Copper is an indispensable trace element, serving as a cofactor for enzymes involved in respiration, antioxidant defense, and connective tissue formation. Yet when copper homeostasis collapses, the consequences for a cell can be fatal in a way that scientists only began to define in 2022. That year, Peter Tsvetkov and colleagues reported in Science that excess mitochondrial copper binds directly to lipoylated components of the tricarboxylic acid cycle, the enzymatic engine at the heart of mitochondrial metabolism. The resulting accumulation of lipoylated TCA cycle proteins triggers a distinctive form of proteotoxic stress that the authors named cuproptosis, setting it apart from apoptosis, necrosis, and other better-known death programs. Crucially, the process depends on the mitochondrial protein ferredoxin 1, or FDX1, which regulates protein lipoylation through its interaction with the lipoic acid synthase LIAS.

What makes this mechanism so intriguing for liver cancer is a biological paradox. Hepatocellular carcinoma cells frequently exhibit elevated copper metabolism, importing and distributing the metal aggressively to fuel their proliferative demands. But the same dependence appears to raise their vulnerability: when copper overload is pharmacologically forced into the mitochondria, these copper-hungry cells die disproportionately. Earlier work from Tsvetkov’s group had shown that highly lipoylated, mitochondria-rich tumors are especially sensitive to elesclomol, an investigational copper ionophore that ferries copper ions into the mitochondrial interior. Disulfiram, an old alcohol-aversion drug that acts as a copper ionophore, has shown similar copper-dependent toxicity against tumor cells in multiple preclinical models, and recent studies have linked DLAT, a lipoylated enzyme of the pyruvate dehydrogenase complex, to elesclomol sensitivity specifically in hepatocellular carcinoma.

The iron side of the equation is equally consequential. Ferroptosis, first described in 2012, is a form of regulated cell death driven by iron-dependent lipid peroxidation. When the antioxidant systems that normally reduce lipid hydroperoxides falter, particularly the glutathione–glutathione peroxidase 4, or GSH–GPX4, axis, polyunsaturated fatty acids in cellular membranes undergo a radical chain reaction that ruptures the lipid bilayer. The liver, as the body’s principal iron storage and metabolic organ, is exquisitely sensitive to this chemistry. Hepatocellular carcinoma cells, meanwhile, must constantly manage iron influx and oxidative stress to survive, and numerous studies have documented that manipulating iron availability, lipid composition, and antioxidant capacity can tip these cells into ferroptotic death.

The review pays particular attention to the regulatory networks that determine how sensitive a given hepatocellular carcinoma cell is to ferroptosis. Nuclear factor erythroid 2–related factor 2, or NRF2, a master transcriptional regulator of antioxidant responses, emerges as a central node. When NRF2 signaling is active, cells upregulate glutathione synthesis, iron efflux, and a battery of cytoprotective enzymes, effectively raising a shield against lipid peroxidation. FSP1, a ferroptosis suppressor protein that reduces coenzyme Q10 at the plasma membrane, provides a parallel rescue pathway that operates independently of glutathione. Both defenses can be subverted: work from Ren and colleagues showed that overcoming the compensatory elevation of NRF2 rendered hepatocellular carcinoma cells markedly more vulnerable to disulfiram/copper-induced ferroptosis, while other studies have demonstrated that blocking the cystine transporter xCT, which feeds glutathione synthesis, cooperates lethally with copper-driven stress.

It is at this intersection that the review’s central thesis emerges. Copper toxicity and ferroptosis are not isolated programs; they converge on shared metabolic vulnerabilities. Mitochondrial copper overload destabilizes iron-sulfur clusters, the ancient cofactors that support respiratory and repair enzymes, and this destabilization can itself sensitize cells to lipid peroxidation through iron regulatory proteins. More strikingly, glutathione sits at the crossroads of both pathways. The antioxidant tripeptide neutralizes copper-driven oxidative stress on one hand and fuels GPX4-mediated suppression of ferroptosis on the other. Experimental studies in primary liver cancer have shown that ferroptosis inducers enhance cuproptosis triggered by copper ionophores, and that disulfiram/copper treatment consumes glutathione in a way that launches what one team described as a cascade of ferroptosis and cuproptosis when xCT compensation is simultaneously blocked.

