Identification of ferroptosis as a novel mechanism for antitumor activity of natural product derivative a2 in gastric cancer.

Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation, thus stimulating ferroptosis may be a potential strategy for treating gastric cancer, therapeutic agents against which are urgently required. Jiyuan oridonin A (JDA) is a natural compound isolated from Jiyuan with anti-tumor activity, unclear anti-tumor mechanisms and limited water solubility hamper its clinical application. Here, we showed , a new JDA derivative, inhibited the growth of gastric cancer cells. Subsequently, we discovered for the first time that induced ferroptosis. Importantly, compound decreased GPX4 expression and overexpressing GPX4 antagonized the anti-proliferative activity of . Furthermore, we demonstrated that caused ferrous iron accumulation through the autophagy pathway, prevention of which rescued induced ferrous iron elevation and cell growth inhibition. Moreover, exhibited more potent anti-cancer activity than 5-fluorouracil in gastric cancer cell line-derived xenograft mice models. Patient-derived tumor xenograft models from different patients displayed varied sensitivity to , and GPX4 downregulation indicated the sensitivity of tumors to . Finally, exhibited well pharmacokinetic characteristics. Overall, our data suggest that inducing ferroptosis is the major mechanism mediating anti-tumor activity of , and will hopefully serve as a promising compound for gastric cancer treatment.