Highlights
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1. Regulatory mechanisms associated with ferroptosis in cancer.
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2. Mechanisms involved in the regulation of cuproptosis in cancer.
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3. Mechanisms associated with lysozincrosis in cancer.
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4. Unique mechanisms of ferroptosis in pancreatic cancer.
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5. Ferroptosis and the treatment of pancreatic cancer.
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6. Prospect of cuproptosis in the treatment of pancreatic cancer.
Introduction
Pancreatic cancer is an aggressive tumour in the digestive tract. A total of 90% pancreatic cancer cases arise from the duct epithelium, specifically pancreatic duct adenocarcinoma (PDAC) (Ref. Reference Jiang, Fagman, Ma, Liu, Vihav, Engstrom, Liu and Chen1). In the early stages of the cancer, patients usually do not have noticeable symptoms, which poses challenges for early diagnosis. Pancreatic cancer cells have a strong tendency to invade surrounding tissues, which obstructs early diagnosis (Ref. Reference Zhao and Liu2). Currently, the dominant treatment strategy involves surgical intervention combined with adjuvant chemotherapy. However, these cancer cells easily develop resistance to chemotherapy drugs, which hinders treatment effectiveness. The emergence of drug resistance in pancreatic cancer cells is strongly associated with the manifestation of undetected metastases (Ref. Reference Zeng, Pöttler, Lan, Grützmann, Pilarsky and Yang3). Gemcitabine, a first-line chemotherapy medication, shows some effectiveness in pancreatic cancer treatment. However, the development of gemcitabine resistance significantly reduces its efficacy, which is attributed to a combination of factors including pancreatic cancer cells, cancer stem cells and tumour microenvironment (TME) (Ref. Reference Zeng, Pöttler, Lan, Grützmann, Pilarsky and Yang3). Although surgery is the only curative option for pancreatic cancer, the 5-year survival rate is only 20% (Ref. Reference Kolbeinsson, Chandana, Wright and Chung4). Moreover, patients face a high risk of recurrence, ranging from 70% to 80% after treatment. The low 5-year survival rate and the risk of recurrence mean that macroscopic surgical resection is often unable to effectively prolong survival in these patients and often results in recurrence. Unfortunately, pancreatic cancer is often diagnosed at advanced stages, making surgical intervention difficult. This, along with other factors, makes pancreatic cancer a complex disease with high mortality. This has led researchers to consider the potential of exploring and identifying strategies to inhibit the progression of pancreatic cancer at the microscopic level.
In recent years, research on metal-related cell death and tumour-associated metal ions has generated progress, prompting a shift in focus towards practical applications. Novel forms of programmed cell death (PCD), such as ferroptosis, lysozincrosis and cuproptosis, are distinct from traditional mechanisms, such as apoptosis, autophagy and pyroptosis. Ferroptosis, first identified in 2012 (Ref. Reference Li, Yin, Liu and Wang5), occurs due to excessive levels of iron leading to intracellular lipid peroxidation and consequent cell death (Ref. Reference Chen, Kang, Kroemer and Tang6). Lysozincrosis is triggered by high concentrations of zinc that hinder adenosine triphosphate (ATP) synthesis, resulting in non-apoptotic cell death. Cuproptosis arises when copper ions directly bind to acylated components in the tricarboxylic acid (TCA) cycle pathway, leading to the aberrant accumulation of acylated proteins and depletion of iron–sulphur cluster proteins. Consequently, this mechanism triggers toxic protein stress reactions and cell death. These specific metal-related cell death mechanisms have prompted the question of whether it is possible to induce pancreatic cancer cell death, thereby accelerating the death of pancreatic cancer cells and prolonging the survival cycle of pancreatic cancer patients, or even curing pancreatic cancer. Under such premises, with a gradual deepening of research on pancreatic cancer, unique changes in pancreatic cancer cells have been found. For example, pancreatic cancer cells may be sensitive to ferroptosis due to special gene mutations. They demonstrate unique changes that link pancreatic cancer to a process termed cell death through metal ion involvement, helping further research on the treatment and diagnosis of pancreatic cancer.
Research on metal-related cell death has generated extensive knowledge, arousing interest in various fields, in which ferroptosis exhibits significant potential for short-term applications. Metal-related cell death provides a novel direction to tackle the obstructions of pancreatic cancer treatment (Ref. Reference Yang, Zhang, Wen, Xiong, Huang, Wang and Liu7).
Ferroptosis
Overview and basic characteristics of ferroptosis
The fundamental basis of ferroptosis is primarily the result of unstable hydroxyl radicals produced through iron-catalysed Fenton reactions (Ref. Reference Liang, Minikes and Jiang8). This procedure promotes the oxidation of polyunsaturated fatty acids (PUFAs) and ultimately leads to the formation of lipid peroxides (Ref. Reference Battaglia, Chirillo, Aversa, Sacco, Costanzo and Biamonte9). The accumulation of lipid peroxides damages cellular membranes, increasing their susceptibility and ultimately leading to cell death (Ref. Reference Li, Cao, Yin, Huang, Lin, Mao, Sun and Wang10). Consequently, the high abundance of iron is a crucial factor driving the occurrence of ferroptosis, with lipid peroxidation acting as the direct trigger that makes ferroptosis exhibit diverse characteristics in biochemical and morphological aspects.
In terms of its biochemical attributes, ferroptosis cells inevitably exhibit high iron accumulation owing to the dependence of the ferroptosis mechanism on iron ions. Ferroptosis is initiated by iron-driven lipid peroxidation, and the disturbance of iron ions causes lipid peroxidation, leading to an excess of lipid peroxides in ferroptosis cells (Ref. Reference Tang, Chen, Kang and Kroemer11).
Morphologically, ferroptosis cells display impairments of various organelles, primarily triggered by membrane disruptions (Ref. Reference Gao, Yi, Zhu, Minikes, Monian, Thompson and Jiang12). Remarkably, ferroptosis elicits unique transformations in mitochondria, as demonstrated by their decreased size, reduced cristae density, increased mitochondrial membrane density and increased frequency of mitochondrial membrane rupture (Refs. Reference Tang, Chen, Kang and Kroemer11, Reference Gao, Yi, Zhu, Minikes, Monian, Thompson and Jiang12).
As a regulated form of cell death distinct from apoptosis, ferroptosis involves a complex interplay of crucial molecules (Ref. Reference Chen, Kang, Kroemer and Tang6). The primary contributors to the ferroptosis process include SLC7A11, which acts as the principal conduit for transporting glutathione (GSH) precursors, GPX4 and GSR, enzymes responsible for GSH oxidation and reduction. TFR1, the main protein responsible for transporting iron, plays a vital role in coordinating the complex process of ferroptosis in cells. These specialized molecules play crucial roles in determining cell death during ferroptosis.
