Triptolide as a multi-target anticancer agent: molecular mechanisms and translational potential

Triptolide, a bioactive diterpenoid epoxide isolated from Tripterygium wilfordii Hook. F. (Thunder God Vine), is a potent multi-target natural compound with significant anticancer potential. This systematic review with narrative synthesis evaluates preclinical evidence published between 2015 and 2026 on its molecular mechanisms, cancer-specific responses, and translational prospects, introducing a confidence-based framework to grade the strength of reported mechanisms. Across 51 studies, triptolide showed broad-spectrum anticancer activity in breast, lung, colorectal, pancreatic, hepatocellular, ovarian, prostate, glioma, and osteosarcoma models, acting mainly through mitochondrial apoptosis (92% of studies), reactive oxygen species generation, cell-cycle arrest, and modulation of NF-κB, PI3K/Akt/mTOR, STAT3, and Wnt/β-catenin signaling, with chemosensitization to cisplatin, gemcitabine, pemetrexed, and gefitinib reported in 31% of studies. Clinical translation, however, remains constrained by a therapeutic-index paradox: the same multi-target actions driving efficacy also underlie systemic toxicity, compounded by poor aqueous solubility, low bioavailability, and a narrow therapeutic window. The prodrug Minnelide has reached phase I/II trials, but substantial toxicity persists and no phase III data yet exist. Future progress will likely depend on improved delivery and toxicity-mitigation strategies rather than the discovery of additional molecular targets.