2. Academic Validation
  3. Methyltransferase-like 3 mediates m6A modification of heme oxygenase 1 mRNA to induce ferroptosis of renal tubular epithelial cells in acute kidney injury

Methyltransferase-like 3 mediates m6A modification of heme oxygenase 1 mRNA to induce ferroptosis of renal tubular epithelial cells in acute kidney injury

  • Free Radic Biol Med. 2025 Mar 1:229:168-182. doi: 10.1016/j.freeradbiomed.2025.01.039.
Linxiao Lv 1,  Mingyang Hu 1,  Jiacheng Li 1,  Runzhi Guo 1,  Mengfei He 1,  Panpan Zhou 1,  Yuqi Lei 1,  Min Chen 2,  Zhangsuo Liu 3,  Sijie Zhou 4
Affiliations

Affiliations

  • 1 Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Research Institute of Nephrology, Zhengzhou University, Zhengzhou, Henan province, China; Henan Province Research Center for Kidney Disease, Zhengzhou, Henan Province, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan Province, China; Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China; Innovation Center of Basic Research for Metabolic-Associated Fatty Liver Disease, Ministry of Education of China, Zhengzhou, Henan Province, China.
  • 2 Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.
  • 3 Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Research Institute of Nephrology, Zhengzhou University, Zhengzhou, Henan province, China; Henan Province Research Center for Kidney Disease, Zhengzhou, Henan Province, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan Province, China; Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China; Innovation Center of Basic Research for Metabolic-Associated Fatty Liver Disease, Ministry of Education of China, Zhengzhou, Henan Province, China. Electronic address: zhangsuoliu@zzu.edu.cn.
  • 4 Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Research Institute of Nephrology, Zhengzhou University, Zhengzhou, Henan province, China; Henan Province Research Center for Kidney Disease, Zhengzhou, Henan Province, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan Province, China; Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China; Innovation Center of Basic Research for Metabolic-Associated Fatty Liver Disease, Ministry of Education of China, Zhengzhou, Henan Province, China. Electronic address: fcczhousj@zzu.edu.cn.
PMID: 39837470 DOI: 10.1016/j.freeradbiomed.2025.01.039
Abstract

Acute kidney injury (AKI) involves a series of syndromes characterized by a rapid increase in creatinine levels. Ferroptosis, as an iron-dependent mode of programmed cell death, reportedly participates in the pathogenesis of AKI. Methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) modification has been recently associated with various kidney diseases; however, the mechanism of METTL3 crosstalk with the molecules involved in Ferroptosis is not clearly understood. Here, we investigated the crosstalk between METTL3-mediated m6A modification and Ferroptosis in AKI. METTL3-mediated m6A modification was elevated in patients with AKI, folic acid-AKI mice, and tert-butyl hydrogen peroxide-stimulated TCMK-1 cells. Inhibition of METTL3 expression in vivo and in vitro alleviated the damage and Ferroptosis in renal tubular cells. Methylated RNA immunoprecipitation Sequencing showed that heme oxygenase 1 (Hmox1/HO-1) was the METTL3 target. RNA immunoprecipitation-qPCR indicated that anti-insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) could be used as a reader to bind to the methylated site of Hmox1 mRNA to maintain its stability. Hmox1 knockdown in vitro reduced the accumulation of iron ions and alleviated Ferroptosis. METTL3 mediates the m6A modification of Hmox1 mRNA and maintains its stability in an IGF2BP3-dependent manner, which causes iron overload in renal tubular epithelial cells, leading to Ferroptosis and AKI.

Keywords

Acute kidney injury; Ferroptosis; Heme oxygenase 1; Methyltransferase-like 3; m6A modification.

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