【摘 要】
：
Ferroptosis is a type ofcell death accompanied by iron-dependent lipid peroxidation,thus stimu-lating ferroptosis may be a potential strategy for treating gastric cancer,therapeutic agents against which are urgently required.Jiyuan oridonin A (JDA) is a n
【机 构】
：
State Key Laboratory of Esophageal Cancer Prevention & Treatment,Key Laboratory of Advanced Drug Pre
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Ferroptosis is a type ofcell death accompanied by iron-dependent lipid peroxidation,thus stimu-lating 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 Rabdosia rubescens with anti-tumor activity,unclear anti-tumor mechanisms and limited water solubility hamper its clinical appli-cation.Here,we showed a2,a new JDA derivative,inhibited the growth of gastric cancer cells.Subsequently,we discovered for the first time that a2 induced ferroptosis.Importantly,compound a2 decreased GPX4 expres-sion and overexpressing GPX4 antagonized the anti-proliferative activity of a2.Furthermore,we demonstrated that a2 caused ferrous iron accumulation through the autophagy pathway,prevention of which rescued a2 induced ferrous iron elevation and cell growth inhibition.Moreover,a2 exhibited more potent anti-cancer ac-tivity than 5-fluorouracil in gastric cancer cell line-derived xenograft mice models.Patient-derived tumor xeno-graft models from different patients displayed varied sensitivity to a2,and GPX4 downregulation indicated the sensitivity of tumors to a2.Finally,a2 exhibited well pharmacokinetic characteristics.Overall,our data suggest that inducing ferroptosis is the major mechanism mediating anti-tumor activity of a2,and a2 will hopefully serve as a promising compound for gastric cancer treatment.
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