From traditional herb to molecular toxicity: Multi-omics analysis of Evodiamine-induced liver injury.

Abstract

Evodiamine (EVO), a major bioactive alkaloid isolated from Tetradium ruticarpum (A.Juss.) T.G.Hartley, possesses diverse pharmacological activities; however, its potential hepatotoxicity remains insufficiently characterized. This study aimed to evaluate the hepatotoxic effects of EVO and explore the molecular events associated with its toxicity. Male mice were administered EVO (10, 20, or 40 mg/kg) for 7, 14, or 28 days. EVO exposure caused dose- and time-dependent liver injury and oxidative stress, as shown by serum biochemistry, histopathology, and oxidative stress markers. An integrated multi-omics strategy combining network toxicology, transcriptomics, and metabolomics was applied to explore the underlying mechanisms. EVO exposure induced significant liver injury and oxidative stress in a dose- and time-dependent manner. Multi-omics analyses suggested that EVO treatment was associated with alterations in pathways related to inflammation, apoptosis, and lipid metabolism, including FOXO, PPAR, and NF-κB signaling pathways. Changes in the expression of SIRT1, CASP2, and FOXO3 and disturbances in glycerophospholipid metabolism were further observed. In conclusion, EVO induces dose- and time-dependent hepatotoxicity in mice. Multi-omics analyses suggest that inflammatory responses, apoptotic processes, and metabolic disturbances may contribute to EVO-induced liver injury. These findings provide toxicological evidence regarding the safety profile of EVO and identify biological pathways associated with its hepatotoxicity.