The molecular mechanism of cuproptosis and research progress in pancreatic diseases.

Introduction
The pancreas is an organ located behind the peritoneum in the human body, with exocrine and endocrine parts. The pancreas plays an important role in digesting food and regulating blood sugar by secreting pancreatic juice and insulin and is an important organ of the digestive system [1]. In recent years, the incidence of pancreatic diseases has been on the rise all over the world. There are more and more reports of pancreatic diseases such as pancreatic cancer, acute pancreatitis (AP), chronic pancreatitis (CP), diabetes, pancreatic cysts, and pancreatic injuries. Pancreatic diseases are gradually being taken seriously [2,3]. Exploring the key genes, signaling pathways, and immune responses involved in the occurrence and development of pancreatic diseases may provide a better understanding of early detection, development, treatment, and prognosis evaluation of pancreatic diseases, and offer new avenues for their treatment and intervention.
The main modes of cell death are regulated cell death (RCD) and accidental cell death (ACD) [4,5]. RCD is a mode of death that can be intervened through genetic or pharmacological means due to changes in the intracellular and extracellular microenvironment caused by various reasons, as well as alterations in multiple signaling pathways [6]. RCD mainly includes apoptosis, pyroptosis, necrosis, autophagy, ferroptosis, and cuprptosis [7,8]. ACD is a rapid and uncontrollable mode of cell death caused by severe mechanical, chemical, or physical stimuli, leading to lipid membrane separation in cells [9]. Cuproptosis is a novel regulatory cell death mechanism identified in 2022 [10], which induces cell death by binding copper ions to TCA cycle acylated proteins. The latest research confirms that cuproptosis plays an important role in the occurrence and development of many diseases[11–13]. In this review, we attempt to: 1. Analyze the literature on the molecular mechanisms of cuproptosis; 2. Determine the role of cuproptosis in pancreatic diseases.

Biological characteristics and physiological functions of copper

Copper ion metabolic pathway
The normal copper content in the human body is about 100-200mg, with 5% −10% present in the blood, 20% distributed in the liver, and the remaining 50% −70% present in muscles and bones [14]. Most of the copper in the human body is obtained through diet such as nuts, milk, and meat products. It is mostly Cu2+ and cannot be directly utilized by cells. Cu2+ is reduced to Cu+ by reductases in the epithelial cells of the digestive tract and is transported to intestinal epithelial cells by binding with copper transporter 1 (CTR1) [15]. Subsequently, copper transport ATPase alpha (ATP7A) carries Cu+ into the portal venous circulation. Most of the Cu+ enters liver cells through CTR1 and is then transported by the copper Transporting ATPase beta (ATP7B) Golgi complex pathway through the copper chaperone protein antioxidant1 to form ceruloplasmin, which is then transported to various parts of the body [16]. Copper ions in liver cells are secreted into bile through ATP7B and ultimately excreted through feces, with a small portion reabsorbed through the digestive tract [17].

The biological significance of copper homeostasis
The absorption, transport, and excretion processes of copper ions maintain a dynamic equilibrium state, known as copper homeostasis [18]. The copper transport system maintains the homeostasis of copper in the body and plays an important role in ensuring the tissue’s normal operation. When the copper ions concentration decreases, copper in the liver is transported to the bloodstream by ATP7A, thereby increasing the copper concentration in the circulation. Excessive or insufficient copper ion content can cause copper homeostasis imbalance, leading to cell death and the occurrence of various diseases [19]. Excessive accumulation of copper leads to abnormal binding with large molecules in the body, causing oxidative damage [20]. Therefore, exploring the mechanism of copper homeostasis imbalance and interfering with its molecular mechanism is of great significance for the diagnosis and treatment of pancreatic diseases (Figure 1).

Discovery and mechanism of cuproptosis

Morphological manifestations of cuproptosis
The process of cuproptosis mainly occurs in mitochondria, and the morphological changes of mitochondria are similar to the mitochondrial abnormalities of ferroptosis. YAGIDA N et al. [21] confirmed that when cuproptosis occurs in cells, mitochondria exhibit distortion of the cristae, reduction in volume, separation of the inner and outer membranes, increased matrix density or replacement by large vacuoles, and some mitochondria often surround the vesicles of the rough endoplasmic reticulum. Liao et al. [22] found that copper can cause damage to liver cell membranes, mitochondrial vacuolization, and rupture of cristae chromatin. Therefore, the morphological changes of cuproptosis mainly include mitochondrial shrinkage and the formation of cristae vacuoles (Table 1).

