Copper homeostasis and cuproptosis in health and disease

Abstract

Copper is a vital trace element in human physiology, essential for the synthesis of numerous crucial metabolic enzymes and facilitation of various biological processes. Regulation of copper levels within a narrow range is imperative for maintaining metabolic homeostasis. Numerous studies have demonstrated the significant roles of copper homeostasis and cuproptosis in health and disease pathogenesis. However, a comprehensive and up-to-date systematic review in this domain remains absent. This review aims to consolidate recent advancements in understanding the roles of cuproptosis and copper homeostasis in health and disease, focusing on the underlying mechanisms and potential therapeutic interventions. Dysregulation of copper homeostasis, manifesting as either copper excess or deficiency, is implicated in the etiology of various diseases. Cuproptosis, a recently identified form of cell death, is characterized by intracellular copper overload. This phenomenon mediates a diverse array of evolutionary processes in organisms, spanning from health to disease, and is implicated in genetic disorders, liver diseases, neurodegenerative disorders, and various cancers. This review provides a comprehensive summary of the pathogenic mechanisms underlying cuproptosis and copper homeostasis, along with associated targeted therapeutic agents. Furthermore, it explores future research directions with the potential to yield significant advancements in disease treatment, health management, and disease prevention.

Keywords: cancer; cardiovascular disease; copper homeostasis; cuproptosis; hereditary disease; liver disease; neurodegenerative disease.

FIGURE 1

Copper homeostasis and cuproptosis in cancer. In colorectal cancer (CRC), copper‐related complexes have been shown to impede tumor cell proliferation by inhibiting the NF‐κB pathway in colorectal cancer cell lines. Additionally, ferredoxin 1 (FDX1) has been found to hinder the growth and advancement of CRC by suppressing epithelial–mesenchymal transition (EMT). Furthermore, JYFY‐001 has been demonstrated to enhance the antitumor effects of programmed cell death protein 1 (PD‐1) inhibitors. Moreover, 4‐octyl itaconate inhibits aerobic glycolysis by specifically targeting glyceraldehyde‐3‐phosphate dehydrogenase, thereby facilitating cuproptosis. Knockdown of tigger transposable element derived 1 (TIGD1) has been observed to potentially enhance cuproptosis in CRC cells. In breast cancer, a platelet vesicle (PV)‐coated cuprous oxide nanoparticle (Cu₂O)/TBP‐2 cuproptosis sensitization system (PTC) has been shown to inhibit metastasis by targeting and inducing cuproptosis. Additionally, knockdown of DLAT has been found to increase breast cancer sensitivity to trastuzumab. Zinc pyrithione hinders the advancement of triple‐negative breast cancer by stimulating the oligomerization of dihydrolipoamide S‐acetyltransferase. In the context of lung cancer, thiotetramide has the potential to counteract the increased expression of BarH‐like homeobox 1 (BARX1), GDNF family receptor alpha 3 (GFRA3), and KH domain containing RNA binding, signal transduction associated 2 (KHDRBS2). Elevated levels of copper in vivo lead to cuproptosis, a process that is intensified by SDT resulting in proteotoxicity, which leads to the destruction of immunogenic cells and the suppression of tumor metastasis. Thiosemicarbonyl mixed‐valent copper(II) complexes have the ability to eliminate lung cancer cells by activating various pathways, including cuproptosis enzymes. In pancreatic cancer, the inhibition of cancer susceptibility candidate 8 (CASC8) impacts the proliferation of pancreatic cancer cells. The Cu(I) nanoparticles induce the aggregation of dihydrolipoamide S‐acetyltransferase (DLAT), resulting in cuproptosis, while also enhancing immune responses and suppressing tumor growth. Copper nanodrug dopamine and hydroxyethyl starch‐stabilized copper diethyldithiocarbamate nanoparticles (CuET@PH NPs) effectively suppress energy metabolism in pancreatic ductal adenocarcinoma stem cells under hyperbaric oxygen conditions. Knockdown of the cuproptosis‐associated long noncoding RNA LINC00853 inhibits glycolysis and enhances cellular mitochondrial respiration by reducing the expression of the glycolytic enzyme glycolytic kinase 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3).

FIGURE 2

Copper homeostasis and cuproptosis in neurodegenerative disease. In Alzheimer's disease (AD), disruption of metal ion homeostasis contributes to the accumulation of β‐amyloid (Aβ) and tau proteins. The interaction between the copper‐binding domain of amyloid precursor protein (APP) and specific amino acid residues of Aβ may play a role in the pathogenesis of AD. Treatment with the copper chelator clioquinol has been shown to decrease levels of Tau protein and growth‐associated protein. In amyotrophic lateral sclerosis (ALS), treatment with tetrathiomolybdate ammonium (TTM) has been found to reduce the formation of superoxide dismutase (SOD1) aggregates and mitigate the loss of motor neurons. Administering trientine prior to disease onset significantly extends the lifespan of ALS mice. In Huntington's disease (HD), d‐penicillamine (DPA) has been shown to decrease the aggregation of β‐amyloid in a drosophila model of HD. Copper has been found to enhance the formation of thioflavin S‐positive β‐amyloid structures within the huntingtin (HTT) protein aggregates and to activate the antioxidant defense system. Prolonged exposure to copper, zinc, and their combinations has been shown to lead to the inhibition and aggregation of polyglutamine (polyQ) in both muscle and neuronal tissues.

FIGURE 3

Copper homeostasis and cuproptosis in hepatocellular carcinoma. Copper‐related genes (CRGs) influence immune cell infiltration. Maternal embryonic leucine zipper kinase (MELK) stabilizes mitochondrial function by activating PI3K/mTOR signaling. Decreased ferredoxin 1 (FDX1) level raises cuproptosis‐related risk score, and sorafenib suppresses the score. Curcumin downregulates cuproptosis potential index. Knockdown of pyridoxal kinase (PDXK) inhibits proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells. Studies have encapsulated Cu and ES with ROS‐sensitive polymers, which induces cuproptosis and activates immune response.

FIGURE 4

Copper homeostasis and cuproptosis in NAFLD. NFE2 like bZIP transcription factor 2 (NFE2L2) and dihydrolipoamide dehydrogenase (DLD) modulate disease progression through the regulation of reactive oxygen species (ROS) levels. Copper overload influences lipid accumulation, while elevated serum copper levels and ferredoxin 1 (FDX1) promote the transition from nonalcoholic fatty liver disease to hepatocellular carcinoma.

FIGURE 5

Copper homeostasis and cuproptosis in hereditary diseases. In Wilson disease, the deficiency of the adaptor protein (AP‐1) hinders the activity of ATPase beta peptide (ATP7B), leading to the accumulation of copper in the liver. Both DMP‐1001 and trientine are effective in reducing copper levels. In Menkes disease, the transport of copper to mitochondria, facilitated by the small molecule elesclomol (ES), enhances the expression of cytochrome c oxidase in the brain. The reduction of ES‐Cu(II) to Cu(I) by ferredoxin 1 (FDX1) catalyzes the metallation of the copper enzyme cytochrome c oxidase (COX) within the mitochondria.

FIGURE 6

Copper homeostasis and cuproptosis in cardiovascular disease. Cuproptosis enhances the accumulation of reactive oxygen species (ROS) in the myocardium. Treatment with a copper chelator has been shown to repair rat myocardial mitochondria and enhance the function of proliferator‐activated receptor γ coactivator factor‐1 α, ultimately restoring cardiac pumping function. Additionally, trientine has been found to improve cardiac pump function.