Trillin attenuates liver ischemia-reperfusion injury by inhibiting autophagy through regulation of the cGAS-STING pathway

Background Liver ischemia/reperfusion (I/R) injury is an unavoidable complication during liver surgery, particularly in liver transplantation. Trillin exhibits anti-inflammatory, antioxidant, anti-apoptotic, and autophagy-inhibitory effects. However, Trillin has not been studied in liver I/R injury. Methods In this study, we investigated the effects of Trillin in liver I/R and AML12 hypoxia/reoxygenation (H/R) models. We assessed Trillin's impact on inflammatory responses, oxidative stress, apoptosis, and autophagy through H&E staining, serum transaminase levels (ALT, AST), cell viability assays, propidium iodide (PI) staining, MitoSOX staining, immunohistochemistry (IHC), transmission electron microscopy (TEM). Qualitative and quantitative analyses of mRNA and protein levels were performed to evaluate inflammatory cytokines, autophagy-related proteins, and the cyclic GMP-AMP synthase (cGAS) – stimulator of interferon genes (STING) pathway. Molecular docking and dynamics simulations were conducted to validate the binding and stability between Trillin and cGAS. Results Our results demonstrate that Trillin alleviates liver ischemia-reperfusion injury through the attenuation of autophagy in both in vitro and in vivo models. Additionally, Trillin could bind to cGAS and inhibit the activation of the cGAS-STING pathway. cGAS overexpression significantly reversed Trillin's protective effects in liver I/R injury and its inhibitory effects on the cGAS-STING pathway. Conclusion Trillin exerts protective effects against liver I/R injury by inhibiting the cGAS-STING pathway.