INTRODUCTION/OBJECTIVE: Triptolide, a diterpenoid epoxide derived from Tripterygium wilfordii Hook F, exhibits potent therapeutic activities but is clinically limited by severe multiorgan toxicity, the mechanisms of which remain poorly understood. This study aimed to elucidate these mechanisms using an integrative computational framework. METHODS: We employed a multi-step computational approach combining network pharmacology, Mendelian randomization (MR), molecular docking, molecular dynamics simulations, and single- cell RNA sequencing analysis to systematically identify and evaluate toxicity pathways. RESULTS: Network analysis identified 29 common toxicity targets across hepatic, renal, cardiac, and reproductive systems. Functional enrichment revealed that disruption of glycolysis and the pentose phosphate pathway is a central mechanism. This supports a dual toxicity model involving: (1) a "cellular energy crisis" due to impaired ATP production (via enzymes such as GCK), and (2) an "oxidative redox imbalance" resulting from NADPH depletion (via enzymes such as RPIA). MR analysis further indicated potential causal links between these targets and organ damage. Molecular docking and dynamics simulations showed stable, high-affinity complexes with these enzymes (binding energies: -7.0 to -9.1 kcal/mol), providing a structural basis for the interactions. Single-cell RNA sequencing analysis highlighted organ-specific vulnerability related to the cell-type-specific expression of these target enzymes. DISCUSSION: Triptolide-induced disruption of glucose homeostasis via direct enzyme interactions may underlie its multi-organ toxicity. This integrative framework bridges molecular-level interactions and organ pathology, providing a comprehensive strategy to dissect complex toxicity mechanisms. CONCLUSION: Our findings suggest that triptolide's multi-organ toxicity is mechanistically rooted in the disruption of glucose metabolism, driven by interactions with core metabolic enzymes. This integrative computational study offers novel insights into pan-organ toxicity and provides a potential basis for designing safer triptolide analogues.
Wang et al. (Fri,) studied this question.