Copper Dyshomeostasis, Redox Buffering and Immune Aging Converge on Cuproptosis in Age-Related Diseases

Copper is an essential trace element that has an important role as a cofactor for many metabolic enzymes, as well as the ability to become toxic at higher intracellular concentrations [1]. Copper is required for mitochondrial oxidative phosphorylation (OXPHOS) and energy metabolism because it serves as an essential cofactor for cytochrome-c oxidase (CcO) in the electron transport chain. In order to balance the need for copper and avoid toxicity, cells have developed complex regulatory processes. High-affinity copper transporter 1 (CTR1; SLC31A1) is a high-affinity importer of dietary copper. Once inside the cell, copper is delivered by copper chaperone proteins like antioxidant protein 1 (ATOX1) and cytochrome c oxidase copper chaperone (COX17) to distinct sites within the cell (e.g., delivery to mitochondria for enzyme metallation) [7]. At the same time, cellular chelators, including glutathione (GSH) and metallothioneins, sequester any excess free copper, while copper-exporting ATPases (ATP7A/B) export excess copper out of the cytosol [8]. These mechanisms coordinate to control the level of free copper within the cytosol and protect cellular function.

Dysregulations of copper homeostasis cause severe alterations in cellular metabolism and cell fate, both in cases of copper excess and deficiency. In response to copper overload, intracellular surplus copper triggers the formation of reactive oxygen species (ROS) and adaptive changes in copper trafficking, including deregulated uptake via CTR1 and adaptive redistribution/upregulation of ATP7A/B-mediated export, resulting in enhanced copper uptake and intracellular copper load and enhanced cuproptosis-related signaling [9]. Copper deficiency, usually as a result of defective uptake via CTR1, leads to the dysfunction of the mitochondrial electron transport chain (particularly CcO activity). The cell experiences a progressive energy crisis due to decreased ATP generation and the failure of the tricarboxylic acid (TCA) cycle flux.

Importantly, both copper excess and deficiency lead to cellular dysfunction, making cells more vulnerable to cell death and tissue damage.

Cuproptosis is a recently characterized copper-mediated regulated cell death (RCD) that is initiated and propagated by elevated levels of intracellular copper, originally reported by Tsvetkov et al. [10]. Unlike classical cell death modes such as apoptosis, necroptosis, pyroptosis, or ferroptosis, cuproptosis is uniquely activated by copper ions and proceeds via its own mechanism [11]. Crucial support for cuproptosis has emerged from experiments involving copper ionophores (e.g., elesclomol, disulfiram). The cell death observed with these compounds can be selectively prevented by copper chelators but not by apoptosis, ferroptosis, or other death pathway inhibitors, indicating a new mechanism [12]. For example, while apoptosis requires caspase-mediated DNA fragmentation, cuproptosis does not, and whereas ferroptosis depends on lipid peroxidation, cuproptosis does not. Other death pathway inhibitors have not reversed the phenotype under the experimental conditions used, yet copper chelation reduces toxicity (e.g., ammonium tetrathiomolybdate (TTM)), highlighting copper dependency [13]. Taken together, these data establish cuproptosis as a new RCD pathway featuring a copper-driven initiation and execution process.

Activation of cuproptosis requires perturbation of copper homeostasis and mitochondrial metabolism. Increased copper entry (via CTR1) but decreased exit (via ATP7A/B) leads to copper buildup inside cells, especially in mitochondria, setting the stage for cuproptosis. On the other hand, induction of ATP7A/B increases copper export, reducing intracellular copper levels and blocking cuproptosis [14]. Inside mitochondria, ferredoxin 1 (FDX1) reduces Cu²⁺ to Cu⁺, which can then bind to the lipoylated sites of several important TCA-cycle enzymes, mainly the E2 component (dihydrolipoamide S-acetyltransferase, DLAT) of the pyruvate dehydrogenase complex [15]. Importantly, this toxic interaction requires the lipoic acid modification of these enzymes, which is made by the lipoylation pathway (enzymes such as lipoic acid synthetase (LIAS) and lipoyltransferase 1 (LIPT1)) [16]. Lipoylated proteins bound by copper undergo abnormal oligomerization and aggregation to form insoluble protein aggregates, causing mitochondrial proteotoxic stress and impairing energy metabolism [11]. In parallel, excess copper also interferes with biogenesis and maintenance of mitochondrial iron–sulfur (Fe-S) cluster proteins (e.g., NUBP2, CIAPIN1, and ISCA2) [17]. Loss of these crucial cofactors incapacitates respiratory complexes and other Fe-S-containing metabolic enzymes, leading to defective electron transfer and ATP synthesis. Together, mitochondrial proteotoxic stress and Fe-S cluster depletion lead to dysfunction and the fatal collapse of mitochondrial structure and metabolism, leading to irreversible cuproptosis (Figure 1).

