m6A reader YTHDC1 mediates MAFF nuclear export to induce VMP1 transcription and alleviate I/R-induced oxidative stress injury in hepatocytes.

Hepatic ischemia/reperfusion (I/R) injury occurs after liver resection surgery, trauma, shock, and transplantation. This study aimed to identify and characterize the role of the YTH domain-containing protein 1 (YTHDC1)/MAFF/vacuole membrane protein 1 (VMP1) axis in hepatic I/R injury. YTHDC1, MAFF, and VMP1 were significantly overexpressed in the hepatic tissues of mice with I/R and hepatocytes exposed to hypoxia-reoxygenation (H/R). Knockdown of MAFF exacerbated oxidative stress and inflammatory injury in mice induced with hepatic I/R, which were reversed by overexpression of VMP1. Similarly, I/R-associated injury mitigated by YTHDC1 overexpression was reversed by MAFF knockdown. Mechanistically, YTHDC1 mediated the nuclear export and stability of MAFF mRNA and promoted MAFF translation. Collectively, the findings establish that YTHDC1-mediated m6A-dependent MAFF expression determines hepatocyte oxidative stress via VMP1, providing valuable insights into the potential mechanisms underlying hepatic I/R injury and offering potential therapeutic strategies for its treatment.