Abstract: Objective To investigate the temporal sequence of development of organ toxicity induced by triptolide (TP) and its relationship with the cumulative dose, and analyze its efficacy-toxicity mechanisms in order to provide data on clinical safety of TP. Methods Using zebrafish embryos at 2 days post-fertilization (dpf) as a model, a fluorescently labeled TP exposure group was set up to dynamically observe the onset sequence of toxicity and related phenotypic alterations in the heart, liver, kidney and intestines 72 hours later. Network pharmacology and toxicology were used to identify common targets of TP in treating systemic lupus erythematosus and inducing organ toxicity before GO/KEGG enrichment analysis was conducted. Results Triptolide sequentially induced damage to the zebrafish liver (72 h), heart (74 h), intestines (78 h), and kidney (80 h). Enrichment analysis revealed that the potential mechanisms underlying its efficacy and toxicity were highly similar, involving molecular pathways related to apoptosis and inflammatory responses. ALB might serve as a potential biomarker for TP-induced organ toxicity. Conclusion The organ toxicity induced by TP is distinctly temporal and dose-dependent. The strong similarity in its potential “efficacy-toxicity” mechanisms suggests that the relationship between the therapeutic effect and toxicity may be associated with the cumulative dose. These findings can provide a reference for clinical oversight of and interventions in time-dependent toxicity, offering new strategies for clinical prevention and treatment. However, differences in drug metabolism and anatomical structure between zebrafish and humans require that the sequence of organ toxicity be studied based on clinical cases.

Key words: Triptolide, Organ Toxicity, Temporal Regularity, Molecular Mechanisms, Zebrafish, Pharmacovigilance of Traditional Chinese Medicine