Integrated multi-omics analysis identifies candidate regulatory networks associated with celastrol-mediated attenuation of sepsis-induced liver injury

Background Sepsis-induced liver injury (SILI) is a severe complication of sepsis characterized by excessive inflammation, metabolic disturbance, and oxidative stress. Celastrol (CEL), a bioactive compound derived from traditional Chinese medicine, exhibits anti-inflammatory and antioxidant activities; however, the mechanisms underlying its protection against SILI remain unclear. Methods A mouse model of SILI was established by cecal ligation and puncture (CLP) to evaluate the protective effects of CEL. Liver histopathology and serum biochemical markers were assessed. Transcriptomic, proteomic, and metabolomic analyses were integrated to characterize molecular alterations associated with CEL treatment. Results CEL treatment significantly attenuated histopathological liver injury and reduced serum ALT and AST levels in septic mice. Multi-omics analysis identified 517 differentially expressed genes, 195 differentially expressed proteins, and 444 differentially expressed metabolites. Integrated analysis showed that CEL-associated changes were enriched in pathways related to immune-inflammatory regulation, metabolic reprogramming, oxidative stress responses, and lipid metabolism. Network analyses identified candidate regulatory molecules, including Cyp2c37, Hpx, SLC16A5, and Xaf1 , as well as metabolic alterations involving L-methionine-related pathways. Conclusions CEL attenuated SILI and was associated with coordinated changes in inflammatory responses, metabolic homeostasis, and oxidative stress-related pathways. These findings provide a multi-omics framework for investigating the potential mechanisms of CEL. Further functional studies are required to validate the causal roles of the identified candidate molecules.