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  3. ALKBH5 targets ACSL4 mRNA stability to modulate ferroptosis in hyperbilirubinemia-induced brain damage

ALKBH5 targets ACSL4 mRNA stability to modulate ferroptosis in hyperbilirubinemia-induced brain damage

  • Free Radic Biol Med. 2024 Aug 1:220:271-287. doi: 10.1016/j.freeradbiomed.2024.05.014.
Jinfu Zhou 1,  Jianping Tang 2,  Chenran Zhang 3,  Guilin Li 3,  Xinpei Lin 3,  Sining Liao 4,  Jinying Luo 5,  Guangxia Yu 6,  Fuli Zheng 6,  Zhenkun Guo 7,  Wenya Shao 6,  Hong Hu 6,  Liangpu Xu 8,  Siying Wu 9,  Huangyuan Li 10
Affiliations

Affiliations

  • 1 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, 350001, Fujian Province, China; Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, 350122, Fujian Province, China.
  • 2 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, 350001, Fujian Province, China.
  • 3 Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, 350122, Fujian Province, China; The Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, 350122, Fujian Province, China.
  • 4 Center for Disease Control and Prevention of Shantou, Shantou, Guangdong, 515000, China.
  • 5 Obstetrics and Gynecology Department, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian Province, China.
  • 6 Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, 350122, Fujian Province, China; The Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, 350122, Fujian Province, China; Fujian Provincial Key Laboratory of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, 350122, Fujian Province, China.
  • 7 The Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, 350122, Fujian Province, China.
  • 8 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, 350001, Fujian Province, China. Electronic address: xiliangpu@fjmu.edu.cn.
  • 9 The Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, 350122, Fujian Province, China; Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, 350122, Fujian Province, China. Electronic address: fmuwsy@163.com.
  • 10 Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, 350122, Fujian Province, China; The Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, 350122, Fujian Province, China. Electronic address: fmulhy@163.com.
PMID: 38734267 DOI: 10.1016/j.freeradbiomed.2024.05.014
Abstract

Bilirubin-induced brain damage is a serious clinical consequence of hyperbilirubinemia, yet the underlying molecular mechanisms remain largely unknown. Ferroptosis, an iron-dependent cell death, is characterized by iron overload and lipid peroxidation. Here, we report a novel regulatory mechanism of demethylase AlkB homolog 5 (ALKBH5) in acyl-coenzyme A synthetase long-chain family member 4 (ACSL4)-mediated Ferroptosis in hyperbilirubinemia. Hyperdifferential PC12 cells and newborn Sprague-Dawley rats were used to establish in vitro and in vivo hyperbilirubinemia models, respectively. Proteomics, coupled with bioinformatics analysis, first suggested the important role of Ferroptosis in hyperbilirubinemia-induced brain damage. In vitro experiments showed that Ferroptosis is activated in hyperbilirubinemia, and Ferroptosis inhibitors (desferrioxamine and ferrostatin-1) treatment effectively alleviates hyperbilirubinemia-induced oxidative damage. Notably, we observed that the Ferroptosis in hyperbilirubinemia was regulated by m6A modification through the downregulation of ALKBH5 expression. MeRIP-seq and RIP-seq showed that ALKBH5 may trigger hyperbilirubinemia Ferroptosis by stabilizing ACSL4 mRNA via m6A modification. Further, hyperbilirubinemia-induced oxidative damage was alleviated through ACSL4 genetic knockdown or rosiglitazone-mediated chemical repression but was exacerbated by ACSL4 overexpression. Mechanistically, ALKBH5 promotes ACSL4 mRNA stability and Ferroptosis by combining the 669 and 2015 m6A modified sites within 3' UTR of ACSL4 mRNA. Our findings unveil a novel molecular mechanism of Ferroptosis and suggest that m6A-dependent Ferroptosis could be an underlying clinical target for the therapy of hyperbilirubinemia.

Keywords

ACSL4; ALKBH5; Ferroptosis; Hyperbilirubinemia; Lipid peroxidation; m(6)A.

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