METTL4 deficiency alleviates sepsis-induced liver injury via inhibiting NCOA4-mediated ferritinophagy and ferroptosis.

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 m6A modification level was markedly increased in septic liver injury, complying with upregulation of the 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, knockdown of 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, 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.