Metallic elements and their molecular roles in gastric cancer: Pathogenic mechanisms and therapeutic implications

Table 1 Mechanisms of action of various metals in gastric cancer

Metal element	Category of core mechanism	Specific molecular mechanism	Ref.
Fe2+	Oxidative damage mediated by the Fenton reaction	Excess free Fe2+ (elevated serum ferritin, high expression of divalent metal transporter 1) generates ∙OH via the Fenton reaction. ∙OH attacks DNA, causing base damage (e.g., 8-hydroxydeoxyguanosine) and double-strand breaks and thereby inducing gene mutations; meanwhile, ∙OH oxidizes cell membrane lipids and disrupts cell structure integrity	Dizdaroglu and Jaruga[48], Kabat and Rohan[49]
	Activation of pro-tumor pathways and metabolic reprogramming	Low concentrations of reactive oxygen species activate pro-tumor pathways such as NF-κB and mitogen-activated protein kinase, promoting GC cell proliferation and anti-apoptosis. Fe2+ upregulates mitochondrial respiratory chain proteins (e.g., cytochrome C oxidase) to enhance oxidative phosphorylation for energy supply. Fe2+ induces high expression of hepcidin, inhibiting Fe2+ efflux and exacerbating Fe2+ accumulation to form an “Fe2+-dependent” cycle	Seĭlanov et al[77], Morgan and Liu[78], Tomeckova et al[79]
	Inhibition of anti-tumor immunity	Excess Fe2+ induces polarization of macrophages to the M2 phenotype, leading to IL-10 and transforming growth factor beta secretion. Fe2+ suppresses the antigen-presenting ability of dendritic cells and inhibits the activity of CD8+ T cells and natural killer cells, facilitating GC immune evasion	Yu et al[80], Chen et al[81], Agoro et al[82]
Cu2+	Excess Cu2+ triggers cuproptosis	Free Cu2+ beyond homeostasis (dysfunction of ATPase copper transporting alpha/beta, high expression of copper transporter 1) binds to the thiol groups of lipoic acid residues in TCA cycle lipoylated proteins (dihydrolipoamide acetyltransferase, dihydrolipoamide dehydrogenase), disrupting protein structure and promoting cross-linking to form aggregates. This leads to TCA cycle arrest and proteotoxic stress, ultimately inducing GC cell death characterized by mitochondrial swelling, serving as a potential therapeutic target	Tsvetkov et al[51], Tang et al[83], Concilli et al[84], Clifford et al[85]
	Regulation of pro-tumor pathways by physiological concentrations	Cu2+ acts as a cofactor for enzymes (e.g., tyrosinase, superoxide dismutase), activating pathways such as phosphoinositide 3-kinase/protein kinase B and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase to promote GC cell proliferation and migration. Cu2+ enhances the activity of MMPs, accelerating extracellular matrix degradation and facilitating invasion and metastasis	Guo et al[86]
Zn2+	Gene regulation mediated by ZFPs	Zn2+ stabilizes the “finger-like” structure of ZFPs: Pro-tumor ZFPs (ZFP217, ZFP X-linked) bind to the promoters/enhancers of cyclin D1 and MYC proto-oncogene, bHLH transcription factor, accelerating cell cycle progression and metabolic reprogramming; snail family transcriptional repressor 1 inhibits E-cadherin and p53, disrupting cell adhesion and weakening proliferation constraints	Fang et al[87], Ecco et al[88]
	Maintenance of MMP activity	Zn2+ is a key ion in the catalytic center of MMPs (MMP2/9/7), helping them polarize substrate peptide bonds and hydrolyze vascular basement membrane collagen IV and intercellular adhesion molecules to promote angiogenesis and invasion. MMP-3 activates pro-MMP-9 via Zn2+, amplifying extracellular matrix destruction	Agrawal et al[89], Khrenova et al[90]
Ca2+	Intracellular Ca2+ elevation activates pro-tumor signals	GC cells upregulate Ca2+ channels (transient receptor potential canonical, voltage-gated calcium channel) or release endoplasmic reticulum Ca2+, increasing intracellular Ca2+. This activates CaM/Ca2+/CaM-dependent protein kinase II, which further activates pathways such as NF-κB and Wnt/β-catenin to promote proliferation, migration, and anti-apoptosis; this also enhances phospholipase C activity, accelerating inositol 1,4,5-trisphosphate production and forming a positive feedback loop of Ca2+ signaling	Liu et al[91]
	Homeostasis imbalance induces apoptosis	Under extreme conditions (e.g., chemotherapy), excessive intracellular Ca2+ disrupts the mitochondrial membrane, promoting cytochrome C release and activating the caspase cascade. Ca2+ also activates Ca2+-dependent nucleases, accelerating DNA fragmentation and enhancing the apoptotic effect	Yu et al[92], Colbran[93]
	Regulation of the tumor microenvironment	Extracellular Ca2+ promotes GC-associated fibroblasts to secrete IL-6 and vascular endothelial growth factor. Ca2+ enhances the migration and proliferation of vascular endothelial cells, facilitating tumor angiogenesis	Sadras et al[94]

Ca²⁺: Calcium; CaM: Calmodulin; Cu²⁺: Copper; Fe²⁺: Iron; GC: Gastric cancer; IL: Interleukin; MMP: Matrix metalloproteinase; NF-κB: Nuclear factor-kappa B; ∙OH, hydroxyl radical; TCA: Tricarboxylic acid; ZFPs: Zinc finger proteins; Zn²⁺: Zinc.