Understanding the Link Between Cancer Metabolism and Cuproptosis
Cancer cells have a remarkable ability to survive under stress. One of their key survival tricks is metabolic reprogramming—shifting how they use nutrients like glucose to support rapid growth. A new review explores how this metabolic shift helps tumors avoid a recently discovered form of cell death called cuproptosis.
Cuproptosis is a copper-dependent cell death mechanism that stands apart from better-known processes such as apoptosis and ferroptosis. It occurs when excess copper interacts with specific mitochondrial proteins involved in energy production, particularly those that are lipoylated—a chemical modification essential for their function. When copper binds to these proteins, it causes them to clump together, disrupts iron–sulfur (Fe–S) clusters, and leads to toxic stress in cells.
According to Song and colleagues, “the aggregation induces proteotoxic stress and results in the loss of Fe–S cluster proteins,” which ultimately triggers cell death. But tumor cells, it turns out, have found ways to sidestep this process.
How Tumor Cells Suppress Cuproptosis
The review details how cancer cells remodel their glucose metabolism in ways that suppress copper toxicity. Normally, healthy cells generate energy in mitochondria through oxidative phosphorylation. In contrast, cancer cells rely heavily on aerobic glycolysis—also known as the Warburg effect—to produce energy even when oxygen is abundant.
This shift has multiple effects that help tumors evade cuproptosis:
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Reduced reliance on mitochondria
By using glycolysis instead of mitochondrial respiration, tumor cells decrease the number of lipoylated proteins that copper can bind to. This means fewer targets for cuproptosis to occur. -
Increased antioxidant defense
Tumor cells divert glucose into the pentose phosphate pathway (PPP), which produces NADPH, a molecule that regenerates glutathione (GSH). GSH binds to copper ions, keeping them from inducing toxic stress. As the authors explain, “GSH forming complexes enable ROS scavenging,” thereby neutralizing reactive oxygen species and copper toxicity. -
Blocking key enzymes
Tumors upregulate pyruvate dehydrogenase kinases (PDKs), which shut down the pyruvate dehydrogenase complex (PDH). This limits the TCA cycle’s activity and prevents the buildup of copper-sensitive, lipoylated enzymes such as DLAT.
Together, these adaptations create a biochemical shield that protects tumor cells from copper-induced death.
Genes That Drive or Block Cuproptosis
The review identifies two groups of genes that determine a cell’s sensitivity to copper stress.
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Cuproptosis-positive genes: FDX1, LIPT1, LIAS, DLD, DLAT, PDHA1, and PDHB. These genes participate in the mitochondrial TCA cycle and promote copper binding.
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Cuproptosis-negative genes: GLS, MTF1, and CDKN2A, which reduce copper sensitivity by maintaining redox balance and supporting glutathione production.
FDX1, in particular, acts as a central regulator. It converts Cu²⁺ to Cu⁺, enabling the fatal interaction with lipoylated proteins. “FDX1 serves as the upstream regulator of cuproptosis by promoting the lipoylation of DLAT,” the authors note. When tumors suppress FDX1 activity or reduce the availability of lipoylated targets, they effectively silence the cuproptosis pathway.
Copper’s Dual Role in Cancer
While copper triggers cell death in normal settings, it can also promote tumor growth under certain conditions. The review summarizes evidence that elevated serum copper levels are observed in patients with lung, liver, and colorectal cancers. Copper acts as a cofactor for enzymes involved in cell proliferation and angiogenesis and activates pathways such as HIF-1α and NF-κB, which enhance tumor survival and metastasis.
This dual role makes copper both a potential therapeutic target and a risk factor. Disrupting copper homeostasis could either inhibit tumor growth or, if mismanaged, promote it.
Therapeutic Opportunities: Turning Cuproptosis Back On
Song and colleagues highlight several potential strategies to restore cuproptosis in tumors:
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Inhibiting glycolysis or the PPP to reduce NADPH and glutathione production.
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Targeting PDKs to reactivate mitochondrial metabolism and increase the number of copper-sensitive proteins.
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Using copper ionophores, which transport copper into cells to exceed their detoxification capacity.
These ideas are still at the conceptual stage, but they open a new frontier in cancer therapy—one that combines metabolic intervention with metal-based cell death.
Outstanding Questions
Despite rapid progress, several unknowns remain. The authors identify three critical areas for future study:
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The exact relationship between Fe–S cluster loss and cell death.
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How FDX1 expression is controlled in different tissues.
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How the effects of cuproptosis vary under different metabolic conditions.
Addressing these questions will help researchers determine whether reactivating cuproptosis can be safely harnessed to treat cancer.
Key Takeaway
The review by Song et al. provides a compelling picture of how cancer cells reshape their metabolism to neutralize copper toxicity. By understanding and reversing these adaptations, scientists may one day use copper’s deadly potential against tumors themselves.
As the authors conclude, “dysregulation of copper homeostasis ultimately leads to cell death via a mechanism analogous to cuproptosis.” Rebalancing that homeostasis—by disrupting tumor metabolism—could mark a new step toward copper-based anticancer strategies.
