Non-small cell lung cancer (NSCLC) remains the foremost contributor to cancer-related fatalities globally, with limited effective therapeutic modalities. Recent research has shed light on the role of ferroptosis in various types of cancers, offering a potential avenue for improving cancer therapy. Herein, we identified E3 ubiquitin ligase deltex 2 (DTX2) as a potential therapeutic target candidate implicated in promoting NSCLC cell growth by inhibiting ferroptosis. Our investigation revealed a significant upregulation of DTX2 in NSCLC cells and tissues, which was correlated with poor prognosis. Downregulation of DTX2 suppressed NSCLC cell growth both in vitro and in vivo, while its overexpression accelerated cell proliferation. Moreover, knockdown of DTX2 promoted ferroptosis in NSCLC cells, which was mitigated by DTX2 overexpression. Mechanistically, we uncovered that DTX2 binds to nuclear receptor coactivator 4 (NCOA4), facilitating its ubiquitination and degradation via the K48 chain, which subsequently dampens NCOA4-driven ferritinophagy and ferroptosis in NSCLC cells. Notably, DTX2 knockdown promotes cisplatin-induced ferroptosis and overcomes drug resistance of NSCLC cells. These findings underscore the critical role of DTX2 in regulating ferroptosis and NCOA4-mediated ferritinophagy, suggesting its potential as a novel therapeutic target for NSCLC.

中文翻译：

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E3 泛素连接酶 DTX2 通过抑制非小细胞肺癌中 NCOA4 介导的铁蛋白自噬促进铁死亡耐药


非小细胞肺癌 （NSCLC） 仍然是全球癌症相关死亡人数的主要贡献者，有效的治疗方式有限。最近的研究揭示了铁死亡在各种类型的癌症中的作用，为改进癌症治疗提供了一条潜在的途径。在此，我们确定 E3 泛素连接酶 deltex 2 （DTX2） 是一种潜在的治疗靶点候选物，与通过抑制铁死亡促进 NSCLC 细胞生长有关。我们的研究显示 NSCLC 细胞和组织中 DTX2 显着上调，这与不良预后相关。DTX2 的下调抑制了 NSCLC 细胞在体外和体内的生长，而其过表达加速了细胞增殖。此外，DTX2 的敲低促进了 NSCLC 细胞的铁死亡，DTX2 过表达减轻了这种现象。从机制上讲，我们发现 DTX2 与核受体共激活因子 4 （NCOA4） 结合，通过 K48 链促进其泛素化和降解，从而抑制 NSCLC 细胞中 NCOA4 驱动的铁蛋白自噬和铁死亡。值得注意的是，DTX2 敲低促进顺铂诱导的铁死亡并克服 NSCLC 细胞的耐药性。这些发现强调了 DTX2 在调节铁死亡和 NCOA4 介导的铁蛋白自噬中的关键作用，表明其作为 NSCLC 新治疗靶点的潜力。