Natural compound library screening identifies triptolide for the treatment of okadaic acid-induced intestinal dysfunction

Okadaic acid (OA), a diarrhetic shellfish toxin, causes significant intestinal and systemic toxicity. Currently, there are no approved therapeutics specifically targeting OA-induced diarrhea. Using high-throughput screening of 2131 natural compounds, we identified triptolide as a compound conferring protection against OA-induced apoptosis. In mice exposed to OA, triptolide administration reduced intestinal permeability and ameliorated mucosal injury. In HUVECs, triptolide (0.1–3 μM) dose-dependently increased cell viability and suppressed apoptotic activity. Biotin-based labeling identified the hydroxyl group as the essential active site of triptolide. RNA sequencing analysis showed that triptolide inhibited the OA-induced upregulation of endoplasmic reticulum (ER) protein synthesis-related genes. Furthermore, triptolide prevented the OA-induced decrease in the p-eIF-2α/eIF-2α ratio, thereby attenuating ER stress. These results demonstrate that triptolide mitigates OA-induced toxicity by inhibiting ER stress-mediated endothelial cell apoptosis and maintaining intestinal barrier integrity, highlighting its potential as a therapeutic agent against OA-related poisoning.