Molecular mechanism of cuproptosis
Cuproptosis is a novel mode of cell death, which involves the accumulation of large amounts of copper ions in the cell, binding to acylated proteins in the mitochondrial TCA cycle, leading to the aggregation of acylated proteins and loss of Fe-S proteins, resulting in increased protein toxicity stress and oxidative stress, leading to cell death [23]. Cuproptosis is closely related to the TCA cycle, mainly manifested in the following aspects: 1. Copper ions directly act on TCA cycle proteins: Copper ions directly bind to acylated proteins in the TCA cycle, such as DLAT and PDHC, causing abnormal protein aggregation and blocking the normal progression of the TCA cycle [24]. 2. Impact on TCA cycle metabolite levels: After cuproptosis occurs, TCA metabolite pyruvate increases and succinic acid decreases, thereby affecting cellular metabolic function [25]. 3. Inhibition of iron sulfur cluster protein synthesis: Copper ion accumulation can inhibit the synthesis of iron sulfur cluster proteins and suppress the efficiency of the TCA cycle. 4. Inducing protein toxicity stress: The aggregation and dysfunction of acylated proteins in the TCA cycle activate stress proteins such as heat shock protein 70 (HSP70), which cannot effectively repair the damaged TCA cycle and ultimately lead to cell death [26].
Todd Golub et al. [27] validated, that elesclomol and disulfiram, two Cu2+ carriers, can kill some cancer cells. Wu et al. [28] detected, that elesclomol forms a chelate with Cu2+ in a 1:1 ratio and transports Cu2+ to the cell mitochondria. Cu2+ is reduced to Cu+, which then produces reactive oxygen species that damage the cell. Subsequently, elesclomol transports Cu2+ from the extracellular to intracellular space, causing copper accumulation in the mitochondria and ultimately leading to cell death [29]. Elesclomol may induce cell reactive oxygen species production, stress protein expression such as heat shock protein 70 (HSP70), promote mitochondrial cardiolipin oxidation, activate cytochrome C-dependent mitochondrial apoptosis pathway, and cause cell death [30]. When there is a deficiency of Cu2+ outside the cell, elesclomol loses its cytotoxicity. Soma S et al. [31] discovered cytochrome C oxidase is the terminal of the mitochondrial respiratory chain, and copper is an important cofactor for it. Elesclomol may rely on oxidative phosphorylation to exert anti-tumor effects. Another study found that [32], The combined application of elesclomol and copper can promote copper accumulation in colon cancer mitochondria, promote the accumulation of reactive oxygen species, and lead to the degradation of solute carrier family 7 member 11 (SLC7A11). Disulfiram is converted into diethyl dithiocarbamate (DTC) in the body, which forms a chelate with Cu2+, promoting the coagulation of nuclear protein localization protein 4 (NPL4) and tightly binding to P97 protein, inhibiting its function of degrading protein, ultimately leading to the accumulation of a large amount of waste protein in the cell and death[33]. In summary, the target site of Cu2+-induced cell death is the tricarboxylic acid cycle process, rather than the electron transfer chain process [10] (Figure 2).
Research shows [27], that ferredoxin 1 (FDX1) can convert Cu2+ into more toxic Cu+, while silymar can directly bind to the FDX1 gene. Zhang et al. [34] corroborated, FDX1 is associated with fatty acid oxidation and glucose metabolism of amino acids. Similarly, Lipoic Acid Synthetase (LIAS), Lipoyltransferase 1 (LIPT1), and other enzymes are involved in the protein acylation process [10]. Therefore, the FDX1 gene and protein acylation process play an important role in the occurrence and development of cuproptosis. Cu2+ binds to acylated proteins, leading to oligomerization of dihydrolipoamide S-acetyltransferase (DLAT) acylation and abnormal assembly of Fe-S proteins, resulting in cell death [35]. The triggering process of cuproptosis includes copper ion accumulation, binding of thioacylated proteins, protein oligomerization and aggregation, inactivation of iron sulfur cluster proteins, protein toxicity stress, and cell death[18,25]. The regulatory pathways of cuproptosis include the following directions: 1. Copper ion transport regulation pathway: uptake pathway, such as CTR1 and copper ion carrier, exclusion pathway, such as ATP7A/B protein in the Golgi apparatus[25,36]. 2. Mitochondrial metabolic regulation pathways: TCA cycle pathways such as the acylation protein DLAT and iron sulfur cluster proteins in TCA.3.Protein toxicity stress regulation pathway: Lipoacylation protein aggregation FDX1, Fe-S cluster protein degradation [37].4.Regulation pathways of redox homeostasis: ROS generation, antioxidant defense system GSH.5.Signal pathway regulation pathways: AMPK signaling pathway, PI3K/MTOR signaling pathway, M6A methylation modification. By targeting signaling pathways or key proteins in these pathways, the regulation of cuproptosis can be achieved, providing new strategies for disease treatment.