The therapeutic implications are substantial. Standard first-line drugs for advanced hepatocellular carcinoma, including sorafenib and lenvatinib, already exert part of their activity through ferroptosis-related mechanisms; lenvatinib, for example, has been shown to induce ferroptosis via fibroblast growth factor receptor-4 inhibition, while sorafenib sensitivity is modulated by metallothioneins and antioxidant pathways. Layering copper ionophores on top of these agents could push tumor cells past a metabolic tipping point that single-agent therapy never reaches. Nanotechnology is accelerating this vision: research groups have developed reactive oxygen species–responsive nanoparticles co-delivering elesclomol and copper together with anti–PD-L1 immunotherapy, as well as injectable hydrogel systems that combine cuproptosis induction with stemness inhibition to overcome lenvatinib resistance. A 2026 study in Antioxidants described a ROS-responsive nanoplatform that targets both cuproptosis and ferroptosis for synergistic therapy against hepatocellular carcinoma, illustrating how rapidly the dual-targeting concept is moving from theory toward experimental implementation.

The tumor microenvironment adds a further dimension of complexity, and opportunity. Both cuproptosis and ferroptosis are immunologically loud forms of cell death: dying cells release damage-associated molecular patterns and oxidized lipids that can stimulate antitumor immunity, and vaccination with early ferroptotic cancer cells has been shown to induce efficient antitumor immune responses. Multiomics and single-cell sequencing analyses have linked cuproptosis signatures to the immunosuppressive architecture of tumors, while ferroptotic tumor cells can enhance the efficacy of checkpoint inhibitors. Yet the picture is not uniformly favorable. Some work has found that disulfiram combined with copper stabilizes PD-L1 in hepatocellular carcinoma, potentially inducing immunosuppression, a reminder that metal-based therapies must be calibrated carefully if they are to synergize with, rather than undermine, immunotherapy. Macrophage polarization, exosome-mediated signaling, and the metabolic state of stromal cells all modulate how these death programs play out in vivo.

The review’s authors are candid about the limits of the current evidence. Direct clinical data demonstrating that pharmacological induction of cuproptosis, or coordinated cuproptosis–ferroptosis targeting, benefits patients with hepatocellular carcinoma are still lacking. Copper chelation trials, trientine-based antiangiogenic strategies, and disulfiram repurposing efforts have generated encouraging preclinical signals, but translating them into validated regimens will require careful attention to dosing, copper delivery, and patient selection. Biomarkers are an urgent need: serum copper, zinc, and metallothionein levels have been proposed as potential biomarkers for hepatocellular carcinoma, and gene-expression signatures built around FDX1, DLAT, ATP7A, and other cuproptosis-related genes are being explored for prognostic and predictive value. Determining which tumors are copper-vulnerable, which rely on NRF2 or FSP1 for ferroptosis resistance, and which harbor metabolic contexts that favor one death program over the other will be essential for rational combination therapy.

Even with these caveats, the synthesis marks a conceptual shift in how liver cancer might be treated. Rather than viewing copper and iron merely as nutrients that tumors consume, the field increasingly regards their homeostatic control as a pair of interlocking kill switches. Disrupting mitochondrial copper handling destabilizes the metabolic core of the cell; dismantling antioxidant defenses unleashes iron-catalyzed membrane destruction; and because glutathione and related systems guard against both threats simultaneously, a single well-designed intervention can pull two levers at once. With combination strategies already showing synergy in preclinical liver cancer models, and nanoparticle delivery platforms maturing quickly, the copper–iron crosstalk framework offers hepatocellular carcinoma research one of its most mechanistically grounded and therapeutically tantalizing frontiers in years.