The observable characteristics of ferroptosis cells provide insights into the methods of inducing or inhibiting cell ferroptosis. By regulating the levels of iron, glutamic acid and cystine, it is possible to influence the course of ferroptosis processes. Targeted pharmacological interventions can regulate specialized molecules involved in ferroptosis and provide an avenue for precise control over this complex cellular phenomenon. The features of ferroptosis cells offer insights for developing novel manipulation approaches.
Metabolic pathways of ferroptosis
The onset of ferroptosis is tightly linked with the metabolic pathways regulating its associated components. Excessive iron is crucial to the development of ferroptosis, leading to lipid peroxidation (Ref. Reference Chen, Kang, Kroemer and Tang13). As a result, the occurrence of ferroptosis largely relies on the complex interplay of iron metabolism, lipid metabolism and glutathione peroxidase (GPX) metabolism. These metabolic processes collectively determine the outcome of ferroptosis events, revealing the mechanisms that drive this cellular phenomenon (Figure 1).
Figure 1. Main pathways and metabolic pathways of ferroptosis. Fe3+ enters cells through a series of transporters and catalyses lipid peroxidation via the Fenton reaction, leading to ferroptosis. System Xc- transports cysteine into cells while exporting glutamic acid, with the critical subunit SCL7A11 being regulated by the P53 gene. Cys is transformed into GSH within cells, and GPX4 facilitates the conversion of GSH into GSSG, while PLOOH, which is harmful, is converted into harmless PLOH. GSR helps GSSG undergo retransformation into GSH, and VDACs provide NADPH that is crucial to this process. Such a process effectively inhibits cell ferroptosis.
Iron metabolism
Iron plays a critical role in the body’s metabolic processes, including oxygen transportation and DNA biosynthesis, and serves as a coenzyme in the TCA cycle and electron transfer chain, influencing ATP synthesis. The body maintains a precise physiological threshold for iron levels to strike a delicate balance between its essential function and optimal quantity. Thus, iron’s multifaceted functions contribute to vital physiological processes.
Typically, iron binds to transferrin and enters cells via the cytosolic pathway facilitated by the transferrin receptor TfR1 on the cell membrane. This serves as the primary route for iron acquisition in almost all cell types. The uptake of iron mediated by transferrin and its receptor plays a crucial role in the endocytosis of transferrin-bound iron, making it a prerequisite for ferroptosis occurrence. This is one of the primary sources of iron required for initiating ferroptosis. Afterwards, it enters iron-demanding areas, where it enters the cell nucleus via TfR1 mediation. Within the nucleus, it transforms to Fe2+ and is then transported to the labile iron pool in the cytoplasm with the assistance of divalent metal transporter 1 (Refs. Reference Ursini and Maiorino14, Reference Čepelak, Dodig and Dodig15). The ferritin light chain and ferritin heavy chain 1 sequester the remaining iron (Refs. Reference Battaglia, Chirillo, Aversa, Sacco, Costanzo and Biamonte9, Reference Gong, Ji, Wu, Tu, Lei, Luo, Liu, Lin, Li, Li, Huang and Zhu16). It is important to mention that lysosomal degradation of these ferritins can lead to an increase in intracellular free iron levels (Ref. Reference Park and Chung17). When there is a failure to store or export intracellular free iron, it accumulates in the cytoplasm, catalyses the Fenton reaction and leads to several lipid peroxidation events inside the cell. Eventually, this results in producing toxic reactive oxygen species (ROS) (Refs. Reference Gong, Ji, Wu, Tu, Lei, Luo, Liu, Lin, Li, Li, Huang and Zhu16, Reference Liu, Kang and Tang18), which damages multiple cellular membrane structures and consequently induces cell ferroptosis (Ref. Reference Hassannia, Vandenabeele and vanden Berghe19). This pathway highlights the correlation between ferroptosis and a cell’s ability to uptake and store iron. Specifically, when a cell takes in more iron than it can use and surpasses its iron storage capacity, the excess iron remaining in the cell can trigger lipid peroxidation, leading to ferroptosis (Ref. Reference Gong, Ji, Wu, Tu, Lei, Luo, Liu, Lin, Li, Li, Huang and Zhu16).
Lipid metabolism
Biological cells contain phospholipids composed of hydrophilic phosphate groups and hydrophobic fatty chains, resulting in both hydrophilic and lipophilic domains within a phospholipid molecule (Ref. Reference Liang, Minikes and Jiang8). This unique property allows them to form a bilayer structure known as a biofilm. Disruption of the biofilm structure occurs when the phospholipid molecules undergo oxidation, resulting in functional impairment. This disruption is a significant factor in initiating cell ferroptosis.
Phospholipids and other lipids with unsaturated double bonds can self-oxidize in the presence of oxygen. This process results in a free radical chain reaction (Ref. Reference Gong, Ji, Wu, Tu, Lei, Luo, Liu, Lin, Li, Li, Huang and Zhu16). The presence of divalent iron or comparable metal cations increases the formation of extremely reactive hydroxyl radicals through peroxides. Hydroxyl radicals remove hydrogen from unsaturated phospholipids or lipids, leading to the creation of lipid free radicals that initiate a chain reaction of free radicals (Ref. Reference Liu, Kang and Tang18). Lipid free radicals react with oxygen to form lipid peroxidation free radicals, then react with other unsaturated lipids and produce additional lipid free radicals. This free radical chain reaction continues until termination (Ref. Reference Gong, Ji, Wu, Tu, Lei, Luo, Liu, Lin, Li, Li, Huang and Zhu16).
Essentially, this process comprises a free radical chain reaction of PUFAs triggered by iron ions or similar metal cations, resulting in the generation of toxic phosphate hydroperoxides (PLOOH). These hydroperoxides not only harm the structure of the cell membrane but also have detrimental effects on cells (Ref. Reference Liang, Minikes and Jiang8). This mechanism is fundamental in the occurrence of ferroptosis.
The specialized lipid peroxides, namely phospholipids PE-AA and PE-AdA derived from arachidonic acid (AA) or adrenic acid (AdA), are the primary facilitators in ferroptosis. These specific lipid molecules undergo either enzymatic-mediated reactions or self-oxidation, producing lipid peroxides. In the presence of divalent iron ions, these peroxides eventually become lipid peroxidation radicals. The lipid peroxidation radicals resulting from this process further oxidize phospholipids found within cell membranes and subcellular organelle membranes, disrupting essential membrane fluidity and properties. Ultimately, these changes lead to ferroptosis at a cellular level.
Glutathione peroxidase metabolism
GSH plays a vital role as an intracellular antioxidant and a key regulator of ferroptosis. Specifically, GSH and GPX4 impede the function of lipid oxidase (LOX) (Ref. Reference Hassannia, Vandenabeele and vanden Berghe19). This impediment helps remove lipid peroxides produced due to iron accumulation, effectively countering lipid bilayer peroxidation and preventing cell membrane damage (Ref. Reference Seibt, Proneth and Conrad20).