Notably, cuproptosis specifically takes place in cells with functional mitochondrial TCA-cycle activity and functional protein lipoylation machinery and is not a form of cell death mediated by ROS (e.g., ferroptosis) or GSH depletion-induced cell death [18]. Several factors influence cellular susceptibility to cuproptosis. Inducers of cuproptosis are FDX1, lipoylation enzymes (LIAS and LIPT1), and lipoylated TCA-cycle proteins (such as DLAT and PDHA1). On the other hand, inhibitors are copper exporters ATP7A/B and metal-responsive transcription factor metal–regulatory transcription factor 1 (MTF1) (which assists in copper sequestration and limiting copper availability) [17] (Table 1).

Aging can impair copper homeostasis across uptake, distribution, trafficking, and excretion, which may shift cells toward copper accumulation and increased susceptibility to cuproptosis. In fact, many aged tissues show abnormal copper redistribution and accumulation, such as increased free copper and ceruloplasmin in serum, and such dyshomeostasis correlates with inflammaging, a feature of aging [21]. At the same time, age-related mitochondrial dysfunction and antioxidant defense decline increase cellular vulnerability to copper-induced proteotoxic stress and cuproptosis [21]. Therefore, aged cells are more susceptible to copper-driven mitochondrial dysfunction and loss of metabolic resilience than young cells.

Similarly, excess copper accumulation in aged cells has been associated with increased ROS generation and aberrant protein aggregation. These changes may activate stress-response pathways (e.g., nuclear factor erythroid 2-related factor 2 (Nrf2) and p38 mitogen-activated protein kinase (MAPK)) [22], increasing cuproptosis risk and severity. Several aging pathways are likely to influence susceptibility, such as chronic oxidative stress, proteostasis dysregulation, mechanistic target of rapamycin (mTOR) signaling dysregulation, reductions in mitochondrial biogenesis, and altered regulation of metal-responsive factors like MTF1 [23]. Current data suggest that aging tissues may have a compromised ability to export copper, possibly through changes in ATP7A/B expression or function alongside reduced antioxidant defenses. This may lower the threshold for copper-triggered mitochondrial stress and increase cuproptosis susceptibility. The extent and universality of ATP7A/B downregulation during human aging requires validation using prospectively acquired age-stratified samples [23,24].

Intracellular antioxidants like GSH provide limited protection through chelation of labile copper and redox homeostasis and by potentially inhibiting lipoylated protein aggregation to delay cuproptosis onset [25,26]. Copper dyshomeostasis may also affect redox homeostasis. For instance, elevated copper levels may induce autophagic clearance of antioxidant enzymes, including glutathione peroxidase 4 (GPX4), an important enzyme that protects cells from lipid peroxidation [27,28]. This observation suggests a potential interplay between cuproptosis and ferroptosis, whereby simultaneous copper toxicity and lipid peroxidation could synergistically exacerbate tissue damage in aging.

Immunosenescence and inflammaging impact host defense and tissue homeostasis, increasing vulnerability to age-related diseases. Sustained low-grade inflammatory signaling has been linked to cardiovascular disease, metabolic disorders including type 2 diabetes, neurodegenerative diseases including Alzheimer’s disease, osteoporosis, sarcopenia, and cancer [40,44]. While the inflammatory response is limited, its duration on a timescale of years may lead to cumulative biological attrition and gradual loss of function across tissues [31].

In parallel, declines in both innate and adaptive immune function reduce protection against infection and weaken vaccine effectiveness and durability in older populations [45,46]. Immune aging also compromises tumor immunosurveillance through reduced cytotoxic activity and increased inhibitory signaling, creating a tumor-permissive environment and contributing to weaker responses to immunotherapy in older patients [47]. Across organ systems, chronic inflammatory signaling provides a permissive background for degenerative pathology, including atherosclerotic progression and neuroinflammatory trajectories [48]. Inflammaging is also associated with musculoskeletal decline and has been linked to chronic inflammatory and autoimmune conditions, including rheumatoid arthritis, osteoporosis, and sarcopenia [1].

Importantly, inflammatory consequences of the aged tissue microenvironment may intersect with intracellular copper handling, thereby influencing susceptibility to copper-dependent proteotoxic stress. Pro-inflammatory cytokines and NF-κB-linked programs are tightly coupled to cellular stress adaptation and metabolic rewiring in aging tissues, and this inflammatory milieu can coexist with shifts in copper handling that favor copper-dependent mitochondrial stress. In this context, copper accumulation may lower the threshold for mitochondrial proteotoxic injury that aligns with cuproptosis biology (Figure 2).

