Hepatic ischemia‑reperfusion injury (HIRI) is a severe, unavoidable complication in liver resection and transplantation, driven by mitochondrial dysfunction, oxidative stress, and inflammatory cascades. Current clinical interventions lack targeted therapies. Now, a team led by Prof. Xiaojiaoyang Li from Beijing University of Chinese Medicine has discovered a novel therapeutic target and mechanism: CMPK2 acts as a central switch that links lipid metabolic disorder, mtDNA release, and TLR9‑NF‑ κ B‑IRF1 inflammatory signaling in HIRI.
Using integrative RNA‑seq, molecular biology, and animal models, the researchers revealed the pathological cascade:
During HIRI, ACOT2 is upregulated, causing excessive free fatty acid (FFA) accumulation and mitochondrial ROS burst. This activates CMPK2, which drives abnormal mtDNA synthesis and oxidation. Released mtDNA then activates the TLR9‑MYD88‑NF‑ κ B pathway, triggering IRF1 nuclear translocation and further transcription of Cmpk2 and Duox2, creating a self‑amplifying inflammatory loop.
The team found that acteoside (ACT), a natural phenylpropanoid glycoside, potently alleviates HIRI through dual mechanisms:
ACT binds directly to IRF1, inhibiting its nuclear translocation and suppressing transcription of Cmpk2 and Duox2, thereby reducing ROS and mtDNA leakage.
ACT directly binds CMPK2 and promotes its PINK1‑Parkin‑dependent mitophagic degradation, without affecting the ubiquitin‑proteasome pathway.
In vitro and in vivo validation confirmed that ACT dose‑dependently reduces liver injury, serum ALT/AST, inflammatory infiltration, oxidative stress, and mtDNA release. Hepatocyte‑specific overexpression of CMPK2 fully reversed ACT’s protective effects, validating CMPK2 as its essential target.
These findings establish CMPK2 as a novel diagnostic and therapeutic target for HIRI and position acteoside as a promising, safe, natural candidate for clinical translation to protect liver function during transplantation and major liver surgery.
This work entitled “ Acteoside mitigates hepatic ischemia‑reperfusion injury by targeting CMPK2‑intervened redox metabolism ” was published online March 31, 2026, in Targetome .
Experimental study
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Acteoside mitigates hepatic ischemia-reperfusion injury by targeting CMPK2-intervened redox metabolism
31-Mar-2026