A study published in Targetome on March 31 by Xiaojiaoyang Li's team at Beijing University of Chinese Medicine reports that ACT protects against hepatic ischemia-reperfusion injury (HIRI) by suppressing CMPK2-driven mitochondrial redox dysregulation and blocking the lipotoxicity-oxidative stress-inflammation cycle, according to a July 16 announcement.
HIRI occurs when blood supply to the liver is temporarily interrupted and then restored, as seen in liver resection and transplantation. The condition involves oxidative stress, mitochondrial dysfunction, metabolic imbalance, and excessive inflammation. Existing strategies such as reducing ischemic time, preconditioning, antioxidants, and mitochondrial protectants have shown limited protective effects. Researchers say a key unresolved issue is how mitochondrial lipid metabolism, mtDNA-centered oxidative stress, and inflammatory signaling interact to worsen liver injury.
To investigate this mechanism and the role of CMPK2 in HIRI protection by ACT, the research team used animal models with 70% hepatic ischemia followed by reperfusion. Mice were treated with different doses of ACT or N-acetylcysteine as a control. A hepatocyte-specific CMPK2 overexpression model was also developed to test if CMPK2 was essential for ACT’s protective effect. In vitro experiments exposed AML12 hepatocytes to hypoxia/reoxygenation before administering ACT treatment or genetic interventions.
RNA sequencing showed that HIRI significantly altered pathways related to ATP synthesis, lipid metabolism, mitochondrial electron transport chain activity, apoptosis, and inflammation. Treatment with ACT reversed many of these changes at the transcriptional level. The researchers identified CMPK2 and MYD88 as critical targets shared across models. They found that HIRI increased acyl-CoA thioesterase 2 (ACOT2), which promoted free fatty acid accumulation in mitochondria, leading to higher reactive oxygen species production and weakened oxidative metabolism.
ACT reduced ACOT2 expression levels in mice livers subjected to HIRI while restoring genes involved in fatty acid β-oxidation and improving ATP production along with activities of mitochondrial complexes I and IV. Further investigation revealed that both HIRI in vivo and hypoxia/reoxygenation in vitro led to increases in CMPK2 expression; this elevated mtDNA synthesis resulted in oxidized mtDNA accumulation inside mitochondria followed by its release into the cytoplasm—a process activating the TLR9-MYD88-NF-κB pathway—and ultimately promoted nuclear translocation of interferon regulatory factor 1 (IRF1). IRF1 stimulated Cmpk2/Duox2 transcription, creating a feedback loop intensifying ROS generation and inflammatory signaling.
The study concludes that targeting CMPK2 through compounds like ACT could disrupt this damaging cycle by inhibiting IRF1 nuclear translocation while limiting mtDNA leakage—thereby providing a mechanistic basis for new therapies aimed at reducing liver damage during transplantation or major surgery.