Subject of Research: Cuproptosis and ferroptosis as coordinated therapeutic targets in hepatocellular carcinoma

Article Title: Harnessing copper-iron crosstalk: A novel strategy to combat hepatocellular carcinoma

Article References: Xie, X., Cao, H., Chen, H., Zhang, S., & Han, Z. (2026). Harnessing copper-iron crosstalk: A novel strategy to combat hepatocellular carcinoma. Medical Oncology, 43(10), Article 268. https://doi.org/10.1007/s12032-026-03399-z

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03399-z

Keywords: cuproptosis, ferroptosis, hepatocellular carcinoma, copper metabolism, iron metabolism, GPX4, NRF2, FDX1, disulfiram, elesclomol, glutathione, targeted therapy

Copper is required for the activity of several enzymes involved in energy production, antioxidant defense, connective-tissue formation and cellular signaling. The liver plays a central role in controlling the body’s copper balance, absorbing the metal from the diet, incorporating it into proteins and directing excess copper toward biliary excretion. This system depends on a network of transporters and binding proteins. Copper transporter 1, or CTR1, helps cells import copper, while ATP7A and ATP7B distribute it to intracellular destinations or remove it when levels rise. Ceruloplasmin carries much of the copper in the bloodstream, and additional chaperone proteins deliver the metal to specific enzymes. In healthy tissue, this carefully regulated traffic prevents copper from accumulating in its reactive, chemically dangerous form.

Cancer can disrupt that balance. Tumor cells often remodel nutrient uptake and energy production to sustain rapid proliferation, and copper appears to be part of this metabolic adaptation. The review highlights evidence that hepatocellular carcinoma may exploit the copper–MYC–CTR1 axis. MYC, a transcription factor frequently activated in cancer, can increase the expression of genes that support proliferation and metabolism, including pathways that influence copper uptake. Elevated CTR1 may consequently provide malignant cells with more copper, potentially supporting enzymes involved in mitochondrial respiration, antioxidant protection and signaling. At the same time, excessive or improperly localized copper can generate reactive oxygen species, damage proteins and membranes, and place severe pressure on the endoplasmic reticulum and mitochondria.

The most intriguing development is cuproptosis, a copper-dependent form of regulated cell death first described in 2022. Unlike apoptosis, which involves caspase activation and controlled cellular dismantling, cuproptosis is closely tied to mitochondrial metabolism and protein lipoylation. Lipoylation is a biochemical modification in which a lipoate group is attached to specific lysine residues on enzymes of the tricarboxylic acid cycle. These modified proteins are essential for processing nutrients and producing energy inside mitochondria. When copper enters susceptible cells in excessive amounts, it can bind directly or indirectly to lipoylated mitochondrial proteins, promoting their aggregation. At the same time, copper can destabilize iron–sulfur proteins, leading to proteotoxic stress and ultimately cell death.

This mechanism creates a possible distinction between tumor cells and normal cells. Many cancers depend heavily on mitochondrial respiration or retain active tricarboxylic acid-cycle pathways, making them potentially sensitive to copper-induced mitochondrial damage. The review discusses research showing that ARID1A-deficient hepatocellular carcinoma may be especially vulnerable when the TCA cycle is targeted through cuproptosis. ARID1A is a component of the chromatin-remodeling machinery, and its loss can alter gene expression, metabolism and stress responses. In experimental models, this genetic defect was associated with a metabolic weakness that could be exploited to produce synthetic lethality, a situation in which blocking one pathway is particularly destructive only when a second vulnerability is already present.

Copper’s effects in liver cancer are not limited to direct toxicity. The metal can influence angiogenesis, the process through which tumors build new blood vessels. Research cited in the review connects copper transport and copper-dependent signaling with vascular endothelial growth factor pathways, including VEGFR2 signaling. Because growing tumors require oxygen and nutrients, changes in copper availability may affect not only cancer-cell metabolism but also the surrounding blood-vessel network. Copper can also interact with inflammatory signaling, antioxidant systems and the tumor microenvironment. These effects may influence immune-cell behavior, stromal remodeling and the capacity of malignant cells to invade nearby tissue.

