The conversion of evodiamine-induced hepatotoxicity into a therapeutic effect on colonitis: insight from the liver-gut axis mediated by PPAR/NF-κB/ZO-1/caspase-3 pathway

BACKGROUND: Evodiamine (EVO) exerts promising therapeutic potential in the treatment of Ulcerative Colitis (UC). However, its clinical application is constrained by concerns regarding potential hepatotoxicity. A comprehensive understanding of underlying both the therapeutic effects and hepatotoxicity of EVO is therefore essential to enhance its safe and effective application in clinical practice. PURPOSE: This study aimed to elucidate the regulatory mechanisms of gut-liver axis homeostasis in EVO-induced hepatotoxicity and its therapeutic effects on UC. METHODS: An integrated experimental strategy employing cell, zebrafish, and murine was implemented to assess the hepatotoxic effects of EVO. Transcriptomic and metabolomic analyses were performed in vitro, while targeted investigations of bile acids (BAs) metabolism were conducted in vivo to understand the overall response profile and the underlying mechanisms associated with EVO-induced hepatotoxicity. Furthermore, the expression patterns of proteins along the gut-liver axis were systematically evaluated under diverse physiological conditions to identify the potential interactions contributing to the alleviative effects of UC on EVO-induced hepatotoxicity and as well as to explore the therapeutic potential of EVO in UC management. RESULTS: High-dose EVO treatment was associated with notable hepatotoxic effects in both in vitro cellular models and normal in vivo animals, primarily manifested through disturbances in BAs metabolism, inflammatory responses, and apoptosis. In contrast, in UC models, EVO administration not only effectively ameliorated intestinal structural damage and functional impairments, but also demonstrated minimal hepatotoxicity. Mechanism studies documented that EVO disrupted bile acid metabolism by interfering with BSEP/MRP2/CYP7A1/CYP27A1 pathways, while simultaneously triggering inflammation and apoptosis through PPAR/NF-κB/ZO-1/caspase-3 pathway, ultimately contributing to hepatotoxicity in healthy subjects. However, in the context of UC, the disease condition attenuated EVO-induced alterations in hepatic protein expression, thereby reducing its hepatotoxic potential. Meanwhile, under UC conditions, EVO restored the expression levels of relevant proteins in the intestinal tract, thereby maintaining its therapeutic efficacy against UC. CONCLUSION: The hepatotoxicity observed under healthy conditions and the therapeutic efficacy of EVO against UC are both associated with EVO's modulation of the PPAR/NF-κB/ZO-1/caspase-3 pathway. The influence of EVO on the expression of these key proteins within the gut-liver axis may be modulated by distinct physiological states, resulting in either antagonistic or synergistic effects that potentially lead to differential biological responses across multiple organs. This study not only provides essential supplementation and refinement to the understanding of EVO-induced hepatotoxicity but also identifies a novel breakthrough in accurately assessing its liver toxicity. Specifically, the evaluation of EVO's hepatotoxic potential should be grounded in the principles of TCM and aligned with its clinical application characteristics. Furthermore, these findings offer valuable insights for the safety assessment and development of traditional Chinese medicines with potential hepatotoxic risks.