Cancer research is continuously exploring new avenues to improve treatments, and ferroptosis induction has emerged as a promising approach. However, the lack of comprehensive analysis of the ferroptosis sensitivity in different cancer types has limited its clinical application. Moreover, identifying the key regulator that influences the ferroptosis sensitivity during cancer progression remains a major challenge. In this study, we shed light on the role of ferroptosis in colorectal cancer and identified a novel ferroptosis repressor, NUDT16L1, that contributes to the ferroptosis insensitivity in this cancer type. Mechanistically, NUDT16L1 promotes ferroptosis insensitivity in colon cancer by enhancing the expression of key ferroptosis repressor and mitochondrial genes through direct binding to NAD-capped RNAs and the indirect action of MALAT1. Our findings also reveal that NUDT16L1 localizes to the mitochondria to maintain its proper function by preventing mitochondrial DNA leakage after treatment of ferroptosis inducer in colon cancer cells. Importantly, our orthotopic injection and Nudt16l1 transgenic mouse models of colon cancer demonstrated the critical role of NUDT16L1 in promoting tumor growth. Moreover, clinical specimens revealed that NUDT16L1 was overexpressed in colorectal cancer, indicating its potential as a therapeutic target. Finally, our study shows the therapeutic potential of a NUDT16L1 inhibitor in vitro, in vivo and ex vivo. Taken together, these findings provide new insights into the crucial role of NUDT16L1 in colorectal cancer and highlight its potential as a promising therapeutic target.

中文翻译：

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NUDT16L1 的过表达维持线粒体的正常功能，并导致结直肠癌对铁死亡不敏感


癌症研究不断探索改进治疗的新途径，铁死亡诱导已成为一种很有前途的方法。然而，缺乏对不同癌症类型中铁死亡敏感性的全面分析限制了其临床应用。此外，确定癌症进展过程中影响铁死亡敏感性的关键调节因子仍然是一项重大挑战。在这项研究中，我们阐明了铁死亡在结直肠癌中的作用，并确定了一种新的铁死亡抑制因子 NUDT16L1，它导致该癌症类型对铁死亡不敏感。从机制上讲，NUDT16L1 通过与 NAD 加帽 RNA 的直接结合和 MALAT1 的间接作用增强关键铁死亡阻遏蛋白和线粒体基因的表达，从而促进结肠癌中的铁死亡不敏感性。我们的研究结果还表明，NUDT16L1定位于线粒体，通过在结肠癌细胞中处理铁死亡诱导剂后防止线粒体 DNA 泄漏来维持其正常功能。重要的是，我们的结肠癌原位注射和 Nudt16l1 转基因小鼠模型证明了 NUDT16L1 在促进肿瘤生长中的关键作用。此外，临床标本显示 NUDT16L1 在结直肠癌中过表达，表明其作为治疗靶点的潜力。最后，我们的研究表明 NUDT16L1 抑制剂在体外、体内和体外的治疗潜力。综上所述，这些发现为 NUDT16L1 在结直肠癌中的关键作用提供了新的见解，并突出了其作为有前途的治疗靶点的潜力。