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

Gastric cancer (GC) remains among the leading causes of cancer-related mortality globally. Increasing evidence indicates that metallic elements such as iron, copper (Cu²⁺), zinc, and calcium (Ca²⁺) play crucial roles in GC pathogenesis, diagnosis, and treatment through diverse molecular mechanisms. This review systematically summarizes recent advances in the application of metallomics in GC. Relevant studies published up to 2024 were retrieved from PubMed, Web of Science, and Scopus using keywords including "gastric cancer", "metal ions", "metallomics", and "metal-based therapy". After screening and evaluation, representative studies elucidating the roles of metallic elements in GC were analyzed and synthesized. The findings revealed that iron overload induces oxidative stress and immune suppression via the Fenton reaction. Further analysis indicated that Cu²⁺ imbalance triggers mitochondrial dysfunction and cuproptosis, zinc deficiency disrupts transcriptional regulation through zinc finger proteins and metalloproteinases, and Ca²⁺ dysregulation activates Ca²⁺/calmodulin-dependent protein kinase kinase- AMP-activated protein kinase signaling to promote proliferation and chemoresistance. Advances in analytical techniques such as laser ablation inductively coupled plasma mass spectrometry have enabled spatial mapping of metal distributions in tumors, providing novel diagnostic and prognostic insights. Moreover, metal-based anti-cancer drugs and combination regimens involving traditional Chinese medicines exhibit promising therapeutic potential. Understanding the molecular crosstalk of metal metabolism offers new perspectives for precision diagnosis and targeted treatment in GC.