Acteoside mitigates hepatic ischemia-reperfusion injury by targeting CMPK2-intervened redox metabolism

Hepatic ischemia-reperfusion injury (HIRI) is an inevitable complication after liver surgery and liver transplantation. Cytosine monophosphate kinase 2 (CMPK2) plays an essential role in controlling mtDNA synthesis and redox metabolism, yet its contribution to HIRI and potential therapies remain undefined. Through integrative sequencing techniques and various molecular biology experiments, we demonstrated that in the initiation stage of HIRI, excessive Acly-CoA promoted the Acyl-CoA thioesterase 2-dependent synthesis and accumulation of free fatty acids in the mitochondria, thus facilitating ROS production in hepatocytes. In response to oxidative stress, CMPK2 stimulated the synthesis and oxidation of mtDNA, which was further released from opening mPTP, and activated the TLR9-MYD88-NF-κB-IRF1 pathway in an autocrine manner. We then demonstrated that acteoside (ACT) significantly protected CMPK2-mediated redox metabolism and following HIRI both in vivo, and in vitro. Mechanistically, ACT inhibited IRF1 nuclear translocation to impose the transcription of both Cmpk2 and Duox2, preventing ROS production and mtDNA leakage. Furthermore, ACT binds to, and promotes the mitophagy-dependent degradation of CMPK2. Notably, specific overexpression of CMPK2 in hepatocytes interposed the therapeutic benefits of ACT. Collectively, our findings establish CMPK2 as a key driver of redox dysregulation in HIRI, and underscore ACT as a multitarget therapeutic agent for clinical translation.