Copper (Cu) is a cofactor of cytochrome c oxidase (CuCOX), indispensable for aerobic mitochondrial respiration. This study reveals that advanced clear cell renal cell carcinomas (ccRCCs) accumulate Cu, allocating it to CuCOX. Using a range of orthogonal approaches, including metabolomics, lipidomics, isotope-labeled glucose and glutamine flux analysis, and transcriptomics across tumor samples, cell lines, xenografts, and PDX models, combined with genetic and pharmacological interventions, we explored Cu’s role in ccRCC. Elevated Cu levels stimulate CuCOX biogenesis, providing bioenergetic and biosynthetic benefits that promote tumor growth. This effect is complemented by glucose-dependent glutathione production, which facilitates detoxification and mitigates Cu-H2O2 toxicity. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics reveal increased oxidative metabolism, altered glutathione and Cu metabolism, and diminished HIF activity during ccRCC progression. Thus, Cu drives an integrated oncogenic remodeling of bioenergetics, biosynthesis, and redox homeostasis, fueling ccRCC growth, which can be targeted for new therapeutic approaches.

中文翻译：

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铜驱动透明细胞肾细胞癌代谢状态的重塑和进展


铜 （Cu） 是细胞色素 c 氧化酶 （CuCOX） 的辅因子，对有氧线粒体呼吸是必不可少的。这项研究表明，晚期透明细胞肾细胞癌 （ccRCC） 积累 Cu，将其分配给 CuCOX。使用一系列正交方法，包括代谢组学、脂质组学、同位素标记的葡萄糖和谷氨酰胺通量分析，以及跨肿瘤样本、细胞系、异种移植物和 PDX 模型的转录组学，结合遗传和药理学干预，我们探讨了 Cu 在 ccRCC 中的作用。Cu 水平升高会刺激 CuCOX 生物发生，提供促进肿瘤生长的生物能量和生物合成益处。葡萄糖依赖性谷胱甘肽的产生补充了这种作用，它促进了解毒并减轻了 Cu-H 2 O 2 毒性。单细胞 RNA 测序 （scRNA-seq） 和空间转录组学显示，在 ccRCC 进展过程中，氧化代谢增加，谷胱甘肽和 Cu 代谢改变，HIF 活性降低。因此，Cu 驱动生物能量学、生物合成和氧化还原稳态的综合致癌重塑，促进 ccRCC 生长，这可以成为新治疗方法的靶向。