The production of GSH within cells mainly relies on System Xc-, which functions as a membrane sodium-dependent reverse transporter for cysteine and glutamic acid (Ref. Reference Ursini and Maiorino14). This system is composed of a disulphide heterodimer consisting of the light-chain subunit SLC7A11 and the heavy-chain subunit SLC3A2, where SLC7A11 acts as the primary transporter. The p53 gene governs the regulation of SLC7A11 (Ref. Reference Gong, Ji, Wu, Tu, Lei, Luo, Liu, Lin, Li, Li, Huang and Zhu16).
System Xc- has a dual function of transporting intracellular glutamic acid and extracellular cystine into the cell. Subsequently, thioredoxin reductase 1 catalyses the conversion of extracellular cystine into cysteine. Finally, cysteine conjugates with glutamic acid and glycine, resulting in the production of GSH (Ref. Reference Liu, Kang and Tang18).
Under the action of GPx4, GSH is oxidized to form oxidized glutathione (GSSG). This oxidation process reduces toxic PLOOH derived from PUFAs to harmless phospholipids. This procedure effectively decreases the production of harmful lipid ROS and effectively prevents ferroptosis (Refs. Reference Chen, Kang, Kroemer and Tang6, Reference Liu, Kang and Tang18, Reference Forcina and Dixon21).
To maintain sufficient levels of GSH, glutathione reductase (GSR) must assist in reducing oxidized GSSG back to GSH. This reduction process requires the participation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) (Ref. Reference Čepelak, Dodig and Dodig15).
NADPH plays a crucial role in providing hydrogen for the reduction of GSSG to GSH. The presence of voltage-dependent anion-selective channels (VDACs), proteins located on the outer membrane of mitochondria, is necessary for the availability of this hydrogen. VDACs are responsible for maintaining the permeability of the outer membrane and are distributed throughout mitochondria. Presently, three subtypes of VDACs have been identified: VDAC1, VDAC2, and VDAC3. When VDAC2/3 is blocked, it causes a decrease in the levels of nicotinamide adenine dinucleotide phosphate (NADP+), which leads to a reduction in NADPH levels. NADPH is critical for providing the necessary hydrogen to convert GSSG to GSH. The decrease in NADPH results in a decrease in intracellular GSH, triggering the accumulation of intracellular lipid ROS and the onset of ferroptosis (Ref. Reference Seibt, Proneth and Conrad20). This same mechanism is also evident in erastin, the ferroptosis agonist, which shows potential for inducing cell ferroptosis.
Conversely, there is a coordinated increase in lipid ROS levels under conditions of cysteine deprivation and GSH depletion. Cysteine deficiency reduces the cellular uptake and triggers the efflux of GSH, leading to its catabolism outside the cell to maintain intracellular cysteine levels. Thus, inhibiting System Xc- may effectively trigger cell ferroptosis (Ref. Reference Seibt, Proneth and Conrad20).
FSP1-related changes
Recent studies have shown that FSP1, also referred to as AIFM2, can prevent cell ferroptosis by inhibiting lipid peroxidation, even without reliance on GPX4 for its activity. This is achieved by regulating CoQ10 levels, which mitigates the accumulation of peroxidized lipid free radicals in cells (Ref. Reference Doll, Freitas, Shah, Aldrovandi, da Silva, Ingold, Goya Grocin, Xavier da Silva, Panzilius, Scheel, Mourão, Buday, Sato, Wanninger, Vignane, Mohana, Rehberg, Flatley, Schepers, Kurz, White, Sauer, Sattler, Tate, Schmitz, Schulze, O’Donnell, Proneth, Popowicz, Pratt, Angeli and Conrad22). It is important to note that the GPX4 pathway operates alongside this pathway, and they collaborate to effectively combat cell ferroptosis (Ref. Reference Bersuker, Hendricks, Li, Magtanong, Ford, Tang, Roberts, Tong, Maimone, Zoncu, Bassik, Nomura, Dixon and Olzmann23).
In summary, ferroptosis is a culmination of various processes, triggered by excessive iron in the cell, resulting in the production of unstable hydroxyl radicals through the Fenton reaction. The production of excessive hydroxyl radicals through the Fenton reaction results in oxidative stress and cell death. The cell comprises unsaturated phospholipids and other lipids that contribute to diverse membrane structures. These structures uphold the cell’s normal physiological functions. The unsaturated phospholipids and lipid molecules react, causing the generation of lipid radicals and a chain of free radical reactions. This oxidation process continuously damages different lipid membrane structures in the cell, including the inner membrane structure. Besides, the oxidation of GSH is catalysed by GPX using System Xc- and cystine-generated GSH. This process reduces harmful PLOOH, which form when PUFAs undergo oxidation. As a result, it prevents cell ferroptosis (Ref. Reference Hassannia, Vandenabeele and vanden Berghe19). To maintain GSH levels, GPX4 oxidizes GSH into GSSG, which is regenerated by GSR using NADPH. VDACs provide NADPH to support this process, enabling cells to withstand ferroptosis. Overall, ferroptosis occurs as a consequence of these various processes, and alterations to these processes may initiate or hinder ferroptosis in cells, with potential implications for future applications of ferroptosis.
Ferroptosis and pancreatic cancer
Pancreatic cancer, a highly aggressive malignancy of the digestive system, have surgical resection as its only curative option. However, nonspecific early symptoms lead to 90% of cases being diagnosed at advanced stages, precluding surgery (Ref. Reference Yang, Zhang, Wen, Xiong, Huang, Wang and Liu7). While chemotherapy remains the mainstay treatment, rapid development of drug resistance often renders it ineffective. Recent studies suggest ferroptosis modulation may selectively target pancreatic cancer cells, offering a novel therapeutic approach (Ref. Reference Hassannia, Vandenabeele and vanden Berghe19). Future directions include using ferroptosis inducers as targets and exploring ferroptosis-related biomarkers for early detection.
Intracellular changes associated with ferroptosis in pancreatic cancer
KRAS gene mutation related
Research findings indicate that KRAS gene mutations are present in 90% of patients diagnosed with pancreatic cancer (Ref. Reference Luo24). These mutations stimulate the proliferation of tumour cells and disrupt cellular metabolism. Specifically, KRAS mutations decrease the expression of pro-apoptotic proteins and increase the expression of anti-apoptotic proteins, ultimately inhibiting apoptosis and potentially leading to the resistance of pancreatic cancer cells to conventional chemotherapy drugs. KRAS mutations increase iron intake and decrease iron storage capacity in tumour cells, disrupting iron homoeostasis. This results in increased levels of ROS in KRAS mutant tumour cells compared to normal cells. Consequently, KRAS mutant pancreatic cancer cells exhibit increased sensitivity to ferroptosis.
To counteract the harmful effects of excessive ROS, these tumour cells with KRAS mutations produce large amounts of GSH. In KRAS-mutated tumour cells, the active expression of System Xc-, which is responsible for importing cystine necessary for GSH synthesis, is significantly increased compared to normal cells (Refs. Reference Son, Lyssiotis, Ying, Wang, Hua, Ligorio, Perera, Ferrone, Mullarky, Shyh-Chang, Kang, Fleming, Bardeesy, Asara, Haigis, DePinho, Cantley and Kimmelman25, Reference Dong, Li, Jiang, Chen and Zhou26). Therefore, targeting System Xc- in pancreatic cancer cells and promoting ferroptosis could potentially serve as a valuable therapeutic strategy in the future management of pancreatic cancer.
