Abstract
Background: Although hepatic ischemia-reperfusion injury (IRI) frequently occurs during liver resection and transplantation, the underlying mechanisms remain incompletely understood. Through high-throughput sequencing, we found that v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) expression was significantly increased after hepatic IRI. The specific role of MAFF, a basic leucine zipper (bZIP) transcription factor, in hepatic IRI is unknown. In the present study, we aimed to explore the effect of MAFF on hepatic IRI injury. Approach and results: Adenovirus vectors carrying the MAFF gene were administered to mice to explore the potential significance of MAFF. After ischemia-reperfusion, MAFF expression was significantly upregulated, suggesting a potential association between MAFF expression and hepatocyte apoptosis. A reduction in MAFF expression was demonstrated to worsen hepatic impairment and enhance the expression of proinflammatory cytokines in mice following ischemia-reperfusion. Conversely, MAFF overexpression had the opposite effect. Mechanistically, the combination of CUT&Tag and RNA sequencing technologies identified cardiotrophic factor-like cytokine 1 (CLCF1) as a direct transcriptional target for MAFF and BTB and CNC homology 1 (BACH1) heterodimers. This interaction subsequently triggers signal transducer and activator of transcription 3 (STAT3) signaling. Conclusions: MAFF alleviates hepatic ischemia-reperfusion injury by reducing hepatocyte apoptosis and the inflammatory response through the activation of the CLCF1/STAT3 signaling pathway, offering valuable insights into the impact of MAFF on liver protection and potential therapeutic targets for liver treatment.