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 Rabdosia rubescens with anti-tumor activity, unclear anti-tumor mechanisms and limited water solubility hamper its clinical application. 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 expression 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 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 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.

铁死亡是一种伴随铁依赖性脂质过氧化作用的细胞死亡，因此刺激铁死亡可能是治疗胃癌的潜在策略，急需针对胃癌的治疗药物。济源冬凌草甲素 A (JDA) 是一种从济源草本植物中分离得到的天然化合物，具有抗肿瘤活性，但抗肿瘤机制尚不清楚，水溶性有限，阻碍了其临床应用。在这里，我们展示了一种新的 JDA 衍生物a2抑制胃癌细胞的生长。随后，我们首次发现a2诱导了铁死亡。重要的是，化合物a2降低了 GPX4 的表达，过表达 GPX4 拮抗了a2的抗增殖活性. 此外，我们证明了a2通过自噬途径引起亚铁积累，预防这种积累可以挽救a2诱导的亚铁升高和细胞生长抑制。此外，在胃癌细胞系来源的异种移植小鼠模型中，a2表现出比 5-氟尿嘧啶更有效的抗癌活性。来自不同患者的患者来源的肿瘤异种移植模型对a2表现出不同的敏感性，GPX4 下调表明肿瘤对a2的敏感性。最后，a2表现出良好的药代动力学特征。总体而言，我们的数据表明诱导铁死亡是介导a2抗肿瘤活性的主要机制和a2有望成为治疗胃癌的有前途的化合物。