Although the KRAS mutation increases the sensitivity to ferroptosis, it also promotes the proliferation, metastasis and invasion of pancreatic cancer cells, affecting both the TME and metabolic reprogramming (Ref. Reference Dai, Han, Liu, Xie, Kroemer, Klionsky, Zeh, Kang, Wang and Tang27). Ferroptosis, a regulated PCD, involves the release of damage-associated molecular patterns (DAMPs) and plays a critical role in this process. DAMPs act as mediators in regulating inflammation and immune response in the TME. Studies suggest that DAMPs released by tumour cells killed through ferroptosis can induce macrophage polarization in the TME of PDAC cells. This polarization results in the transformation of macrophages into the M2 type, further promoting tumour growth (Ref. Reference Dai, Han, Liu, Xie, Kroemer, Klionsky, Zeh, Kang, Wang and Tang27). These findings suggest that ferroptosis could be a double-edged sword in pancreatic cancer, maybe exacerbating cancer development.
Cytoplasmic aspartate aminotransferase related
NADPH plays a vital role in cellular redox reactions and biosynthesis. In pancreatic cancer cells, the production of NADPH depends on malate aspartate shuttle. This process is mainly regulated by KRAS mutation, which controls cytosolic aspartate aminotransferase (GOT1) activity (Ref. Reference Kremer, Nelson, Lin, Yarosz, Halbrook, Kerk, Sajjakulnukit, Myers, Thurston, Hou, Carpenter, Andren, Nwosu, Cusmano, Wisner, Mbah, Shan, das, Magnuson, Little, Savani, Ramos, Gao, Sastra, Palermo, Badgley, Zhang, Asara, McBrayer, di Magliano, Crawford, Shah, Olive and Lyssiotis28). It is crucial to note that in pancreatic cancer cells, NADPH production heavily relies on this process. While inhibiting GOT1 in normal cells does not have significant consequences, as NADPH production does not heavily rely on these pathways, the dependency of pancreatic cancer cells on GOT1 provides a potential avenue for inducing ferroptosis in cancer cells. Previous experiments have also shown that on the premise of inhibiting GOT1, the use of ferroptosis inducers such as erastin or inhibiting the input of GSH in pancreatic cancer cells can lead to an increase in lipid peroxide in pancreatic cancer cells and finally induce ferroptosis (Ref. Reference Kremer, Nelson, Lin, Yarosz, Halbrook, Kerk, Sajjakulnukit, Myers, Thurston, Hou, Carpenter, Andren, Nwosu, Cusmano, Wisner, Mbah, Shan, das, Magnuson, Little, Savani, Ramos, Gao, Sastra, Palermo, Badgley, Zhang, Asara, McBrayer, di Magliano, Crawford, Shah, Olive and Lyssiotis28). Therefore, targeting GOT1 inhibition holds potential for triggering ferroptosis in pancreatic cancer cells.
In pancreatic cancer cells, the production of α-ketoglutarate and aspartate relies on mitochondrial aspartate aminotransferase (GOT2), which plays a key role in this process. The aspartate generated is transported to the cytoplasm and converted by cytosolic aspartate aminotransferase (GOT1), resulting in oxaloacetic acid (OAA). Cytoplasmic malate dehydrogenase 1 (MDH1) converts OAA into malate. Malate is oxidized by malate dehydrogenase 1 (ME1) to produce NADPH (Ref. Reference Son, Lyssiotis, Ying, Wang, Hua, Ligorio, Perera, Ferrone, Mullarky, Shyh-Chang, Kang, Fleming, Bardeesy, Asara, Haigis, DePinho, Cantley and Kimmelman25).
As previously discussed, NADPH plays a crucial role in the ferroptosis process by providing hydrogen for the reduction of GSSG to its reduced form, GSH. However, in pancreatic cancer cells, the reliance on cytosolic aspartate aminotransferase (GOT1) suggests that inhibiting GOT1 decreases NADPH levels. This decrease in intracellular reductant results in accumulated toxic ROS, ultimately triggering the onset of ferroptosis.
Ferroptosis and treatment of pancreatic cancer
Diagnosis of pancreatic cancer
The low survival rate of pancreatic cancer patients is largely because pancreatic cancer is usually diagnosed in advanced stages. However, the above-mentioned discovery of unique changes related to ferroptosis in pancreatic cancer cells provides a new perspective for the early diagnosis of pancreatic cancer. The distinctive changes detected in pancreatic cancer cells offer a chance to improve early diagnosis accuracy by identifying particular biomarkers (Ref. Reference Yuan, Pratte and Giardina29). Many unique changes mentioned above have shown the specific relationship between pancreatic cancer and ferroptosis by providing potential new biomarkers to assist in the early diagnosis of pancreatic cancer, such as iron content, GPX4 expression and ferroptosis sensitivity. Some researchers have demonstrated that KRAS mutation can promote pancreatic cancer progression by implanting cells with KRAS mutation into mice and conducting cell experiments (Ref. Reference Dai, Han, Liu, Xie, Kroemer, Klionsky, Zeh, Kang, Wang and Tang27), with a close relationship to ferroptosis. In short, an assessment of tissue cell iron content, GPX4 expression and ferroptosis sensitivity, which are recognized to be impacted by KRAS gene mutations, can enable a more accurate diagnosis of pancreatic cancer in early stages. If these biomarkers can improve the diagnostic accuracy of early pancreatic cancer, it will be a great breakthrough in pancreatic cancer treatment. This enhanced diagnostic capability potentially extends patient survival to have adequate treatment and provides additional treatment alternatives.
Treatment of pancreatic cancer
Pancreatic cancer cells have higher levels of intracellular iron compared to normal cells in order to fulfil the demands of rapid cell proliferation, making them more vulnerable to ferroptosis while not damaging normal cells. Therefore, artificially controlled ferroptosis in pancreatic cancer may become a standalone treatment in the future.
Besides, to counteract the sensitivity to ferroptosis, pancreatic cancer cells exhibit increased activity of System Xc-, providing sufficient GSH to mitigate lipid peroxidation (Ref. Reference Dong, Li, Jiang, Chen and Zhou26). Therefore, strategies such as increasing iron or inhibiting System Xc- and reducing GSH levels can potentially induce ferroptosis as a therapeutic approach in pancreatic cancer (Ref. Reference Yuan, Pratte and Giardina29). These findings present the prospect of deliberately inducing ferroptosis as a targeted therapeutic strategy for pancreatic cancer.
