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

Abstract

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.

Acknowledgments

This work was supported by grants from the Scientific Research Innovation Capability Support Project for Young Faculty (ZYGXQN-JSKYCXNLZCXM-H4); National Natural Science Foundation of China (Grant No. 82274186 to Xiaojiaoyang Li); National High-Level Talents Special Support Program to Xiaojiaoyang Li.

Ethical statements

All experiments involving animals were conducted according to the ethical policies and procedures approved by the Institutional Animal Care and Use Committee of the Beijing University of Traditional Chinese Medicine (Approved project: BUCM-2023112904-4146 and BUCM-2025030306-1093).

Author contributions

The authors confirm contributions to the work as follows: analysis and interpretation of results, draft manuscript preparation: Luo R, Yang Y; formal analysis: Luo R; methodology: Luo R, Zhang Y, Wang L, Dou Y; visualization: Che X, Kang W; validation: Chen R; investigation: Liu R; study conception and design, writing, review & editing: Li X. All authors reviewed the results and approved the final version of the manuscript.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Conflict of interest

The authors declare that there are no conflicts of interest.

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