肝癌是最致命的恶性肿瘤之一，每年致死830,000起以上。虽然靶向治疗药物已取得一定的临床疗效，但目前仅有索拉非尼和雷伐替尼作为一线靶向药物用于治疗晚期肝癌患者。因此，迫切需要开发更多的药物。铁死亡（ferroptosis）是一种铁依赖的程序性细胞死亡（PCD），不同于包括凋亡、坏死和自噬在内的已知PCD。靶向铁死亡被认为是一种有前景的肝癌潜在治疗方式。激活转录因子3（ATF3）是一个重要的铁死亡诱导剂，靶向ATF3提供了一种潜在的癌症治疗手段。在本研究中，我们首次报道了一种具有良好的体外和体内抗肝癌效果的白藜芦醇衍生物6j。化合物6j能通过促进细胞内Fe2+、活性氧（ROS）和MDA积累来诱导肝癌细胞的铁死亡。铁死亡抑制剂ferrostatin-1可减轻6j诱导的Fe2+、ROS和MDA积累，恢复细胞的活力。进一步的研究揭示，化合物6j通过内质网应激上调ATF3的表达，而通过RNA干扰抑制ATF3则减弱6j诱导的铁死亡和细胞增殖抑制作用。本研究为铁死亡诱导剂的设计和抗肝癌药物的开发提供了新的见解。© 2023. 细胞死亡和分化协会（ADMC）。

Liver cancer is one of the most lethal malignancies with an annual death of over 830,000 cases. Although targeted therapeutic drugs have achieved certain clinical efficacy, only sorafenib and lenvatinib are currently marketed as first-line targeted drugs to treat patients with advanced liver cancer. Therefore, developing more drugs are urgently needed. Ferroptosis is an iron-dependent programmed cell death (PCD) distinct from known PCDs including apoptosis, necrosis, and autophagy. Targeting ferroptosis is recognized as a promising potential therapeutic modality for liver cancer. Activating transcription factor 3 (ATF3) is an important ferroptosis inducer and targeting ATF3 offers a potential means to cancer therapy. In the present study, we reported for the first time a sophoridine derivative 6j with promising anti-liver cancer effects in vitro and in vivo. Compound 6j could induce liver cancer cells ferroptosis by promoting the accumulation of intracellular Fe2+, reactive oxygen species (ROS), and MDA. Inhibition of ferroptosis by ferrostatin-1 alleviated 6j induced accumulation of Fe2+, ROS, and MDA and restored cell viability. Further study revealed that compound 6j upregulated the expression of ATF3 via ER stress and knockdown of ATF3 by RNA interference attenuated 6j induced ferroptosis and cell proliferation inhibition. This study would provide new insights for the design of ferroptosis inducers and the development of anti-liver cancer drugs.© 2023. Cell Death Differentiation Association (ADMC).