HIRI is a major clinical challenge that occurs when the blood supply to the liver is temporarily interrupted and then recovered, as is often seen in liver resection or liver transplantation. Current research indicates that this injury involves oxidative stress, mitochondrial dysfunction, metabolic imbalance, and excessive inflammation. Strategies such as shortening ischemic time, ischemic preconditioning, antioxidants, and mitochondrial protectants have been investigated, but their protective effects remain limited. An important unresolved question is how mitochondrial lipid metabolism, mtDNA-centered oxidative stress, and inflammatory signaling interact to amplify liver damage.
The study (DOI: 10.48130/targetome-0026-0011) target tome On March 31, 2026, Xiaojiaoyang Li’s team from Beijing University of Traditional Chinese Medicine reported that ACT protects against HIRI by suppressing mitochondrial redox dysregulation by CMPK2 and blocking the lipotoxicity-oxidative stress-inflammation cycle.
To elucidate the role of CMPK2 and the protective mechanism of ACT, the researchers combined animal and cell models, sequence analysis, and molecular biology experiments. In mice, we established a 70% hepatic ischemia model followed by reperfusion and treated animals with different doses of ACT, using N-acetylcysteine as a positive control. They also constructed a hepatocyte-specific CMPK2 overexpression model to test whether CMPK2 is essential for ACT-mediated protection. In vitro, AML12 hepatocytes were exposed to hypoxia/reoxygenation to mimic ischemia-reperfusion stress, followed by ACT treatment, gene silencing, recombinant protein stimulation, and mtDNA transfection. RNA sequencing of whole liver tissue and isolated hepatocytes showed that HIRI strongly altered pathways associated with ATP synthesis, lipid metabolism, mitochondrial electron transport, apoptosis, and inflammation. ACT reversed many of these transcriptional changes. Further analysis identified CMPK2 and MYD88 as common important targets. The research team found that HIRI increases acyl-CoA thioesterase 2 (ACOT2), which promotes the accumulation of free fatty acids in mitochondria. This lipid overload increased ROS production and weakened mitochondrial oxidative metabolism. ACT decreased ACOT2 expression, lowered free fatty acid levels, restored fatty acid β-oxidation-related genes, increased ATP production, and improved mitochondrial complex I and IV activity. Next, the researchers examined mtDNA-related oxidative damage. HIRI and hypoxia/reoxygenation increased CMPK2 expression, mtDNA synthesis, oxidized mtDNA accumulation, mitochondrial permeability transition pore opening, and mtDNA release. Released mtDNA activated TLR9-MYD88-NF-.Mr.B route. Promotes nuclear translocation of interferon regulatory factor 1 (IRF1). IRF1 further stimulated the transcription of Cmpk2 and Duox2, creating a detrimental feedback loop that enhanced ROS generation and inflammatory signaling. ACT disrupted this cycle by inhibiting nuclear translocation of IRF1, decreasing transcription of Cmpk2 and Duox2, and limiting mtDNA leakage. Binding assays such as DARTS, CETSA, SPR, and MST further suggested that ACT could directly interact with CMPK2 and promote its mitophagy-dependent degradation. Importantly, hepatocyte-specific overexpression of CMPK2 attenuated the protective effects of ACT, confirming CMPK2 as a central therapeutic target.
Overall, this study establishes that CMPK2 is a pivotal regulator associated with mitochondrial lipid metabolism, redox imbalance, mtDNA release, and inflammatory activation in HIRI. ACT provides a mechanistic basis for developing novel interventions to reduce liver injury associated with transplantation and major liver surgery by targeting CMPK2 and the TLR9-IRF1-CMPK2/DUOX2-mtDNA axis.
sauce:
Chinese Academy of Sciences
Reference magazines:
Luo, R. Others. (2026). Acteoside attenuates hepatic ischemia-reperfusion injury by targeting CMPK2-mediated redox metabolism. target tome. DOI: 10.48130/targetome-0026-0011. https://www.maxapress.com/article/doi/10.48130/targetome-0026-0011
