SIRT5介导的FDX1去琥珀酰化赋予肺腺癌抗铜下垂能力
SIRT5-mediated FDX1 desuccinylation confers cuproptosis resistance in lung adenocarcinoma.
摘要(中文译文)
铜死亡是一种由过量铜诱导的铜依赖性细胞死亡过程，代表了肿瘤学中一种新兴的治疗策略。然而，调控该过程的肿瘤特异性分子通路仍不明确。在此，我们证明肺腺癌（LUAD）中铜水平升高，且LUAD细胞系对铜死亡表现出增强的抵抗性。在机制上，升高的铜应激促进去琥珀酰化酶SIRT5的表达，同时降低LUAD细胞中的整体琥珀酰化水平。此外，我们发现SIRT5通过去琥珀酰化修饰铁氧还蛋白1（FDX1）蛋白Lys84位点，是铜死亡的关键介导因子。该修饰触发TRIM8介导的泛素化，导致FDX1蛋白酶体降解并增强铜死亡抵抗性。这些结果揭示了SIRT5在LUAD铜死亡抵抗中的重要作用。值得注意的是，将SIRT5抑制剂MC3482与铜死亡诱导剂Elesclomol-Cu联合使用可在体内协同抑制肿瘤生长，提示了一种有前景的治疗策略。这些发现阐明了铜死亡抵抗的潜在机制，并为LUAD提出了一种新的治疗方法。
Abstract
Cuproptosis, a copper-dependent cell death process induced by excessive copper, represents an emerging therapeutic strategy in oncology. However, tumor-specific molecular pathways regulating this process remain poorly defined. Here, we demonstrate that copper levels are elevated in lung adenocarcinoma (LUAD), and LUAD cell lines exhibit increased resistance to cuproptosis. Mechanistically, elevated copper stress promotes the expression of the desuccinylase SIRT5 while reducing global succinylation in LUAD cells. Furthermore, we found that SIRT5 is a critical mediator of cuproptosis through the desuccinylation modification on ferredoxin1 (FDX1) protein at Lys84. This modification triggers TRIM8-mediated ubiquitination, leading to FDX1 proteasomal degradation and enhanced cuproptosis resistance. These results reveal the important role of SIRT5 in LUAD cuproptosis resistance. Notably, combining the SIRT5 inhibitor MC3482 with the cuproptosis inducer Elesclomol-Cu synergistically suppresses tumor growth in vivo, suggesting a promising therapeutic strategy. These findings elucidate mechanisms underlying cuproptosis resistance and propose a novel treatment approach for LUAD.
如何引用
AMA
Qifan Hu, Zuorui Wang, Wenxin Deng, Lei Wang, Jiayuan Chen, Hui Wang, et al. SIRT5-mediated FDX1 desuccinylation confers cuproptosis resistance in lung adenocarcinoma.. Cell reports. 2026; doi:10.1016/j.celrep.2026.117481.
APA
Qifan Hu, Zuorui Wang, Wenxin Deng, Lei Wang, Jiayuan Chen, Hui Wang, et al (2026). SIRT5-mediated FDX1 desuccinylation confers cuproptosis resistance in lung adenocarcinoma.. Cell reports. https://doi.org/10.1016/j.celrep.2026.117481
GB/T 7714
Qifan Hu, Zuorui Wang, Wenxin Deng, Lei Wang, Jiayuan Chen, Hui Wang, et al. SIRT5-mediated FDX1 desuccinylation confers cuproptosis resistance in lung adenocarcinoma.[J]. Cell reports, 2026 doi:10.1016/j.celrep.2026.117481.
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