In the context of induced ferroptosis, the integration of this process with radiotherapy has emerged as a promising approach to enhance radiotherapy effectiveness while minimizing associated side effects. By acting as a sensitizer for radiotherapy, this combination approach can effectively decrease the adverse impact of excessive radiation exposure. This, in turn, reduces harm to normal tissues and cells while simultaneously bolstering radiotherapy efficacy (Ref. Reference Lei, Mao, Yan, Zhuang and Gan30). Moreover, the combination of ferroptosis and chemotherapy shows the potential to enhance the cytotoxic effects of anticancer drugs on pancreatic cancer cells. It can also increase their sensitivity to chemotherapy agents, improving the overall effectiveness of chemotherapy (Ref. Reference Lei, Mao, Yan, Zhuang and Gan30). It is worth noting that using a ferroptosis inducer in combination with the anticancer drug gemcitabine shows great promise in reducing the resistance of pancreatic cancer cells to gemcitabine treatment.
Given the aforementioned associations between pancreatic cancer cells and ferroptosis, specifically the increased susceptibility to ferroptosis in pancreatic cancer, inducing ferroptosis is a promising approach in the future treatment of pancreatic cancer. It has significant potential for clinical applications alongside conventional chemotherapy or radiotherapy, or as a standalone treatment. This emerging approach presents promising opportunities to effectively treat pancreatic cancer and deserves further exploration.
Prognosis of pancreatic cancer
Numerous studies have demonstrated that the expression of SIRT6 decreases substantially in pancreatic cancer cells compared to normal cells. The low overall survival rate for pancreatic cancer patients and bleak prognosis are largely due to low SIRT6 levels. Furthermore, SIRT6 has a crucial function in regulating ferroptosis and glycolysis by inhibiting the NF-κB signalling pathway. In cancer cells, glycolysis is a significant energy acquisition pathway. NF-κB serves to inhibit cell ferroptosis and promote glycolysis. In contrast, SIRT6 inhibits NF-κB activity. Therefore, higher expression of SIRT6 can promote ferroptosis and restrict cell glycolysis, leading to anticancer effects (Ref. Reference Gong, Xiong, Luo, Yin, Huang, Zhou and Li31). Existing cell experiments have demonstrated that the low expression of SIRT6 in pancreatic cancer cells and the upregulation of SIRT6 expression can increase the ROS content in cells and promote the occurrence of ferroptosis in pancreatic cancer cells (Ref. Reference Gong, Xiong, Luo, Yin, Huang, Zhou and Li31). The decrease in SIRT6 expression in pancreatic cancer cells could impede ferroptosis and enhance glycolysis, thus promoting aggressive cancer cell growth. This results in a poor prognosis closely linked to reduced SIRT6 expression (Ref. Reference Gong, Xiong, Luo, Yin, Huang, Zhou and Li31). Thus, increasing the expression of SIRT6 has the potential as a feasible approach to enhancing ferroptosis in pancreatic cancer cells, leading to improved prognosis for those affected by this disease.
Cuproptosis
Overview and basic characteristics of cuproptosis
The term ‘cuproptosis’ was first coined by Peter Tsvetkov in 2022 (Ref. Reference Tsvetkov, Coy, Petrova, Dreishpoon, Verma, Abdusamad, Rossen, Joesch-Cohen, Humeidi, Spangler, Eaton, Frenkel, Kocak, Corsello, Lutsenko, Kanarek, Santagata and Golub32). Further research has demonstrated the harmful consequences of an excessive accumulation of copper can cause mitochondrial protein aggregation and cell death. Cuproptosis, which is copper dependent, is associated with mitochondrial respiration regulation (Ref. Reference Wang, Tian, Zhang, Zhen, Meng, Sun, Xu, Jia and Li33). Cuproptosis is also related to the interaction between copper ions and fatty acylated constituents within the TCA cycle.
Cuproptosis is triggered by copper-dependent fatty acylated protein accumulation along with the reduction of Fe-S cluster proteins, resulting in a distinct cell death process (Ref. Reference Luo, Li, Fu, du, He, Zhang, Wang, Zhou, Yunpeng, Li and Hong34). Therefore, the accumulation of copper and the resulting increase in fatty acylated proteins have significant impacts on regulating cuproptosis (Ref. Reference Cobine, Moore and Leary35).
In summary, cuproptosis cells characterize the higher intracellular concentrations of copper ions and fatty acylated proteins, along with the reduction of Fe-S cluster proteins. Furthermore, in terms of cytology, cuproptosis induces mitochondrial damage, which may lead to cellular respiratory dysfunction.
Metabolic pathways of cuproptosis
In normal cells, three copper transport proteins (SLC31A1 (CTR1), ATP7A and ATP7B) are primarily responsible for maintaining stable copper levels. SLC31A1 is responsible for copper uptake, while ATP7A and ATP7B aid in copper translocation. The absorption, export and storage of copper can trigger changes in copper distribution, leading to an increase in the concentration of free copper ions in cells. Several circumstances can result in this phenomenon and lead to cuproptosis: (1) direct introduction of copper into cells through the use of copper ion carriers such as ES and DSF; (2) increased expression of SLC31A1, indicating the specificity of copper permeation in reducing copper ions; (3) inhibition of GSH synthesis by BSO, which does not release free copper ions; and (4) reduction in copper export due to lower ATP7B levels (Figure 2).
Figure 2. Main pathways and metabolic pathways of cuproptosis. Excessive copper could directly lead to cuproptosis. Excessive copper entering mitochondria disrupts Fe-S cluster proteins, leading to mitochondrial damage and ultimately triggering cuproptosis. Excessive copper in the nucleus disrupts the Npl4-p97 pathway, leading to proteotoxic stress and cuproptosis.
Copper ion carriers cause intracellular copper ion levels to exceed the threshold. The excess copper leads to the aggregation of thioacylated proteins and destabilizes Fe-S cluster proteins, resulting in increased cellular protein toxicity stress and ultimately leading to cell death. The critical gene that causes cuproptosis is ferredoxin1 (FDX1), which is associated with mitochondrial enzyme modification. Mitochondria are the primary target of cuproptosis. FDX1 facilitates the acylation of dihydrothiotransferase (DLAT) and reduces Fe-S cluster proteins by converting Cu2+ to Cu+, which ultimately leads to cell death. Excessive binding of Cu (I) to lipid DLAT leads to DLAT oligomerization, which further destabilizes Fe-S clusters and causes cuproptosis. Copper also induces a decrease in Npl4-p97 stability(Figure 3).
Figure 3. The relationship between Fe-S cluster proteins and cuproptosis. With the plethora of intracellular concentration of Cu2+, excessive Cu2+ binds to DLAT, inducing abnormal oligomerization of DLAT. The increase in insoluble DLAT leads to cytotoxicity and induces cell death. Meanwhile, FDX1 transforms Cu2+ to Cu+, leading to the inhibition of Fe-S cluster protein synthesis and a decrease in intracellular Fe-S cluster proteins, resulting in cell death.
