Ferroptosis contributes to hemolytic hyperbilirubinemia‑induced brain damage in vivo and in vitro

Zhou,Jinfu; Lin,Xinpei; Liao,Sining; Li,Guilin; Tang,Jianping; Luo,Jinying; Zhang,Chenran; Wu,Siying; Xu,Liangpu; Li,Huangyuan

doi:10.3892/mmr.2023.13123

Ferroptosis contributes to hemolytic hyperbilirubinemia‑induced brain damage in vivo and in vitro

Authors:
- Jinfu Zhou
- Xinpei Lin
- Sining Liao
- Guilin Li
- Jianping Tang
- Jinying Luo
- Chenran Zhang
- Siying Wu
- Liangpu Xu
- Huangyuan Li
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Affiliations: 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, Fujian Provincial Key Laboratory of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, Fujian 350122, P.R. China, Department of Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
Published online on: November 3, 2023 https://doi.org/10.3892/mmr.2023.13123
Article Number: 236
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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