The therapeutic possibilities are therefore moving in two opposite directions. One strategy is to increase copper stress inside cancer cells. Copper ionophores such as elesclomol can transport copper across membranes and direct it toward mitochondria, while disulfiram, an established drug used to treat alcohol dependence, can form copper-containing complexes with potential anticancer activity. By increasing intracellular copper or changing its distribution, these agents may push metabolically vulnerable tumor cells toward cuproptosis. Nanoparticles and drug-delivery systems are also being investigated as ways to concentrate copper or copper-based compounds within tumors. Such approaches could theoretically improve selectivity, but their safety depends on controlling exposure in the liver, an organ that naturally handles copper and is already vulnerable in patients with cirrhosis or chronic hepatitis.

The opposite strategy is copper deprivation. Chelating agents can bind copper and reduce its availability to cancer cells, potentially suppressing copper-dependent growth, angiogenesis or epithelial–mesenchymal transition, a process associated with invasion and metastasis. This approach could also influence resistance to chemotherapy and radiotherapy. However, copper depletion is not automatically beneficial: normal tissues require copper for essential enzymes, immune function and blood formation. The challenge is to distinguish the copper requirements of a tumor from those of healthy organs. The review therefore presents copper metabolism as a precision-treatment target rather than a simple “more is harmful” or “less is better” system.

The connection between cuproptosis and other forms of regulated cell death may make combination therapy especially powerful. Copper-dependent mitochondrial injury can overlap with oxidative stress, ferroptosis and autophagy. Ferroptosis is driven by iron-dependent lipid peroxidation, whereas cuproptosis centers on copper, lipoylated mitochondrial proteins and proteotoxic stress, but the pathways can interact through glutathione, reactive oxygen species and nutrient metabolism. Studies cited by the authors suggest that disulfiram and copper may consume glutathione and cooperate with suppression of the xCT antioxidant pathway, creating a cascade involving both ferroptosis and cuproptosis. Other experimental work has explored combinations with chemotherapy, radiotherapy, immune-based treatment and engineered nanomaterials. These findings raise the possibility that copper manipulation could sensitize resistant tumors rather than act as a stand-alone therapy.

Yet the field remains far from routine clinical use. Much of the current evidence comes from cell cultures, animal models or retrospective analyses of gene-expression datasets. Cuproptosis-related signatures have been associated with prognosis, immune activity and treatment sensitivity in hepatocellular carcinoma, but a gene-expression pattern is not the same as proof that cuproptosis is occurring in an individual patient. Researchers still need reliable biomarkers showing copper distribution, mitochondrial lipoylation, protein aggregation and pathway activation in living tumors. They must also determine how hypoxia, a common feature of solid cancers, affects treatment response. Recent research indicates that HIF-1α can promote resistance to cuproptosis, suggesting that oxygen availability and metabolic adaptation may decide whether copper-based therapy succeeds. The review concludes that carefully designed clinical studies, improved delivery systems and patient selection will be essential. If those challenges can be solved, copper homeostasis may become more than a biochemical curiosity: it could provide a new route for attacking liver cancer through the very metabolism that allows it to grow.

Subject of Research: Copper homeostasis, cuproptosis, mitochondrial metabolism and therapeutic strategies in hepatocellular carcinoma

Article Title: Cuproptosis in hepatocellular carcinoma: bridging copper homeostasis with therapeutic horizons

Article References: Tsvetkov P, Coy S, Petrova B et al. “Copper induces cell death by targeting lipoylated TCA cycle proteins.” Science 375, 1254–1261 (2022). DOI: 10.1126/science.abf0529; Xing T, Li L, Chen Y et al. “Targeting the TCA cycle through cuproptosis confers synthetic lethality on ARID1A-deficient hepatocellular carcinoma.” Cell Reports Medicine 4, 101264 (2023). DOI: 10.1016/j.xcrm.2023.101264; Fan S, Wang A, Peng R et al. “Cuproptosis in hepatocellular carcinoma: bridging copper homeostasis with therapeutic horizons.” Molecular Biology Reports 53, 1412 (2026).

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12605-0

Keywords: Hepatocellular carcinoma, copper homeostasis, cuproptosis, copper metabolism, mitochondrial metabolism, oxidative stress, ferroptosis, cancer therapy, tumor microenvironment, precision oncology