Although a direct, subset-resolved causal chain linking immunosenescence or inflammaging to copper transporter remodeling and altered cuproptosis sensitivity is still largely unavailable, a small number of recent functional studies provide direct anchors for key steps of this connection in DAMP-dominant innate immune contexts. In inflammatory macrophages, a mitochondria-associated reactive Cu(II) pool has been shown to sustain inflammatory metabolic and epigenetic programming, and disrupting this copper signaling axis suppresses inflammation in vivo, demonstrating that danger-associated inflammatory states can actively re-route intracellular copper rather than merely correlate with it [49]. Copper can also act as an intracellular signal that tunes innate immune sensing through ALPK1 kinase, placing copper regulation within pathways aligned with PRR and DAMP-linked danger responses [50]. Consistent with these direct links, in LPS-stimulated macrophages and an in vivo inflammatory model, copper chelation attenuates inflammation while shifting expression of key copper transport genes, including ATP7A and CTR1, together with cuproptosis-associated molecular readouts, supporting the idea that inflammatory activation can be coupled to transporter remodeling and a shifted threshold for copper-dependent mitochondrial stress that is compatible with cuproptosis sensitivity [51]. Taken together, these findings suggest a plausible intersection between immunosenescence, inflammaging, and copper transporter remodeling that could influence cuproptosis sensitivity in certain immune subsets. But the specific regulatory mechanism still needs further in-depth analysis in the future.

Neurodegenerative diseases emerge from a convergence of neuronal metabolic vulnerability and age-dependent failure of immune-mediated tissue maintenance. In the aging central nervous system, barrier dysfunction and altered glial homeostasis can change regional copper distribution, while chronic microglial activation sustains a cytokine-rich environment that perturbs redox buffering and mitochondrial quality control. Within neurons, cuproptosis may be engaged when copper accumulates in mitochondria that retain an active TCA cycle and a lipoylation-competent protein network. Under these conditions, mitochondrial copper stress may contribute to neuronal metabolic failure and loss of viability [52]. Age-related immune changes can amplify this primary insult. Inefficient clearance of damaged neurites and dying cells allows damage-associated molecular patterns to persist, reinforcing microglial priming and sustaining a feed-forward loop between cell death and neuroinflammation [53].

Multiple neurodegenerative phenotypes intersect with copper-dependent proteostasis and mitochondrial stress. In Alzheimer’s-related pathology, copper can interact with amyloid beta and tau species and may influence aggregation and synaptic toxicity, while parallel mitochondrial impairment can increase cuproptosis susceptibility [54,55]. In Parkinson’s-related pathology, copper imbalance co-occurs with alpha synuclein misfolding and mitochondrial dysfunction, consistent with a model in which copper-driven stress promotes both proteopathic spread and neuronal loss [56]. In amyotrophic lateral sclerosis, altered copper handling, including pathways linked to SOD1 biology, can contribute to motor neuron injury, and copper-targeted interventions have been investigated as neuroprotective approaches in experimental settings [57]. Beyond chronic neurodegeneration, acute ischemic injury can also create local copper dysregulation and mitochondrial damage that may engage cuproptosis-related mechanisms, linking copper burden to secondary inflammatory injury after stroke [52,58].

Cardiovascular aging is characterized by progressive mitochondrial stress, altered redox signaling, endothelial dysfunction, and a chronic inflammatory tone that may reshape copper handling and cuproptosis sensitivity [59]. Copper is indispensable for multiple cardiac enzymes, yet aging can shift copper toward a more reactive pool through changes in transport, binding, and compartmentalization. When labile copper increases within cardiomyocyte or vascular-cell mitochondria, copper stress can impair respiratory capacity and promote cell injury, thereby contributing to age-associated remodeling. Age-associated myeloid bias and inflammasome activation can amplify tissue damage and impair repair, while dying cells provide signals that further recruit inflammatory leukocytes, sustaining maladaptive remodeling [60].

In atherosclerosis, plaque progression depends on endothelial injury, lipid accumulation, and inflammatory immune cell activity. Copper accumulation within lesions can intensify oxidative modification of lipids and proteins and may increase the susceptibility of plaque resident endothelial cells, macrophages, and smooth muscle cells to copper-dependent mitochondrial injury. Cell death within plaques can release proinflammatory mediators and debris that are incompletely cleared in aging, thereby amplifying inflammatory circuits and destabilizing lesions [60]. The idea that copper modulation could impact lesion biology has been demonstrated experimentally and warrants exploration of copper chelation as an adjunctive approach in atherosclerotic disease [61].