To prevent the excessive accumulation of copper ions within cells, certain stabilizing mechanisms exist (Ref. Reference Tsvetkov, Coy, Petrova, Dreishpoon, Verma, Abdusamad, Rossen, Joesch-Cohen, Humeidi, Spangler, Eaton, Frenkel, Kocak, Corsello, Lutsenko, Kanarek, Santagata and Golub32). The intracellular level of Cu is maintained at a steady state by a complex network of Cu-dependent proteins, including copper enzymes, Cu chaperones and membrane transporters. These proteins work together to regulate the intake, efflux and utilization of Cu within cells, thereby ensuring that intracellular Cu levels remain within a specific range. This regulatory function mitigates the consequences of Cu overload or deficiency. Cu2+ binds to growth factor receptors located on the cell membrane in the extracellular space and plays a regulatory role, but the process of exerting its function is not fully understood (Ref. Reference Grubman and White36).
Copper homoeostasis is crucially regulated by copper transporters, and imbalances in this delicate principle can result in cuproptosis (Ref. Reference Scheiber, Dringen and Mercer37). Disturbances in copper homoeostasis, such as excessive accumulation or aberrant transportation of copper, may exceed the intracellular copper concentration threshold and cause cellular damage (Ref. Reference Wang, Tian, Zhang, Zhen, Meng, Sun, Xu, Jia and Li33). The accumulation of copper is strongly correlated with the onset of cuproptosis.
Cuproptosis and pancreatic cancer
Emerging evidence suggests that cuproptosis plays a crucial role in the onset and progression of various cardiovascular conditions such as myocardial ischemia/reperfusion (I/R) injury, heart failure and chronic fatigue (Ref. Reference Scheiber, Dringen and Mercer37). Copper, an indispensable nutrient, exhibits both beneficial and detrimental effects in cellular contexts due to its redox characteristics. Recent developments in the field of transition metal signalling have encouraged interdisciplinary collaboration among researchers, facilitating the translation of basic research in copper chemistry and biology into clinical applications for treatment and diagnosis. This methodology aims to exploit the vulnerabilities associated with copper-dependent diseases. In cancer, the demand for copper as a metal-related nutrient increases with tumour growth and metastasis, challenging the traditional view of copper as solely an active site metabolic cofactor. The copper concentration found in tumour tissues and sera derived from patients with various cancer types, such as breast, lung, gastrointestinal, oral, gallbladder and pancreatic cancer, has been observed to increase (Ref. Reference Chen, Min and Wang38). This increased accumulation of copper may promote tumour growth by promoting the migration and proliferation of cancer cells. Recently discovered evidence highlights copper as a dynamic signal transduction metal and metal allosteric regulator. For example, copper-dependent phosphodiesterase 3B (PDE3B) participates in the process of lipolysis, while mitogen-activated protein kinases 1 (MEK1) and MEK2 are involved in cell growth and proliferation. Additionally, kinases ULK1 and ULK2 play a role in autophagy. Studies showed that cuproptosis PCD-related lncRNAs (CRLs) have been linked to Pancreatic Adenocarcinoma (PAAD), such as AC005332.6, LINC02041, LINC00857 and AL117382.1 (Ref. Reference Hao39), and cuproptosis-related genes can provide an essential basis for assessing the prognosis of pancreatic cancer patients (Ref. Reference Yingkun40). These findings reveal the diversified participation of copper, beyond its known metabolic functions.
Although it is found that cancer cells have an increased demand for copper, higher copper content may not only fail to induce cuproptosis to reach the treatment but also promote proliferation of cancer cells and damage to normal tissues. But cuproptosis provides a direction to induce a similar apoptotic process by adjusting intracellular fatty acylation proteins and Fe-S cluster proteins, which could be a promising approach to treat pancreatic cancer. However, it still needs further research to find out more significant associations between pancreatic cancer and cuproptosis to realize the application of cuproptosis in pancreatic cancer treatment.
Lysozincrosis
Overview and basic characteristics of lysozincrosis
Zinc plays a crucial role in cellular processes. When the concentration of zinc in cells exceeds moderate levels, it can lead to lysozincrosis. Lysozincrosis results from the excessive zinc accumulation, which impedes the synthesis of ATP and ultimately leads to non-apoptotic cell death.
Therefore, the increase in zinc concentration is a necessary prerequisite for lysozincrosis, and the damage to mitochondria and lysosomes is the result of excessive zinc concentration, accompanied by a decrease in intracellular ATP. A summary of the characteristics of lysozincrosis based on existing research is presented here, but further in-depth research on lysozincrosis is needed.
Metabolic pathways of lysozincrosis
The mammalian zinc transporters are categorized into two families, the SLC39A and the SLC30A families (Refs. Reference Prasad, Raina, Mishra, Tomar, Kumar, Palmer, Maroni and Agarwal41, Reference Fukada and Kambe42). The SLC39A family comprises 14 members, including ZIP1 and ZIP14. These members are responsible for facilitating the transport of zinc ions from the extracellular environment or organelles into the cytoplasm, leading to the absorption and uptake of zinc ions (Ref. Reference Meng, Wang, Li and Zhang43). Conversely, the function of the SLC30A family, which contains 10 members, is opposite to that of the SLC39A family. Zinc transporter families facilitate the release of zinc ions from the cytoplasm into organelles or the extracellular space, promoting their efflux (Ref. Reference Meng, Wang, Li and Zhang43). Recent research indicates that these transporter families not only mediate intracellular zinc ion homoeostasis but also have complex effects on tumour development and metabolic disorders. Therefore, these transporter families have become key areas of research in the fields of zinc nutrition and metabolic disorders (Ref. Reference Nagamatsu, Nishito, Yuasa, Yamamoto, Komori, Suzuki, Yasui and Kambe44).
The two main groups of zinc transporters show different patterns of distribution within various subcellular organelles, cells and organs. For example, ZIP4/SLC39A4, ZIP5/SLC39A5, ZIP6/SLC39A6, ZIP10, ZIP14 and ZnT1/SLC30A1 are predominantly located on the cell membrane, while many other zinc transporters are mainly found on different organelle membranes. Regarding tissue and organ distribution, the expression of ZIP4/SLC39A4 and ZnT5 is prominent in small intestinal epithelial cells, whereas ZIP10 and ZnT1 are prevalent in renal epithelial cells. Furthermore, pancreatic gland cells contain ZIP5, ZnT1 and ZnT2, and ZIP8 and ZIP10 are distributed in blood cells, among other locations (Ref. Reference Nagamatsu, Nishito, Yuasa, Yamamoto, Komori, Suzuki, Yasui and Kambe44).
Mucous phospholipid TRP channel 1 is a cation channel that allows both Ca2+ and Zn2+/Fe2+ ions to pass through. It is mainly located on the membrane of late endosomes and lysosomes in different types of mammalian cells. The viscophospholipid TRP channel 1 plays a crucial role in lysosomal functionality by releasing both Ca2+ and Zn2+. This process is dependent on the levels of lysosomal Zn2+ (Ref. Reference Cheng, Shen, Samie and Xu45) (Figure 4).