Cuproptosis inducers and chelators
Cuproptosis inducers can transport copper ions into cells, increase intracellular copper ion levels, and lead to an increase in intracellular ROS and cell death, also known as copper ion carriers [38]. The commonly used cuproptosis inducers currently include Disulfiram(DSF), Cu(II) Elesclomol, 8-Hydroxyquinoline, Elesclomol(ES), UM4118 [39]. Copper ion carriers induce cuproptosis to make radiation-resistant cancer cells, cell lines, and patient-derived xenografts sensitive to radiotherapy [40]. In the early stage of pancreatic injury, copper ion carriers promote the recovery of pancreatic injury.
Cuproptosis chelators refer to those that bind to intracellular copper ions, reduce the content of free copper ions in cells, and thereby inhibit cell death [38]. The commonly used Cuproptosis chelators currently include Tetrathiomolybdate(TTM), D-Penicillamine, GSH\, Trientine, and Cuprizone [41]. Wilson’s disease patients are first treated with Cuproptosis chelators such as D-penicillamine, which help remove circulating copper bound to albumin and increase urinary copper excretion [24]. The use of Cuproptosis chelators TTM can inhibit cell copper ion concentration and ROS content, and treat pancreatic cancer, pancreatitis, and diabetes.

Biomarkers and therapeutic targets of cuproptosis
The biomarkers of cuproptosis include: 1. Copper ion level: Elevated intracellular copper ion concentration can be detected by copper ion fluorescent probes and other methods 2. Protein acylation markers: The aggregation of acylated proteins, such as DLAT, indicates cuproptosis, which can be detected by Western blot and other techniques [25,42]. 3. Changes in Fe-S cluster proteins: cuproptosis can lead to inactivation of Fe-S cluster proteins such as FDX1, and their expression levels can be detected by Western blot and other methods 4. Oxidative stress-related indicators: cuproptosis triggers oxidative stress, leading to an increase in ROS levels, which can be detected by DCFH-DA fluorescent probe [43]. 5. Mitochondrial functional indicators: decreased ATP synthesis, decreased mitochondrial membrane potential, etc, which can be detected by JC-1 staining for membrane potential.
The therapeutic targets for cuproptosis include: 1. Inhibition of SLC31A1 activity by copper ion transporters can reduce intracellular copper accumulation, which is a potential therapeutic target. 2. Protein lipid acylation regulatory factors: Inhibiting FDX1 activity or blocking the lipid acylation process can inhibit cuproptosis [37,44]. 3.Copper chelators, such as tetrathiomolybdate (TTM), can bind with intracellular copper ions to reduce free copper concentration and induce cuproptosis [37,45]. 4.Mitochondrial metabolic regulator: By regulating mitochondrial respiratory chain function, it can inhibit cell cuproptosis. 5.Immune regulatory targets: Regulating the function of immune cells such as T cells may promote copper death in tumor cells.

