Authors
Qiong Luo, Ling Li, Zhe Jin, Mengmeng Shen, Yicheng Li, Lin Hu, Miao Yang, Jin Wang, Jing Zhang
Published in
Cellular signalling. Pages 112810. Aug 09, 2026. Epub Aug 09, 2026.
Abstract
The liver represents a primary target organ frequently compromised during the progression of sepsis. Ferroptosis is a distinct mode of regulated cell death driven by iron-dependent lipid peroxidation, which has been identified as being involved in the pathogenesis of sepsis-induced hepatic dysfunction. However, the regulation of ferroptosis in hepatocytes by m6A-modified RNAs under sepsis remains unclear. In this study, we demonstrated that the methylation level is highly expressed in the septic liver injury, complying with the up-regulation of m6A methyltransferase METTL4 and the reader YTHDF1. Further analyses were conducted to explore METTL4-mediated m6A modification in septic mice, and NCOA4 was identified as the target gene. Furthermore, the knockdown of the NCOA4 ameliorated LPS-induced mitochondrial dysfunction, lipid peroxidation, and liver injury. Accordingly, METTL4-mediated m6A methylation on NCOA4 stabilized its mRNA and facilitated NCOA4-mediated ferritinophagy in LPS-induced THLE-2 cells. As a reader for m6A-modified NCOA4 mRNA, the YTHDF1 protein improves the stability of NCOA4. This regulatory axis subsequently accelerates ferroptotic pathways, contributing to the exacerbation of sepsis-associated hepatic impairment. In conclusion, the present study has demonstrated the critical roles of METTL4 in the regulation of ferroptosis in LPS-induced hepatocytes and provides a potential therapeutic target to treat sepsis-induced liver injury.
PMID:
42571828
Bibliographic data and abstract were imported from PubMed on 10 Aug 2026.
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