The translation of the preceding English text in Chinese:
理解癌症代谢与铜死亡（Cuproptosis）之间的联系
癌细胞具有在压力下存活的惊人能力。它们的重要生存策略之一是代谢重编程——改变利用葡萄糖等营养物质的方式，以支持快速生长。一篇新的综述探讨了这种代谢转变如何帮助肿瘤逃避一种近期发现的细胞死亡形式：铜死亡（cuproptosis）。
铜死亡是一种依赖铜的细胞死亡机制，不同于更为人熟知的凋亡和铁死亡。其发生于过量铜与参与能量生成的特定线粒体蛋白相互作用时，尤其是那些被脂酰化（lipoylated）的蛋白——这种化学修饰对其功能至关重要。当铜与这些蛋白结合时，会导致蛋白聚集，破坏铁–硫（Fe–S）簇，并引发细胞内的毒性应激。
正如 Song 及其同事所说，“这种聚集会诱导蛋白毒性应激，并导致 Fe–S 簇蛋白的丢失”，最终触发细胞死亡。但事实证明，肿瘤细胞已经找到了绕开这一过程的方法。
肿瘤细胞如何抑制铜死亡
该综述详细说明了癌细胞如何通过重塑葡萄糖代谢来抑制铜毒性。通常，健康细胞通过线粒体内的氧化磷酸化产生能量。相反，癌细胞高度依赖有氧糖酵解——也称为瓦博格效应（Warburg effect）——即使在氧气充足的情况下也以此方式产能。
这种转变通过多种效应帮助肿瘤逃避铜死亡：
- 降低对线粒体的依赖
通过使用糖酵解而非线粒体呼吸，肿瘤细胞减少了可供铜结合的脂酰化蛋白数量，这意味着铜死亡可作用的靶点更少。 - 增强抗氧化防御
肿瘤细胞将葡萄糖分流进入磷酸戊糖途径（PPP），该途径产生 NADPH——一种可再生**谷胱甘肽（GSH）**的分子。GSH 可与铜离子结合，防止其诱发毒性应激。正如作者所解释，“GSH 形成的复合物能够清除 ROS”，从而中和活性氧和铜毒性。 - 阻断关键酶的作用
肿瘤会上调丙酮酸脱氢酶激酶（PDKs），这些激酶会关闭丙酮酸脱氢酶复合体（PDH）。这限制了 TCA 循环的活性，并阻止诸如 DLAT 等对铜敏感的脂酰化酶的积累。
这些适应性改变共同形成了一道生化屏障，使肿瘤细胞免受铜诱导的死亡。
驱动或阻断铜死亡的基因
该综述指出，有两类基因决定细胞对铜应激的敏感性。
- 铜死亡促进基因：FDX1、LIPT1、LIAS、DLD、DLAT、PDHA1 和 PDHB。这些基因参与线粒体 TCA 循环并促进铜结合。
- 铜死亡抑制基因：GLS、MTF1 和 CDKN2A，它们通过维持氧化还原平衡并支持谷胱甘肽生成来降低对铜的敏感性。
其中，FDX1 起到核心调控作用。它将 Cu²⁺ 还原为 Cu⁺，从而促成与脂酰化蛋白的致命相互作用。作者指出：“FDX1 通过促进 DLAT 的脂酰化而作为铜死亡的上游调控因子。”当肿瘤抑制 FDX1 活性或减少脂酰化靶点的可用性时，实际上就“关闭”了铜死亡通路。
铜在癌症中的双重作用
尽管在正常情况下铜可触发细胞死亡，但在某些条件下，它也可能促进肿瘤生长。该综述总结的证据显示，肺癌、肝癌和结直肠癌患者可观察到血清铜水平升高。铜作为多种参与细胞增殖和血管生成的酶的辅因子，并激活 HIF-1α 和 NF-κB 等通路，从而增强肿瘤生存与转移能力。
这种双重作用使铜既可能成为治疗靶点，也可能成为风险因素。扰乱铜稳态可能抑制肿瘤生长，但如果控制不当，也可能促进肿瘤。
治疗机会：重新“打开”铜死亡
Song 及其同事提出了几种在肿瘤中恢复铜死亡的潜在策略：
- 抑制糖酵解或 PPP，以降低 NADPH 和谷胱甘肽生成。
- 靶向 PDKs，重新激活线粒体代谢，并增加对铜敏感的蛋白数量。
- 使用铜离子载体（copper ionophores），将铜转运入细胞，使其超过解毒能力。
这些想法仍处于概念阶段，但它们为癌症治疗开辟了一个新方向——将代谢干预与金属介导的细胞死亡结合起来。
尚待解决的问题
尽管进展迅速，仍有若干未知问题。作者指出未来研究的三个关键方向：
- Fe–S 簇丢失与细胞死亡之间的确切关系。
- FDX1 表达在不同组织中如何被调控。
- 在不同代谢条件下，铜死亡效应如何变化。
解决这些问题将帮助研究者判断，是否能够安全地利用重新激活铜死亡来治疗癌症。
核心要点
Song 等人的综述描绘了癌细胞如何重塑代谢以中和铜毒性。通过理解并逆转这些适应性变化，科学家或许有一天能够将铜的致命潜力用于对抗肿瘤本身。
正如作者总结：“铜稳态失衡最终会通过一种类似铜死亡的机制导致细胞死亡。”通过干预肿瘤代谢来重新平衡这种稳态，可能成为铜基抗癌策略的新一步。
Reference:
Xiao-Hang Song, Yi-Hang Ding, Jing-Song Chen
Tumor glucose reprogramming suppresses cuproptosis: A review.
Biomol Biomed [Internet]. 2025 Aug. 6 [cited 2025 Dec. 12];26(2):251–261.
Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/12751
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