粒体自噬
脂质过氧化
癌症研究
GPX4
癌症
程序性细胞死亡
线粒体
帕金
癌细胞
旁观者效应
细胞生物学
细胞凋亡
自噬
化学
生物
医学
免疫学
氧化应激
生物化学
病理
内科学
过氧化氢酶
疾病
谷胱甘肽过氧化物酶
帕金森病
作者
Shan Liu,J.-H. Chen,Lichao Li,Zhipeng Ye,Jian‐Nan Liu,Yuhong Chen,Bingxin Hu,Jiahong Tang,Gong‐Kan Feng,Zhiming Li,Chu‐Xia Deng,Rong Deng,Xiao‐Feng Zhu,Hai‐Liang Zhang
标识
DOI:10.1002/advs.202412593
摘要
The identification of ferroptosis-sensitive cancers is critical for the application of ferroptosis-inducing therapies in cancer therapy. Here, patient-derived organoid screening models of colorectal cancer are established to identify tumors that are sensitive to ferroptosis-inducing therapy. This study discovers that patient-derived tumors characterized by mitophagy deficiency are hypersensitive to ferroptosis-inducing therapies. Mechanistically, a novel negative feedback regulatory pathway of lipid peroxidation is identified, which is one of the important intrinsic anti-ferroptosis mechanisms of cancer cells. Lipid peroxidation-mediated endoplasmic reticulum stress transcriptionally upregulates Parkin to promote mitophagy through ATF4. Mitophagy limits the generation of lipid peroxidation products and subsequently inhibits ferroptosis by inhibiting the accumulation of mitochondrial ROS. Mitophagy-deficient tumors lack this anti-ferroptotic mechanism, unleashing the generation of lipid peroxidation and potent ferroptotic cell death induced by erastin, RSL3, cysteine deprivation, radiotherapy, and immunotherapy. More importantly, ferroptosis-inducing therapy selectively inhibits the growth and distant metastasis of mitophagy-deficient tumors in vivo. In summary, patient-derived organoids of colorectal cancer patients for screening ferroptosis-sensitive tumors are established, providing a paradigm for identifying that patient-derived tumors are sensitive to ferroptosis-inducing therapies. This study concludes that mitophagy-deficient tumors are vulnerable to ferroptosis induction, which may lead to the development of new therapeutic strategies for tumors deficient in mitophagy.
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