Copper, mitochondria, and immunity also come together in the setting of myocardial ischemia and reperfusion injury. Ischemia reprograms cardiac metabolism, reperfusion produces abrupt oxidative stress, and local copper redistribution can accompany this transition. Mitochondrial injury can, therefore, engage copper-sensitive proteotoxic pathways and promote cardiomyocyte death, while the ensuing sterile inflammation influences infarct expansion and remodeling [62]. Changes in cardiac copper transporters during injury suggest that copper trafficking is dynamically regulated under stress, and copper-targeted interventions have been evaluated for their ability to attenuate inflammation and preserve function in experimental and clinical settings [63].

In heart failure and metabolic cardiomyopathies, chronic metabolic stress can maintain a background of mitochondrial dysfunction and inflammation that increases vulnerability to copper-dependent injury. In these settings, altered expression of cuproptosis-related genes and copper transport machinery has been associated with disease progression, supporting the need for mechanistically informed biomarkers to identify patients most likely to benefit from copper modulation [64,65].

Metabolic diseases of aging, including obesity, type 2 diabetes, and fatty liver disease, are shaped by tissue-specific copper imbalances, mitochondrial dysfunction, and chronic inflammation. Such conditions provide a metabolic environment whereby cuproptosis susceptibility may rise in hepatocytes, adipocytes, beta cells, and cardiometabolic tissues via cumulative copper stress and mitochondrial susceptibility [66]. Insulin resistance and high-fat feeding may impact intestinal uptake, liver sequestration, and redistribution, causing copper insufficiency in certain compartments and copper excess in other compartments [67,68].

Mitochondrial dysfunction caused by inflammatory macrophage infiltration and oxidative stress in obesity and fatty liver disease may create a situation where any remaining TCA capacity is more heavily relied upon, which may render cells more vulnerable to copper-induced proteotoxic stress in mitochondria. Cuproptosis-related genes’ transcriptomic signatures have been linked to fatty liver phenotypes, suggesting that mitochondrial stress mediated by copper may play a role in disease progression in predisposed patients [69].

In type 2 diabetes, chronic hyperglycemia, ROS, and advanced glycation products can damage mitochondria and alter protein modification pathways, potentially sensitizing pancreatic beta cells to copper-dependent injury. Concurrent immune dysregulation, including persistent low-grade cytokine signaling, can further impair beta cell survival and systemic metabolic control [70,71].

In metabolic-associated steatotic liver disease, copper dyshomeostasis is often better understood as compartmental remodeling rather than a uniform increase or decrease. Shifts in copper trafficking and buffering may lower the threshold for mitochondria-centered proteotoxic stress, especially when hepatocytes face sustained lipotoxic and inflammatory pressure and have limited respiratory reserve [72]. Under these conditions, copper-linked stress could be more likely to destabilize mitochondrial metabolism, consistent with observations that cuproptosis-related genes track with steatosis-associated features and markers of more advanced disease.

Cuproptosis-associated states may also extend beyond classic liver–adipose axes into metabolic–endocrine and cardiorenal complications. In polycystic ovary syndrome, reported cuproptosis-related signatures coincide with the enrichment of lipid-handling and atherosclerosis-relevant pathways, suggesting a plausible connection between copper-linked mitochondrial vulnerability and cardiometabolic risk features [73]. In diabetic kidney disease, cross-program comparisons do not consistently position cuproptosis as the dominant global cell death route, yet single-cell analyses indicate that cuproptosis activity can be concentrated in specific epithelial subtypes, highlighting cell-type-restricted vulnerability that may be obscured in bulk tissue assessments [74]. Together, these observations support a context-dependent model in which copper distribution, mitochondrial metabolic reliance, and inflammatory tone jointly determine whether cuproptosis functions as a peripheral signal or a pathogenic amplifier across metabolic disease tissues.

Musculoskeletal diseases of aging, including osteoarthritis and osteoporosis, are the consequence of accumulated mechanical strain, cellular senescence, mitochondrial dysfunction, and an inflammatory-biased joint/bone immune environment. In this setting, aberrant copper metabolism may promote mitochondrial stress and cell death in chondrocytes and osteoblast lineage cells through cuproptosis-linked processes and may contribute to tissue breakdown [75,76].

Synovial inflammation and oxidative stress in osteoarthritis may modify copper transporter expression in cartilage cells, leading to elevated intracellular labile copper and sensitization of mitochondria to copper-induced proteotoxic stress. Synovial macrophages and other immune cells influence cytokine exposure and debris removal, and aging decreases the effectiveness of resolution, leading to extended inflammatory tissue damage and death signaling [77,78].

