METTL4 knockout alleviates sepsis-induced liver injury via inhibiting NCOA4-mediated ferritinophagy and ferroptosis.
TL;DR
It is 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, and provides a potential therapeutic target to treat sepsis-induced liver injury.
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.