Cuproptosis and pancreatic-related diseases
Pancreatic diseases refer to diseases occurring in the pancreas, including pancreatic cancer, acute and chronic pancreatitis, diabetes, pancreatic cysts, pancreatic injuries, et al. [46] (Figure 3). An increasing number of studies have confirmed that copper metabolism is abnormal in pancreatic diseases [47]. Abnormal copper metabolism is closely related to the occurrence and development of pancreatic diseases. In-depth research on cuproptosis can help us further understand the pathogenesis of pancreatic diseases and provide new targets for the treatment of pancreatic diseases.

Pancreatic cancer
Pancreatic cancer, known as the king of cancer, is a malignant tumor originating from pancreatic acinar cells and ductal epithelium, often manifested as jaundice, emaciation, abdominal discomfort, and mental disorder [48]. The cause of pancreatic cancer is not clear. Research shows that long-term smoking, drinking, high-fat diet, diabetes, and chronic pancreatic damage can all lead to an increased risk of pancreatic cancer [49,50]. These different causes cause pancreatic cancer to experience similar pathological processes, including decreased cell necrosis, vigorous growth, immunosuppression, and oxidative stress imbalance [51]. Ultrasonography is an important auxiliary means for clinical diagnosis of pancreatic cancer. Transabdominal ultrasound has the advantages of convenient operation, non-invasive, and good repeatability. It is widely used in the primary screening of pancreatic cancer. It often shows that the pancreatic tumor is hypoechoic, with irregular boundaries, and is generally not difficult to diagnose [52]. When pancreatic cancer is found, most of them have distant metastasis or invasion of important blood vessels. It is important to explore the mechanism of its occurrence and development for the prevention and treatment of pancreatic cancer [53].
Research has confirmed that there is abnormal copper metabolism in tumor tissues and an increase in copper ion content may be related to promoting tumor angiogenesis, cancer cell proliferation, migration, and invasion [54]. Abnormal copper metabolism in tumors is related to some abnormal protease metabolism, such as a copper chaperone for superoxide dismutase (CCS), DLAT, CTR1, cytochrome oxidase 17 (COX17), antioxidant protein 1 (ATOX1), et al. [55,56]. Studies have shown that copper ions in blood samples of pancreatic cancer patients are abnormally high, suggesting that copper metabolism may be abnormal during the occurrence and development of pancreatic cancer [57]. Ammonium tetrathiomolybdate (TM) is a high-affinity copper chelator that forms a complex with copper ions in serum and albumin, preventing copper ions from being taken up by cells and subsequently reducing copper ion levels and inhibiting cell growth in cancer cells [58]. TM is clinically used to treat Wilson’s disease, and can also effectively inhibit the proliferation of cervical cancer and breast cancer cells, reduce the resistance to cisplatin during chemotherapy, and enhance sensitivity [59]. DLAT can promote the activation of the pentose phosphorylation pathway and promote tumor cell growth. It is highly expressed in many malignant tumors, including pancreatic cancer. Reducing DLAT may play an important role in the treatment of pancreatic cancer [60]. Therefore, intervention of copper metabolism-related genes such as CTR1 and copper chelator to reduce copper content may provide new therapeutic strategies and targets for the treatment of pancreatic cancer.

