Anlotinib-mediated angiogenic remodeling was delineated in various tumors. Meanwhile, we previously showed that anlotinib inhibited tumor angiogenesis in anaplastic thyroid cancer (ATC). However, the potential role of anlotinib on cell lethality in ATC remains an enigma. Herein, we found that anlotinib inhibited the viability, proliferation, and migration of KHM-5M, C643, and 8505C cells in a dose-dependently manner. Under anlotinib treatment, PANoptosis (pyroptosis, apoptosis, and necroptosis) markers were not changed; however, ferroptosis targets (transferrin, HO-1, FTH1, FTL, and GPX4) were significantly downregulated. ROS levels also increased in a concentration-dependent manner after anlotinib treatment in KHM-5M, C643, and 8505C cells. In addition, protective autophagy was activated in response to anlotinib, and autophagic blockade potentiated anlotinib-mediated ferroptosis and antitumor effects in vitro and in vivo. Our new discovery identified autophagy-ferroptosis signaling pathway which provides mechanistic insight into anlotinib-mediated cell death, and synergistic combination therapy may help develop new ATC treatment strategies.

在各种肿瘤中描述了安罗替尼介导的血管生成重塑。同时，我们之前证明安罗替尼可抑制甲状腺未分化癌（ATC）的肿瘤血管生成。然而，安罗替尼对 ATC 细胞致死率的潜在作用仍然是个谜。在此，我们发现安罗替尼以剂量依赖性方式抑制 KHM-5M、C643 和 8505C 细胞的活力、增殖和迁移。在安罗替尼治疗下，PANoptosis（细胞焦亡、细胞凋亡和坏死性凋亡）标志物没有改变；然而，铁死亡靶标（转铁蛋白、HO-1、FTH1、FTL 和 GPX4）显着下调。在安罗替尼处理 KHM-5M、C643 和 8505C 细胞后，ROS 水平也以浓度依赖性方式增加。此外，保护性自噬因安罗替尼的反应而被激活，自噬阻断增强了安罗替尼介导的铁死亡和体外和体内抗肿瘤作用。我们的新发现确定了自噬-铁死亡信号通路，为安罗替尼介导的细胞死亡提供了机制见解，协同联合疗法可能有助于开发新的 ATC 治疗策略。