全面研究铜死亡在透明细胞肾细胞癌临床特征、分子特征和免疫状况中的作用。

BACKGROUND: Copper-induced cell death has been widely investigated in human diseases as a form of programmed cell death (PCD). The newly recognized mechanism underlying copper-induced cell death provided us creative insights into the copper-related toxicity in cells, and this form of PCD was termed cuproptosis. METHODS: Through consensus clustering analysis, ccRCC patients from TCGA database were classified into different subgroups with distinct cuproptosis-based molecular patterns. Analyses of clinical significance, long-term survival, and immune features were performed on subgroups accordingly. The cuproptosis-based risk signature and nomogram were constructed and validated relying on the ccRCC cohort as well. The cuproptosis scoring system was generated to better characterize ccRCC patients. Finally, validation was conducted using ccRCC clinical samples and cell lines. RESULT: Patients from different subgroups displayed diverse clinicopathological features, survival outcomes, tumor microenvironment (TME) characteristics, immune-related score, and therapeutic responses. The prognostic model and cuproptosis score were well validated and proved to efficiently distinguish the high risk/score and low risk/score patients, which revealed the great predictive value. The cuproptosis score also tended out to be intimately associated with the prognosis and immune features of ccRCC patients. Additionally, the hub cuproptosis-associated gene (CAG) FDX1 presented a dysregulated expression pattern in human ccRCC samples, and it was confirmed to effectively promote the killing effects of copper ionophore elesclomol as a direct target. functional assays revealed the prominent anti-cancer role of FDX1 in ccRCC. CONCLUSION: Cuproptosis played an indispensable role in the regulation of TME features, tumor progression, and long-term prognosis of ccRCC.

背景：铜诱导的细胞死亡已在人类疾病中作为一种程序性细胞死亡（PCD）形式得到广泛研究。新发现的铜诱导细胞死亡的机制为我们提供了对细胞中与铜相关毒性的创造性见解，这种形式的 PCD 被称为铜死亡。

方法：通过共识聚类分析，根据不同的铜死亡相关分子模式，将 TCGA 数据库中的 ccRCC 患者分为不同的亚组。相应地对亚组进行临床意义、长期生存和免疫特征的分析。根据 ccRCC 队列构建和验证了基于铜死亡的风险特征和列线图。生成了铜死亡评分系统，以更好地描述 ccRCC 患者。最后，使用 ccRCC 临床样本和细胞系进行验证。

结果：不同亚组的患者表现出不同的临床病理特征、生存结局、肿瘤微环境（TME）特征、免疫相关评分和治疗反应。预后模型和铜死亡评分得到了很好的验证，并证明能够有效地区分高风险/评分和低风险/评分患者，具有很好的预测价值。铜死亡评分也与 ccRCC 患者的预后和免疫特征密切相关。此外，铜死亡相关基因（CAG）FDX1 的关键基因在人类 ccRCC 样本中表现出失调的表达模式，并且证实其作为直接靶点可有效增强铜离子载体 elesclomol 的杀伤作用。功能测定揭示了 FDX1 在 ccRCC 中具有显著的抗癌作用。

结论：铜死亡在调节 ccRCC 的 TME 特征、肿瘤进展和长期预后中起着不可或缺的作用。