Multi-omics analysis reveals the mechanism of indirect hepatotoxicity of triptolide upon LPS stimulation

Purpose: Triptolide (TP), an active compound derived from the traditional Chinese herb Tripterygium wilfordii Hook F, is notable for its therapeutic properties. However, hepatotoxicity remains its primary adverse effect. There is a new perspective about TP hepatotoxicity: hepatic hypersensitivity triggered by lipopolysaccharide (LPS) stimulation. However, the global molecular alterations underlying this synergistic effect remain poorly defined.

Methods: We employed an integrated proteomics and metabolomics approach to systematically characterize the molecular landscape in the livers of mice treated with TP and LPS. Liver injury was assessed by serum biochemistry and histopathology.

Results: The TP+LPS combination induced severe liver damage, based upon histopathological and biochemical analyses, which was not observed with either agent alone. Proteomic analysis revealed that TP+LPS co-treatment induced aberrant expression of fatty acid/Cholesterol metabolizing Enzymes and dysregulation of cytoskeletal proteins, which collectively contributed to hepatocyte steatosis, structural disruption, and impaired regeneration. Metabolomics results showed that TP+LPS co-treatment significantly inhibited glucose metabolic pathways compared to LPS treatment alone, leading to a reduction of critical metabolic intermediates. This inhibition significantly impaired ATP production and triggered energy depletion. Integrated analysis showed that the suppression of these Enzymes in the TP+LPS group impaired mitochondria integrity and the electron transport chain, contributing to ROS-mediated oxidative stress and consequent aggravation of inflammatory response. The inflammatory environment further inhibits mitochondrial function, worsening metabolic disorders and promoting ROS accumulation, thereby forming a self-perpetuating cycle of "metabolism-oxidation-inflammation".

Conclusion: Our multi-omics data provide a comprehensive resource and novel insights into the mechanism of TP-potentiated, LPS-induced hepatotoxicity. TP might amplify hepatotoxicity by influencing energy metabolism, activating oxidative stress and inflammation in the context of LPS-induced inflammation.

Indirect hepatotoxicity; Multi-omics; Triptolide.