CIAO1 as a crucial signature gene of cuproptosis in gastric cancer.

Gastric cancer is a global health challenge, necessitating the identification of novel biomarkers and therapeutic targets. The present study aimed to assess the role of cuproptosisrelated genes (CRGs) in gastric cancer, with the goal of establishing a predictive model consisting of key regulators with prognostic significance, thereby enabling the identification of key genes. Data from The Cancer Genome Atlas and Gene Expression Omnibus databases were used to analyze CRGs in stomach adenocarcinoma (STAD). Least absolute shrinkage and selection operator regression analysis was applied to create a risk model, and its predictive accuracy was confirmed for several clinical subgroups. Moreover, the prognostic value of essential regulators was evaluated through multiple analyses. A risk model with 15 CRGs was used to effectively predict STAD prognosis, demonstrating areas under the receiver operating characteristic curve values of 0.822, 0.811 and 0.922 for 1-, 3- and 5-year overall survival rates, respectively. The risk scores were associated with survival and tumor site. Among the CRGs, the gene for cytosolic iron-sulfur assembly component 1 (CIAO1) was revealed to be critical and associated with histological type, age and treatment outcome. Moreover, single-cell analysis demonstrated that CIAO1 is highly expressed in numerous types of cancer cells, and a high expression of CIAO1 was associated with upregulated transcription levels of immune checkpoints, increased tumor mutation load and decreased immune scores, highlighting its complex role in the tumor microenvironment. CIAO1 knockdown experiments were performed, and eliminating CIAO1 was associated with a reduction in the levels of iron-sulfur proteins and an increase in heat shock protein 70 expression, thereby inducing copper-dependent cell death. Furthermore, treatment with the drugs dasatinib and AT-9283 were associated with an inhibition of CIAO1 expression in gastric cancer cells, and decreased rates of tumor spread and invasion. Taken together, the findings of the present study suggest that CIAO1 is a promising biomarker both for assessing prognosis and evaluating the tumor immune microenvironment of gastric cancer.