Pancreatitis
Pancreatitis refers to an inflammatory disease of pancreatic tissue caused by various reasons, including acute pancreatitis and chronic pancreatitis [61]. Acute pancreatitis refers to acute damage to pancreatic tissue such as bleeding, edema, and necrosis caused by various reasons, and is divided into mild, moderate, and severe acute pancreatitis [62]. Chronic pancreatitis refers to a chronic inflammatory disease of pancreatic tissue caused by various reasons, often accompanied by irreversible damage to pancreatic endocrine function. It is divided into alcoholic, biliary, idiopathic, autoimmune, and recurrent chronic pancreatitis [63,64]. Acute pancreatitis often presents with symptoms such as abdominal pain, nausea, vomiting, fever, and multiple organ failure [65]. Research has shown that in the early stages of acute pancreatitis, ultrasound is the only suitable diagnostic method, and there is no significant difference in diagnostic accuracy between ultrasound and CT. However, ultrasound is more sensitive to gallstones and pancreatic duct dilation [66]. The cause of pancreatitis is unclear and may be related to biliary diseases, alcohol, pancreatic duct obstruction, duodenal diseases, metabolic disorders, and overeating. Gallstones block the pancreatic duct, activating digestive enzymes in the pancreas and stimulating pancreatic cells to cause inflammation, leading to pancreatitis [67,68]. The treatment of pancreatitis includes dietary restriction, etiological management, inhibition of pancreatic enzyme secretion, fluid resuscitation, nutritional therapy, antibiotics use, and abdominal pressure reduction [69,70].
The normal pancreas secretes about 1000 ml of fluid per day, and over 90% of the protein secretion is composed of proteases or enzymes that almost completely enter the duodenum, with only a small amount of these enzymes entering the bloodstream for measurement [71]. Copper and zinc are important essential minerals in biological systems, and their deficiency can lead to serious health defects. However, excessive copper and zinc can also cause significant toxic reactions [72]. Copper is an important component of over 50 enzymes, including superoxide dismutase (SOD) necessary for free radical detoxification. When pancreatitis occurs, a large amount of SOD is consumed, and a decrease in SOD leads to a decrease in copper content, which in turn reduces the body’s immunity to diseases and increases the chance of infection [73,74]. Many studies have confirmed that the secretion of copper is closely related to the secretion of zinc [75]. The release of copper ions from metallothionein in patients with pancreatitis can enhance the generation of reactive oxygen species and disrupt the balance between oxidation and antioxidation [76].
In the occurrence and development of acute pancreatitis, oxygen-free radicals play an important role. The increase of xanthine oxidase in pancreatic tissue produces a large amount of oxygen free radicals, which damage pancreatic tissue [77]. Liebe et al. [78] confirmed, that the copper content in the serum of patients with acute pancreatitis is lower than that of normal individuals, and the copper content in pancreatic tissue is increased, which may be related to free radical damage. Szuster Ciesielska et al. [79] found, compared with the control group, the activity of Cu/Zn SOD in the blood of patients with acute pancreatitis was significantly increased. In patients with chronic pancreatitis, copper ions generate oxidative stress through the Fenton reaction, causing damage to the body [80]. Even at the minimum increase, copper ions can cause severe oxidative damage to acinar cells. The Cu/Zn ratio of red blood cells can serve as a non-invasive biomarker for exocrine and endocrine dysfunction in patients with chronic pancreatitis. The Cu/Zn ratio is significantly increased in patients with chronic pancreatitis, and the copper level is significantly elevated [25]. The Cu/Zn ratio and Cu/Zn SOD activity are both increased in the serum of patients with chronic pancreatitis [81]. Gjorup et al. [82] found the decrease in serum zinc concentration in patients with chronic pancreatitis may be due to the lack of specific zinc binding ligands involved in zinc transport, resulting in a reduced ability of the pancreas to excrete zinc and an increase in the Cu/Zn ratio. Metallothionase (MT) plays an important role as an antioxidant, and the low concentration of zinc in the blood of patients with chronic pancreatitis can explain the decrease in MT concentration. These research results indicate that copper ions play different roles in antioxidant balance during different stages of pancreatitis development. An increase in intracellular copper ion concentration can trigger cuproptosis, and by intervening in copper ion transport regulatory pathways such as CRT1, it can affect the treatment of pancreatitis. Exploring the mechanism of cuproptosis during the development stage of pancreatitis and intervening in it has practical significance for pancreatitis treatment.