The aging process causes a disruption in bone homeostasis due to an increase in inflammatory cytokine signaling, coupled with a reduction in anabolic signals that would otherwise synchronize osteoblast and osteoclast function. Both copper dyshomeostasis and cytokines of immune origin can compromise osteoblast mitochondrial health and matrix synthesis, as well as stimulate osteoclastogenesis [79].

Inherited disorders of copper handling are useful to include here because the direction of copper misdistribution is genetically fixed, which makes copper-linked mitochondrial vulnerability easier to interpret than in multifactorial age-related diseases. Menkes disease is an X-linked condition caused by ATP7A loss-of-function [80]. Defective copper export and systemic distribution lead to profound copper deficiency with markedly reduced copper delivery to the brain. A consistent downstream consequence is impaired mitochondrial respiration, including reduced CcO function and limited respiratory capacity, illustrating how copper scarcity can cap bioenergetic output in highly dependent tissues [81] (Table 2). CTR1 deficiency provides a complementary example from the import side. Loss of CTR1, the major copper importer, produces severe intracellular copper depletion, rapid neurodevelopmental deterioration, and cellular evidence of mitochondrial dysfunction, reinforcing that adequate copper entry is a prerequisite for maintaining mitochondrial metabolism [6].

Copper-overload disorders sit at the opposite extreme and connect more directly to cuproptosis-relevant toxicity. In Wilson’s disease, ATP7B dysfunction impairs biliary copper excretion and drives progressive hepatic copper accumulation [82]. Sustained excess can focus stress on mitochondria and, in overload states, is consistent with the cuproptosis framework, in which copper interacts with lipoylated mitochondrial enzymes and perturbs Fe-S biology. MEDNIK syndrome (AP1S1) disrupts ATP7A/B trafficking and can be associated with hepatic copper accumulation, although direct evidence that cuproptosis is a primary driver remains limited [81].

Geriatric oncology is characterized not only through tumor-intrinsic changes but also by an aged host environment with immunosenescence, inflammaging, and disturbed metal metabolism. Many tumors show increased dependence on copper-related pathways that support proliferation, angiogenesis, and redox buffering, while aging can impair systemic copper regulation and shift copper toward a more bioactive pool [83]. These host and tumor features are consistent with heightened susceptibility to copper stress and may limit the efficiency with which tumor cell death is converted into durable antitumor immunity, but direct validation in geriatric cancer models remains limited [84].

At the tumor cell level, altered expression of copper import and export machinery can increase intracellular copper availability. When combined with high mitochondrial metabolic activity, this configuration may lower the threshold for cuproptosis. However, the immune context of the aged tumor microenvironment is often suppressive. Presentation of antigens may be less efficient, effector T cell activation may be diminished, and exhausted or regulatory phenotypes may prevail. As a consequence, tumor cell death may not reliably translate into sustained immune control in older hosts, even when immunogenic programs are engaged in principle [28,85].

In organ-specific discussions of cuproptosis, because aging tissues share broad stress programs, the most direct organ-adapted route is currently in the liver. The hepatic copper can be quantified in biopsy-based cohorts and linked to disease severity or progression in steatotic liver disease [86]. In cardiovascular disease, circulating copper phenotypes (e.g., serum copper) are supported by systematic evidence relating higher levels to myocardial infarction, stroke, and cardiovascular mortality, providing a practical validation layer beyond expression-only analyses [87]. In the kidney, DKD can move beyond transcriptomic inference by incorporating clinically tractable urinary biomarkers, including urinary ceruloplasmin within multi-marker panels, which can be integrated with renal tissue analyses and age stratification [88]. By contrast, in the brain, Alzheimer’s-related associations remain largely transcriptome-driven and are better strengthened by copper phenotyping, which enables patient stratification (including non-ceruloplasmin copper), and by proteomic/multi-omics anchoring [89]. Endocrine–metabolic contexts can similarly reduce reliance on expression-only inference by combining copper phenotyping with metabolic readouts across diabetes-related trajectories [90]. In reproductive disease, meta-analytic evidence supports altered circulating copper in PCOS, offering an accessible but still indirect layer that requires tissue-level validation in age-relevant models [91]. In musculoskeletal disorders such as osteoarthritis, trace-element meta-analyses combined with Mendelian randomization provide stronger support than transcriptomics alone, although execution-level confirmation in aged tissues remains necessary [92,93]. Accordingly, each organ section is stratified into direct versus indirect evidence to avoid overinterpreting shared aging stress programs as cuproptosis.

No new data were created or analyzed in this study. Data sharing is not applicable to this article.