Comprehensive analysis of the function of helicobacter-associated ferroptosis gene YWHAE in gastric cancer through multi-omics integration, molecular docking, and machine learning.

ABSTRACT

Gastric cancer is strongly associated with Helicobacter pylori (H. pylori) infection. However, the molecular mechanisms underlying the development of gastric cancer in the context of H. pylori infection, particularly in relation to ferroptosis, remain poorly understood. In this study, we investigated the role of the Helicobacter-associated ferroptosis gene YWHAE in gastric cancer. We analyzed multi-omics data, performed molecular docking, and employed machine learning to comprehensively evaluate the expression, function, and potential implications in gastric cancer, including its influence on drug sensitivity, mutation, immune microenvironment, immunotherapy, and prognosis. Our findings demonstrated that the YWHAE gene exhibits high expression in both H. pylori-associated gastritis and gastric cancer. Pan-cancer analysis revealed elevated expression of YWHAE in several cancer types compared to normal tissues. We also examined the methylation, single nucleotide variations (SNVs), and copy number variations (CNVs) associated with YWHAE. Single-cell analysis indicated that the YWHAE gene is expressed in various cell types, with its expression level potentially influenced by H. pylori infection. Functionally, we observed a positive correlation between YWHAE gene expression and ferroptosis in gastric cancer and associated with multiple cancer-related signaling pathways, including MAPK, NF-κB, and PI3K. Furthermore, we predicted five small molecule compounds that show promise for treating gastric cancer patients and screened five drugs with the highest correlation with YWHAE and validated them by molecular docking. Additionally, significant differences were observed in various immune cell types and immunotherapeutic response between the high and low YWHAE gene expression groups. Moreover, we found a positive correlation between YWHAE gene expression and the tumour mutation burden (TMB). By applying 10 machine learning algorithms and 101 integration combinations, we developed a prognostic model for YWHAE-related genes. Finally, qRT-PCR and immunohistochemistry (IHC) consistently demonstrated the upregulation of YWHAE in gastric cancer. In conclusion, we conducted a comprehensive analysis of YWHAE gene in gastric cancer. Our findings provided novel insights into the role of YWHAE as a gene associated with H. pylori infection and ferroptosis in gastric cancer and expanded our understanding of the molecular mechanisms underlying gastric carcinogenesis.