Crocetin preconditioning attenuates ischemia reperfusion-induced hepatic injury by disrupting Keap1/Nrf2 interaction and activating Nrf2/ HO-1 pathway

Background: Ischemia reperfusion (I/R) injury is a frequent occurrence during liver transplantation surgery, resulting from the temporary cessation of blood flow and subsequent restoration of blood flow. Serious I/R injury is a significant factor causing transplant failure. Hepatic I/R process is characterized by excessive inflammation, oxidation, and apoptosis. Crocetin (Crt) is a natural compound exhibiting beneficial roles in various I/R-induced organ damages. However, Crt's potential role in hepatic I/R remains unexplored. Objective and methods: In order to reveal the impact of Crt on hepatic I/R and the associated signaling pathway, we utilized a syngeneic orthotopic liver transplantation rat model to induce hepatic I/R injury. Results: Pretreatment with Crt significantly mitigated hepatic I/R injury. This was evident by decreased activities of serum ALT, AST and LDH, indicating improved liver function. Crt treatment also alleviated oxidative stress, as demonstrated by decreased serum MDA content and elevated serum SOD and GSH-Px activities. Furthermore, Crt suppressed inflammatory responses by downregulating both the serum and liver IL-1 beta, IL-6 and TNF-alpha while upregulating IL-10 expression. Additionally, Crt reduced apoptosis by decreasing pro-apoptotic Bax, cleaved caspase-3 and cleaved caspase-9, while increasing anti-apoptotic Bcl2 expression. Notably, these protective effects of Crt were dose-dependent. Moreover, our data indicates that Crt plays protective functions during hepatic I/R via disrupting Keap1/Nrf2 interaction and activating Nrf2/HO-1 signaling. This was further supported by observations of alleviated hepatic histopathological changes in I/R rats treated with Crt. Conclusions: Crt shows potential as a therapeutic agent for preventing hepatic I/R injury during clinical liver transplantation.