析表明，对照组和 PHZ 组大鼠脑组织之间差异表达的蛋白质显著参与铁死亡、GSH 代谢和脂肪酸生物合成途径。DFO 预处理诱导抗氧化活性并减轻脂质过氧化介导的 HHIBD。此外，用柠檬酸铁铵处理 PC12 细胞后，线粒体收缩，线粒体膜密度增加，脂质活性氧和细胞内亚铁增加，用铁死亡抑制剂 1 或 DFO 预处理可拮抗这些变化，而用铁死亡抑制剂 1 或 DFO 预处理可逆转这些变化。本研究表明铁死亡参与 HHIBD，并为溶血性高胆红素血症期间大脑中潜在涉及铁死亡的候选蛋白提供了新的见解。
