Protective effect of Caftaric Acid against hepatic cold ischemia/reperfusion injury in the liver

Hepatic cold ischemia/reperfusion (I/R) injury persists during the perioperative period of liver transplantation (LT), exerting a profound impact on graft survival and being closely associated with the occurrence of early allograft dysfunction (EAD). Currently, preventive strategies against cold I/R injury remain limited. This study aimed to investigate the protective effects and underlying molecular mechanisms of caftaric acid (CA), a metabolite specifically elevated in cold-adapted hibernating animals, against hepatic cold I/R injury. The results demonstrated that CA significantly reduced the area of hepatic necrosis, attenuated liver injury, inhibited hepatocyte apoptosis, and promoted the restoration of redox homeostasis. RNA-seq analysis suggested that the MAPK pathway, particularly the activation of JNK1, plays a pivotal role in the process of cold I/R injury. Through integrated experiments including drug-target screening, molecular docking, and surface plasmon resonance (SPR), this study confirmed that CA directly binds to and interacts with JNK1, thereby regulating its phosphorylation function. Further investigations revealed that CA modulates the MAPK cascade (JNK1/FOS) to alleviate oxidative stress, mitochondrial dysfunction, and cellular apoptosis during hepatic cold I/R injury. In summary, these findings suggest that CA holds promise as a potential therapeutic strategy for ameliorating hepatic cold I/R injury, with significant clinical implications.