Figure 4. Main pathways and metabolic pathways of lysozincrosis. The SLC39A and SLC30A families are two zinc transporter families found in mammals that regulate the transport of zinc ions inside and outside of cells, respectively. The SLC39A6 protein is primarily located in the cell membrane and transports zinc ions from the extracellular layer or organelles to the cytoplasm. The expression of SLC39A6 is associated with pancreatic cancer proliferation. Inhibiting SLC39A6 significantly decreases the metastasis and proliferation of pancreatic cancer cells.
When the intracellular concentration of zinc abnormally increases, excessive zinc can cause damage to lysosomes and mitochondria, affecting cellular ATP synthesis and supply, resulting in insufficient intracellular energy and ultimately leading to cell death.
Lysozincrosis and pancreatic cancer
Zinc homoeostasis in human cells is tightly regulated by the SLC39A, SLC30A and metallothionein families. The occurrence and development of cancer cells will be affected by disruptions in zinc homoeostasis or disrupt it themselves. Although decreased serum zinc levels have been observed in individuals with pancreatic cancer, there is limited knowledge about the expression patterns and prognostic consequences of genes associated with zinc homoeostasis in pancreatic cancer.
Existing studies have identified a relationship between the expression level of SLC39A6 and tumour size, along with lymph infiltration. A previous study has demonstrated the relationship between SLC39A6 and pancreatic cancer by creating a nude mouse model with downregulated SLC39A6 expression. This research revealed that blocking SLC39A6 could effectively impede the growth and spreading of pancreatic cancer cells in both in vivo and in vitro experiments. These findings demonstrate the correlation between SLC39A6 expression and pancreatic cancer cell proliferation. It is suggested that targeting SLC39A6 could significantly reduce both metastasis and proliferation of pancreatic cancer cells (Refs. Reference Zhu, Huo, Zhi, Zhan, Chen and Hua46, Reference Liu, Yang, Zhang, Zhou, Cui, Zhang, Fung, Zheng, Allard, Yee, Ding, Wu, Liang, Zheng, Fernandez-Zapico, Li, Bronze, Morris, Postier, Houchen, Yang and Li47). Through in-depth research in this direction, artificially downregulated SLC39A6 expression can lead to lysozincrosis and reduce both metastasis and proliferation of pancreatic cancer cells, which could be a potential approach to treating pancreatic cancer or reducing its recurrence.
Compared to the normal pancreatic control group, there was an increase in the expression levels of ZIP1, ZIP3, ZIP4, ZIP7, ZIP9, ZIP10, ZIP11, ZIP13, ZnT1, ZnT5, ZnT6, ZnT7 and ZnT9, whereas the expression levels of ZIP5, ZIP14, ZnT2, MT1G, MT1H and MT1X were found to decrease. Notably, higher expression of ZIP4, ZIP11, ZnT1 or ZnT6 indicates a poor prognosis. The aforementioned findings hint at the potential involvement of PAAD patients in different cancer-related processes and pathways, which can be linked to differentially expressed genes relevant to zinc homoeostasis (Ref. Reference Zhu, Huo, Zhi, Zhan, Chen and Hua46). Detecting the above-mentioned biomarkers to differentiate normal pancreatic tissue from pancreatic cancer tissue may lead to effective approaches to providing better prognosis for pancreatic cancer patients and increase their 5-year survival rate.
As an essential metal ion and nutrient, zinc plays a crucial role in cellular function. Disruptions in zinc homoeostasis have been linked to mechanisms of cell death and development of chemoresistance in pancreatic cancer. A recent study revealed that circular RNA ANAPC7 has inhibitory effects on pancreatic cancer growth by sequestering miR-373 and improving the overall disease condition. This study identified PHLPP2 as a new target gene of miR-373 in pancreatic cancer as it regulates AKT signal transduction. PHLPP2, a protein phosphatase, impedes CREB phosphorylation, a zinc-dependent transcription factor monitored by ZIP4, thereby promoting miR-373 expression through transcriptional regulation. This investigation revealed a previously unknown feedforward cycle involving CREB, miR-373 and PHLPP2 in the signalling axis mediated by ZIP4 in pancreatic cancer. Furthermore, the study discovered that circANAPC7 reduces TGF-β expression and secretion via STAT5-β, effectively reversing muscle atrophy induced by ZIP4 and improving the overall prognosis of the disease (Ref. Reference Shi, Yang, Liu, Zhang, Zhou, Luo, Fung, Xu, Bronze, Houchen and Li48). It showed the crucial influence of ZIP4 in lysozincrosis and the unique association between pancreatic cancer and lysozincrosis, guiding the direction for the further research on the combination of lysozincrosis and pancreatic cancer treatment.
ZIP4, a key zinc transporter, is upregulated in pancreatic cancer. Overexpression of ZIP4 triggers the activation of the IL6/STAT3 pathway, leading to an increased expression of VEGF and MMP2. However, the specific mechanism by which the activation of downstream signalling pathways enhances migration and invasion in pancreatic cancer is unclear (Ref. Reference Zhu, Huo, Zhi, Zhan, Chen and Hua46). In view of the particularity of lysozincrosis, the application of lysozincrosis in the treatment of pancreatic cancer may need further research, but it has inspired a new way to assist the early diagnosis of pancreatic cancer and its prognosis by measuring zinc transporter.
Discussion
Ferroptosis is a unique PCD with specific metabolic pathways that provide insights into its induction. Iron overload is a fundamental trigger for ferroptosis, leading to a cascade of PUFAs undergoing peroxidation. This accumulation of toxic intracellular ROS ultimately leads to cell death (Ref. Reference Ursini and Maiorino14). Notably, cells undergoing ferroptosis exhibit increased levels of iron and ROS in comparison to normal cells, emphasizing the pivotal role of iron in this process. The destructive impact of lipid peroxidation on the integrity of cellular membranes adversely affects diverse organelles. Among them, mitochondria are particularly susceptible and show significant changes compared to other organelles. Deciphering the interconnected metabolic pathways associated with ferroptosis provides insights into inducing and inhibiting this process through targeted interventions.
Significant advances in ferroptosis research suggest that the practical application of ferroptosis-based methods in pancreatic cancer treatment is imminent. Pancreatic cancer presents distinctive challenges due to its susceptibility to drug resistance when compared to other cancers (Ref. Reference Yang, Zhang, Wen, Xiong, Huang, Wang and Liu7). Mutations in pancreatic cancer cells enhance their susceptibility to ferroptosis. Given the reliance of pancreatic cancer cells on specific components, the targeting of ferroptosis exhibits potential to become a novel therapy by inducing cell death and overcoming drug resistance during pancreatic cancer treatment.