Diabetes
Diabetes refers to the metabolic disorder of sugar, fat, and protein caused by the absolute or relative insufficiency of insulin secretion and utilization obstacles. Chronic diseases based on hyperglycemia are divided into type I and type II diabetes [83]. The etiology of diabetes has not been clarified, including genetic factors, environmental factors, and autoimmune system defects [84]. Diabetes is often manifested as polydipsia, polyuria, polydipsia, weight loss, skin infection, exertion, and vision changes [85]. Ultrasonography is a non-invasive, effective, and safe examination method, which plays an important role in the clinical diagnosis of atherosclerosis in diabetes [26]. The occurrence, development, and complications of diabetes cause serious damage to multiple organs and tissues of the body, with a high risk of death and disability. It is of great significance to explore the mechanism of the occurrence and development of diabetes for its prevention and treatment.
Research has shown that copper is an important nutrient for the human body, playing a crucial role in the synthesis, secretion, storage, activity, and energy metabolism of insulin. The increase in copper level is closely related to the increased risk of diabetes. The elderly and diabetic patients with complications have higher serum copper [86]. Copper promotes the secretion of somatostatin-releasing peptide and insulin-like growth hormone, thereby reducing blood glucose levels [87]. The increase and loss of copper will affect the synthesis and release of insulin, thus affecting the occurrence and development of diabetes. Research has shown that copper and zinc compete for the same carrier protein located in the duodenal mucosa in terms of absorption, and copper absorption enhances competitive inhibition of intestinal zinc absorption [88]. Zinc is distributed in pancreatic beta cell granules, playing a role in stabilizing insulin and regulating insulin glucose lowering [87]. When type 2 diabetes occurs, the intestinal absorption of copper increases, and the absorption of zinc decreases. Copper is absorbed into the blood through the duodenum and combined with serum proteins to form ceruloplasmin increases; The catabolism of diabetes patients is hyperactive, and the demand for ceruloplasmin is increased, which makes the intestinal copper compensatory increase, thus increasing the proportion of copper and zinc [89]. The ratio of copper to zinc is currently considered an important indicator of the prognosis and recurrence of diabetes treatment transition. Dietary zinc supplementation can inhibit the absorption of copper, so diabetes patients should eat more zinc-rich foods [90]. Copper metabolism-related indicators such as nonbinding copper and ceruloplasmin are abnormally elevated in type 2 diabetes and can promote the occurrence and development of chronic complications [91]. Serum copper level in patients with type 2 diabetes is positively correlated with glycosylated hemoglobin [92]. Chacko et al. [91] found, that the level of serum copper oxidase in type 2 diabetes patients increased significantly, and the level of serum copper oxidase in patients with complications was higher than that in asymptomatic patients. Masad et al. [93] proved, that during the formation of amyloid protein from human amylin (HA), hydrogen peroxide can be produced, and the binding of copper to HA greatly promotes this process, damaging pancreatic beta cells. Diethylenetriaminepentaacetic acid (DETAPAC), a copper chelating agent, can reduce the level of nonbound copper in diabetes, reduce the production of ROS, and have a certain role in delaying and reversing the complications of diabetes [94]. The increase in intracellular copper ion concentration can trigger cuproptosis. For example, the copper chelator can inhibit the cuproptosis of pancreatic β cells and then treat diabetes. The above research confirms that copper plays an important role in the occurrence and development of diabetes and its complications. Exploring the mechanism of cuproptosis in diabetes and intervening in it will help to find new targets for the prevention and treatment of diabetes and its complications.

Pancreatic injury
Pancreatic injury refers to the destruction of the anatomical structure and function of the pancreas due to various reasons and is divided into traumatic pancreatic injury and iatrogenic pancreatic injury [95]. When the upper abdomen is subjected to external pressure, the pancreas is compressed onto the hard spine behind it, causing pancreatic contusion, laceration, or even rupture; Iatrogenic causes include accidental splenectomy and endoscopic retrograde cholangiopancreatography leading to pancreatic injury [96]. After pancreatic injury, a large amount of pancreatic juice flows into the abdominal cavity, causing nausea, vomiting, bloating, abdominal pain, and abdominal muscle tension. In severe cases, shock may occur due to bleeding and loss of body fluids [97]. The pancreas is located behind the peritoneum and spans across the front of the spine. After pancreatic injury, it is often misdiagnosed due to hidden signs that are difficult to diagnose. Ultrasound can quickly determine the location, scope, and degree of pancreatic injury. The ultrasound grading of pancreatic injury provides a fast imaging examination method for clinical diagnosis and treatment [98]. Pancreatic injury often leads to secondary acute pancreatitis, abdominal infection, pancreatic necrosis, pancreatic fistula, pancreatic abscess, and pseudopancreatic cyst, with a total mortality rate of about 5-30% [99]. The treatment of pancreatic diseases includes surgical repair, double tube drainage, splenectomy, inhibition of pancreatic enzyme secretion, and anti-infection therapy [100]. Exploring the mechanism of pancreatic injury occurrence and development, and intervening in it, has important practical significance.
Research has shown that severe trauma can lead to acute micronutrient deficiencies in the body, which are closely related to the severity of the trauma [101]. In the early stage of severe trauma, the copper content and Cu/Zn SOD activity in the body’s serum decrease significantly due to the large amount of copper transferred into the liver under stress conditions; Around 12 h after injury, serum copper gradually increases, indicating compensation after stress. The activity of Cu/Zn SOD in the serum after injury also significantly increased, and its activity does not depend on the increase of copper content, to maintain the physiological metabolism of important organs and enhance the clearance of metabolic products produced by trauma tissues such as oxygen free radicals [102]. Nano copper can promote the synthesis and expression of tissue transforming growth factor - β 1 (TGF - β 1) during wound healing, alleviate wound inflammation, promote fiber proliferation and collagen deposition, and enhance the ability of angiogenesis [103]. Nano copper promotes the synthesis and expression of vascular endothelial growth factor (VEGF), facilitates the formation of new blood vessels, and accelerates the healing process of wound tissues [104]. Therefore, in the early stage of pancreatic injury, supplementing a small amount of copper can promote the recovery of the pancreas. In the middle and late stages of pancreatic injury, reducing copper intake can reduce cuproptosis and promote the recovery of pancreatic injury.

