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

Glioblastomas and related malignant gliomas represent the predominant form of primary brain tumors in the United States, constituting approximately 78% of all malignant brain tumors. Despite their relative rarity, these tumors are notorious for their lethality, with a survival outlook that remains grim. Conventional therapies continue to grapple with the tumor’s aggressive growth and invasive nature, underscoring the urgent need for novel molecular targets to disrupt the cancer’s distinct biological mechanisms.

Central to this new research initiative is the gene MBLAC1, a relatively obscure gene until now, which plays a pivotal role in maintaining intracellular copper homeostasis. Copper, a vital transition metal, is critical for mitochondrial function and oxidative stress regulation within cells—processes intimately linked to cancer cell metabolism and survival. By focusing on how MBLAC1 mediates these processes, FAU researchers hope to expose vulnerabilities within glioblastoma cells that depend heavily on mitochondrial energy production and oxidative stress management to sustain their unchecked growth.

The mechanistic underpinnings of MBLAC1’s function are examined through sophisticated methodologies, including the use of 3D tumor models that faithfully recapitulate the tumor microenvironment, and genetically engineered murine models, with some lacking this target gene altogether. This experimental design enables researchers to unravel how the absence or inhibition of MBLAC1 gene function impacts tumor invasion dynamics and copper regulation, potentially hindering tumor progression at the molecular and cellular levels.

The research team is led by Dr. Randy D. Blakely, a distinguished neuroscientist known for his contributions to brain energy and stress regulation studies, and Dr. Gregg B. Fields, an expert in cancer biology and institutional research leadership. Their complementary expertise bridges the traditionally separate fields of neuroscience and oncology, fostering a novel vantage point on how modulating metal ion homeostasis within neural cells can influence tumor physiology.

Dr. Blakely emphasizes the gene’s role in regulating copper balances within brain cells, noting that copper acts as a critical micronutrient involved in cellular respiration and antioxidant defenses. Glioblastoma cells exploit these pathways extensively, making MBLAC1 a tantalizing candidate for therapeutic intervention. Disrupting copper regulation through targeted inhibition of MBLAC1 could, therefore, starve these cells of key metabolic support, potentially arresting their aggressive proliferation and invasive behavior.

Simultaneously, Dr. Fields highlights the translational potential of this research, aiming to identify pharmacological agents capable of blocking MBLAC1 activity. This drug discovery angle is facilitated by the development of sensitive assays that screen compound libraries for molecules that selectively impair MBLAC1’s function. Success in this domain could pave the way for a new class of anti-glioblastoma drugs that operate through a hitherto unexplored biological axis involving copper metabolism.

Further compounding the project’s novelty is the consideration of tumor microenvironmental contributions to glioblastoma progression. The team is investigating whether MBLAC1 expression in non-cancerous support cells within the brain influences tumor growth and invasiveness. This dimension acknowledges the complex interplay between malignant cells and surrounding glial and neuronal cells, which collectively orchestrate the tumor milieu.

An integral collaborator on the project is Dr. Ania Knapinska, whose cancer biology expertise complements the neuroscience focus with molecular insights into how MBLAC1 mutations compromise mitochondrial efficiency and exacerbate oxidative stress. These deleterious effects can fuel tumor aggressiveness by disturbing cellular energy equilibrium and promoting genetic instability, both hallmarks of malignant transformation.

The targeted inhibition of MBLAC1 stands not only to impair cancer cells’ bioenergetic and antioxidant defenses but also to disturb copper-dependent signaling pathways that may be crucial for tumor survival and dissemination. Given copper’s role as a cofactor in several enzymatic systems, including those modulating angiogenesis and immune evasion, its precise control within the tumor microenvironment represents an intriguing therapeutic leverage point.

This multidisciplinary project exemplifies how amalgamating divergent scientific perspectives can catalyze breakthroughs in challenging diseases like glioblastoma. By integrating neuroscience’s focus on cellular metabolism and metal ion regulation with cancer biology’s molecular targeting strategies, the researchers at FAU are charting a path toward innovative interventions that could transcend current treatment limitations.

In summary, this pioneering research into MBLAC1 offers a compelling new paradigm that links elemental biochemistry with tumor biology. The ongoing studies promise to elucidate fundamental mechanisms of glioblastoma invasion and survival, while concurrently opening avenues for drug discovery aimed at crippling the tumor’s metabolic foundation. Such advancements hold the potential not only to extend patient survival but also to enhance quality of life by introducing more effective, less toxic treatment modalities.

With glioblastoma’s notorious resistance to conventional treatments, the focus on copper metabolism and mitochondrial function mediated by MBLAC1 represents a bold and scientifically adventurous leap. Continued support and validation of these findings could ultimately revolutionize the therapeutic landscape for aggressive brain cancers and inspire a wave of research that harnesses elemental biology for clinical gain.

Subject of Research: Investigating the role of the MBLAC1 gene in copper regulation and glioblastoma progression.

Article Title: Florida Atlantic University Scientists Target Novel Gene to Disrupt Glioblastoma Growth and Survival

News Publication Date: [Not provided in the source content]

Web References:

• https://www.fau.edu/
• https://www.fau.edu/brain/randy-blakely/
• https://www.fau.edu/research/vpr/gregg-fields-bio/
• https://www.fau.edu/i-health/

Image Credits: Alex Dolce, Florida Atlantic University

Keywords: Glioblastomas, Brain cancer, Neuroscience, Glia, Cellular neuroscience, Genes, Oxidative stress, Copper, Drug discovery, Biochemistry, Molecular biology