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Microbes & Immunity Copper and cuproptosis in immunity

encompassing liver problems such as hepatitis, cirrhosis, 4. The role of copper and cuproptosis in
and liver failure; neurological issues such as movement Mycobacterium tuberculosis and their
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disorders, cognitive impairments, and behavioral changes; broader implications
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and ocular manifestations, notably the Kayser–Fleischer ring
– a green or brown deposit at the corneal edge. Additional Copper plays a crucial role in cellular function, but its
complications associated with Wilson’s disease include dysregulation can lead to toxicological effects, particularly
kidney injury, anemia, and joint pain. 29 in the context of infections such as M. tuberculosis.
The mechanisms underlying copper-induced cell
Menkes disease is a rare X-linked genetic disorder
primarily caused by mutations in the ATP7A gene, death primarily involve oxidative stress, mitochondrial
50
damage, and inflammatory responses. A comprehensive
causing disruption to the absorption and transport of understanding of these processes is essential, especially in
copper in the body. This leads to a cellular deficiency the context of developing therapeutic strategies targeting
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of copper, with symptoms often appearing within a few copper metabolism disorders, such as Wilson’s disease,
months of birth. Affected individuals may experience which is characterized by excessive copper accumulation in
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growth retardation, neurological issues such as mental the body. Within the copper-related network, several key
retardation, seizures, and poor motor coordination, as well genes significantly influence cellular responses to varying
as distinct hair abnormalities characterized by thinning copper levels. Genes such as ATP7A and ATP7B are pivotal
and copper coloration. Additional complications may for maintaining copper homeostasis, they facilitate copper
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include abnormal bone development and low immune transport and excretion, thereby preventing toxicity.
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function. 33,34 Menkes disease is diagnosed by a combination In addition to these transport mechanisms, antioxidant
of clinical evaluation, biochemical tests for measuring genes such as superoxide dismutase 1 and glutathione
blood levels of copper and related proteins (such as peroxidase are critical in mitigating oxidative stress
ceruloplasmin), and genetic testing to confirm ATP7A associated with elevated copper levels. 51,52 The regulation
mutations. Current treatment strategies mainly involve of cell fate in response to copper stress is also governed
35
copper supplementation, particularly with copper-amino by apoptosis-related genes. For instance, genes such as
acid complexes, alongside symptomatic management to Bcl-2 and Bax play vital roles in the apoptotic pathways
address neurological symptoms, though the effectiveness that determine whether a cell survives or undergoes
of these interventions is limited. 36
programmed cell death under conditions of copper-
In addition to Wilson’s disease and Menkes disease, induced stress. In addition, inflammatory-related genes
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abnormal copper metabolism can be linked to other involved in the nuclear factor kappa B signaling pathway
conditions. Copper deficiency may arise from malnutrition further complicate the interplay between cell survival and
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or absorption disorders, such as Crohn’s disease, and can death in environments rich in copper. The activation of
manifest as anemia, immune dysfunction, and osteoporosis. this pathway is often linked to the inflammatory response
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Conversely, while relatively rare, copper overload can occur associated with infection and stress, influencing the
due to certain liver and kidney diseases or prolonged use of overall cellular outcome. Recent research has shed light
specific medications, such as oral contraceptives, leading to on the protective role of the cuproptosis regulatory factor
copper accumulation and potential toxicity. 38 ferredoxin 1 (FDX1) in clear cell renal cell carcinoma. The
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Table 1. Cuproptosis‑related immune markers for the diagnosis and treatment of diseases

Disease Copper‑related immune markers References
Wilson’s disease Plasma ceruloplasmin, non-ceruloplasmin-bound copper 26,39
Menkes disease Activity and expression level of copper transporter ATP7A 40
Rheumatoid arthritis, etc. Serum copper level, copper/zinc ratio 41
Breast cancer, lung cancer, etc. Copper content in tumor tissue and serum ceruloplasmin level 42,43
Primary biliary cholangitis Serum copper, ceruloplasmin 44
Alzheimer’s disease Urinary copper excretion and hepatic copper content 45
Amyotrophic lateral sclerosis Copper content in the brain and copper concentration in cerebrospinal fluid 46
Multiple sclerosis Ceruloplasmin fragments of cerebrospinal fluid 47
Hemochromatosis Copper/iron ratio 48
Inflammatory bowel disease Intestinal mucosal copper content, serum copper-related protein 49

Volume 2 Issue 1 (2025) 61 doi: 10.36922/mi.5657