Pancreatic neuroendocrine tumor
Pancreatic neuroendocrine tumors refer to a type of tumor originating from pancreatic multipotent neuroendocrine stem cells, often characterized by intermittent episodes of hypoglycemia, abdominal pain, diarrhea, bloating, jaundice, and abdominal masses [105]. This disease is divided into non-functional and functional types, with the latter being classified as insulinoma, glucagon tumor, growth hormone tumor, vasoactive intestinal peptide tumor, and gastrinoma [24]. The pathogenesis of pancreatic neuroendocrine tumors is still unclear, and a few are related to genetic factors. Patients with pancreatitis, diabetes, and a high-fat diet are more likely to get sick [3]. Exploring the mechanism of occurrence and development of pancreatic neuroendocrine tumors is of great significance for their prevention and treatment.
Research has shown that different levels of copper can regulate tumor growth, and copper may become the limiting nutrient for tumors [24]. The serum copper levels of cancer patients are elevated and correlated with the severity of the disease and response to treatment [3,106]. When used as a monotherapy in mouse pancreatic neuroendocrine tumor models and human papillomavirus 16-driven mouse cervical cancer models, TM exhibits anti-tumor activity by inhibiting tumor cell growth [36,107]. Combining TM with other copper chelators and platinum-based chemotherapy can increase the introduction of platinum-based drugs through CTR1, directly impair oxidative phosphorylation and ATP production, and inhibit tumor growth [3,108].

Conclusions
Copper is an important metallic element that plays a crucial role in biosynthesis and mitochondrial respiration processes [5]. Excessive copper affects the occurrence and development of diseases through oxidative stress, promotion of angiogenesis, regulation of autophagy, and other mechanisms [42]. Cuproptosis is a novel mode of cell death caused by the accumulation of copper in cells, which leads to the aggregation of mitochondrial lipid-containing proteins, instability of Fe-S proteins, and oxidative stress in cells [43]. Cuproptosis common in cancer, neurological disorders, and cardiovascular diseases [109]. However, recent studies have increasingly confirmed the close relationship between cuproptosis and pancreatic diseases. In addition to the pancreatic diseases discussed in Section 3, there are also pancreatic cysts, insulinomas, annular pancreas, and pancreatic separation [110].

Future perspectives and research gaps
The mechanism of cuproptosis in the occurrence and development of pancreatic diseases is still unclear. It has been confirmed that cuproptosis is involved in the occurrence and development of pancreatic cancer. Copper ion carriers have shown significant efficacy in the treatment of pancreatic cancer [111]. Copper-induced cell death can affect the tumor microenvironment; therefore, cuproptosis regulators can be added to traditional treatments. Due to breakthroughs in immune checkpoint blockade, cancer immunotherapy has attracted widespread attention, and cuproptosis is closely related to the regulation of anti-tumor immunity. Therefore, regulating cuproptosis is expected to improve cancer management [112,113]. Further research on copper-regulated cell death pathways may become potential therapeutic targets, and understanding how to intervene in regulating these pathways may become new prevention and treatment strategies for pancreatic diseases.