Pancreatic cancer tends to be highly resistant to current therapy and remains one of the great challenges in biomedicine with very low 5-year survival rates. Here, we report that zalcitabine, an antiviral drug for human immunodeficiency virus infection, can suppress the growth of primary and immortalized human pancreatic cancer cells through the induction of ferroptosis, an iron-dependent form of regulated cell death. Mechanically, this effect relies on zalcitabine-induced mitochondrial DNA stress, which activates the STING1/TMEM173-mediated DNA sensing pathway, leading to macroautophagy/autophagy-dependent ferroptotic cell death via lipid peroxidation, but not a type I interferon response. Consequently, the genetic and pharmacological inactivation of the autophagy-dependent ferroptosis pathway diminishes the anticancer effects of zalcitabine in cell culture and animal models. Together, these findings not only provide a new approach for pancreatic cancer therapy but also increase our understanding of the interplay between autophagy and DNA damage response in shaping cell death.

Abbreviations: ALOX: arachidonate lipoxygenase; ARNTL/BMAL1: aryl hydrocarbon receptor nuclear translocator-like; ATM: ATM serine/threonine kinase; ATG: autophagy-related; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; ER: endoplasmic reticulum; FANCD2: FA complementation group D2; GPX4: glutathione peroxidase 4; IFNA1/IFNα: interferon alpha 1; IFNB1/IFNβ: interferon beta 1; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; MDA: malondialdehyde; mtDNA: mitochondrial DNA; NCOA4: nuclear receptor coactivator 4; PDAC: pancreatic ductal adenocarcinoma; POLG: DNA polymerase gamma, catalytic subunit; qRT-PCR: quantitative polymerase chain reaction; RCD: regulated cell death; ROS: reactive oxygen species; SLC7A11: solute carrier family 7 member 11; STING1/TMEM173: stimulator of interferon response cGAMP interactor 1; TFAM: transcription factor A, mitochondrial

胰腺癌往往对目前的治疗具有高度耐药性，并且仍然是生物医学面临的巨大挑战之一，其 5 年生存率非常低。在这里，我们报道扎西他滨（一种治疗人类免疫缺陷病毒感染的抗病毒药物）可以通过诱导铁死亡（一种铁依赖性调节细胞死亡形式）来抑制原代和永生化人类胰腺癌细胞的生长。从机制上讲，这种效应依赖于扎西他滨诱导的线粒体 DNA 应激，该应激激活 STING1/TMEM173 介导的 DNA 传感途径，通过脂质过氧化导致巨自噬/自噬依赖性铁死亡细胞死亡，但不是 I 型干扰素反应。因此，自噬依赖性铁死亡途径的遗传和药理学失活降低了扎西他滨在细胞培养和动物模型中的抗癌作用。总之，这些发现不仅为胰腺癌治疗提供了一种新方法，而且加深了我们对自噬和 DNA 损伤反应在形成细胞死亡过程中相互作用的理解。

缩写： ALOX：花生四烯酸脂氧合酶； ARNTL/BMAL1：芳烃受体核易位子样； ATM：ATM丝氨酸/苏氨酸激酶； ATG：自噬相关； cGAMP：环状 GMP-AMP； CGAS：环 GMP-AMP 合酶； ER：内质网； FANCD2：FA互补组D2； GPX4：谷胱甘肽过氧化物酶4； IFNA1/IFNα：干扰素α1； IFNB1/IFNβ：干扰素β1； MAP1LC3B/LC3：微管相关蛋白1轻链3β； MDA：丙二醛； mtDNA：线粒体DNA； NCOA4：核受体共激活因子4； PDAC：胰腺导管腺癌； POLG：DNA聚合酶γ，催化亚基； qRT-PCR：定量聚合酶链式反应； RCD：调节细胞死亡； ROS：活性氧； SLC7A11：溶质载体家族7成员11； STING1/TMEM173：干扰素反应 cGAMP 相互作用子 1 的刺激剂； TFAM：转录因子 A，线粒体