Nevertheless, due to the relationship between ferroptosis and immunity, there are challenges in using ferroptosis in pancreatic cancer treatment. The impact of ferroptosis on immunity primarily occurs within the TME. It is important to pay caution as the release of DAMPs from dying cells containing iron can affect the polarization of macrophages in the TME towards the M2 subtype, exacerbating the condition of pancreatic cancer (Ref. Reference Dai, Han, Liu, Xie, Kroemer, Klionsky, Zeh, Kang, Wang and Tang27). This effect is not limited to macrophages, but also extends to T cells. It has been demonstrated that the activity and function of CD8+ T cells and CD4+ T cells are influenced by lipid peroxidation and ferroptosis. Additionally, the activation of CD8+ T cells downregulates the expression of System Xc-, which reduces the uptake of cystine by cancer cells, thereby reducing GSH in cancer cells and improving the sensitivity of cells to ferroptosis. This effect of ferroptosis on T cells may also be utilized in pancreatic cancer treatment in the future, but more in-depth research is needed. Therefore, it is crucial to consider the potential pathological implications of ferroptosis in the treatment of pancreatic cancer as it may contribute to the malignant progression of the disease. Moreover, while it is possible to induce ferroptosis in pancreatic cancer cells according to their unique associations, it is unclear whether this method may cause harm to healthy cells or have negative impacts on patients. It highlights the complex and diverse biological impacts of ferroptosis in the treatment of pancreatic cancer. This underscores the importance of a comprehensive understanding when utilizing ferroptosis as a therapeutic approach in the future.
Before considering ferroptosis induction as a viable cancer treatment approach, it is crucial to address these concerns and investigate potential solutions. Moreover, if the aforementioned obstacles can be overcome, it warrants the enquiry of whether inducing ferroptosis for pancreatic cancer treatment can be extended to other domains. By exploring the correlation between other cancer types and ferroptosis, insights into and approaches to addressing cancer-related problems may be obtained. Furthermore, the investigation of ferroptosis could yield insights into other metal-related forms of cell death, potentially paving the way for further research and advancements in related fields.
Copper and zinc are essential cofactors for enzymes throughout the organism. They exhibit a dual nature, exerting their function at moderate intracellular concentrations while causing toxicity and leading to cell death at high intracellular concentrations.
Genetic variations in copper homoeostasis contribute to severe and potentially life-threatening diseases. Additionally, agents involved in copper ion transport and chelation are acknowledged as potential anticancer therapeutics (Ref. Reference Zhang, Dang, Liu, Qiao and Sun49). The accumulation of copper and increase in of fatty acylated proteins are key factors in regulating cuproptosis (Ref. Reference Wood, Canto, Jaffee and Simeone50). Disruptions in copper homoeostasis can influence cancer cell migration and proliferation, promoting tumour growth. When cuproptosis or a similar apoptotic process inspired from cuproptosis is used in cancer treatment, considering further research on cuproptosis is done, it is necessary to consider the efficacy and the risk to normal tissues and cells by cuproptosis. Certain cancers with increased mitochondrial metabolism, tumours containing stem cell-like cells and drug-resistant cancers are expected to display more positive responses to these treatments. Proteasome inhibitors have demonstrated the ability to induce elevated mitochondrial metabolic states in cells. In addition, the use of copper ion carriers in tumour treatment provides a promising avenue for future applications.
The recently discovered lysozincrosis, a distinct type of regulatory cell death, shows potential in cancer and disease research. ZIP4, a key protein, playing a significant role in cell proliferation, metastasis, drug resistance and pancreatic cancer-related cachexia, plays a crucial role in finding out the deeper association between pancreatic cancer and lysozincrosis. Downregulating lysozincrosis gene expression such as SCL39A6 to intervene pancreatic cancer is a promising direction. To explore the complex interplay between zinc and cancer metabolism, especially in relation to tumour initiation, growth, metastasis, stem cell habitats and inflammatory responses, further research into nutritional zinc sensing is crucial. Utilizing methodologies such as advanced sequencing, proteomics, metabolomics and other analytical tools can reveal new understandings of metal biology in relation to cancer and other illnesses.
Nowadays, with the advances in studying metal-related cell death, new types of metal-related cell death have been found. Calcicoptosis is a new form of metal-related cell death that has great potential in the treatment of pancreatic cancer. Calcium participates in normal physiological activities in cells, but excessive calcium can lead to mitochondrial damage and other cellular pathologies, which is called calcicoptosis. In the tumour environment, it may lead to an increase in intracellular calcium content in cancer cells. At the same time, radiotherapy and chemotherapy may also increase intracellular calcium levels. If more in-depth research can be carried out on calcicoptosis, it may also become an effective method for the treatment of pancreatic cancer in the future. There may also be great research prospects for other undetected or poorly studied metal-related cell deaths.
Finally, a table listing the types of metal death discussed and their activators is presented to help understand these processes and help future research in the field (Table 1).
Table 1. Activators of the studied metal-related cell death mechanisms
Conclusion
This review explores the intrinsic characteristics of pancreatic cancer and associated treatment challenges objectively. It discusses three separate forms of metal-related cell death, highlighting their potential as adjunctive therapies for pancreatic cancer treatment due to their unique characteristics, pathways and associations with the disease, which makes their association with pancreatic cancer especially remarkable since they affect different aspects of the disease. By utilizing these distinct traits, this review endeavours to provide innovative insights into and strategies for future treatments of pancreatic cancer. Pancreatic cancer cells have a higher level of iron ions, PLOOH and GSH, which makes them highly sensitive to ferroptosis. Therefore, ferroptosis has more feasibility in the diagnosis, treatment and prognosis of pancreatic cancer. Cuproptosis is a process that occurs due to the accumulation of copper ions along with the reduction of Fe-S cluster proteins, resulting in cell death. Recent studies have revealed the potential of cuproptosis in pancreatic cancer treatment. However, lysozincrosis requires further in-depth research to be applied in pancreatic cancer treatment. However, it is essential to acknowledge that the implementation of these three types of metal-related cell death as treatment methods may have adverse effects on the body, making them double-edged swords. Therefore, comprehensive research dedicated to this topic is crucial to address these potential challenges. Mitigating the adverse effects associated with metal-related cell death in clinical applications is a crucial aspect for future translational efforts. The successful exploration of metal-related cell death as a therapeutic approach for pancreatic cancer treatment could have implications that extend beyond this specific field.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Authors’ contribution
S.J. Dai, H.W. Sun and H.R. Kong designed the review and supervised the review. S.J. Dai, Z.M. Chen, C.C. Wang, Y. Ja, T.T. Liu, K. Lin, L.Y. Huang, C.Q. Ren and S.Y. Zhou participated in writing the manuscript.
Data availability statement
No data were used for the research described in the article. None of the data associated with the review have been deposited into a publicly available repository.
Funding statement
This work was supported by grants from International Clinical Exchange Program of Health Commission of Zhejiang Province, Exploration Project of Zhejiang Natural Science Foundation (LY24H160025), Project of Zhejiang Provincial Administration of Traditional Chinese Medicine (GZY-ZJ-KJ-24088), Unveiling and Leading Project of Wenzhou Medical University Oncology Discipline Group (z2–2023018) and Youth Cultivation Project of National Clinical Key Specialty (General Surgery, 2021).
Competing interests
The authors declare no conflicting financial interests.
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