Screening and Validation of Genes Associated With Lysosomal‐Dependent Cell Death in Colorectal Cancer

This study investigates the correlation between CRC and lysosomal-dependent cell death (LDCD) to identify potential therapeutic targets and prognostic indicators. Utilizing CRC datasets (TCGA-CRC) and GSE17538, differentially expressed genes and LDCD-related genes (LDCDRGs) were analyzed to identify candidate genes. A risk model was constructed using Cox regression analysis, proportional hazards test and least absolute shrinkage and selection operator analysis. Independent prognostic factors were determined through Cox analysis (univariate and multivariate). Additionally, nomogram establishment, enrichment analysis, tumor immune microenvironment analysis, sensitivity analysis of chemotherapeutic drugs and single-cell sequencing analysis were conducted. Furthermore, prognostic gene expression in CRC and normal groups was further evaluated in TCGA-CRC as well as in clinical samples. A total of 37 candidate genes were identified. ATP6V0A4, CLU and IL13RA2 were selected for constructing a risk model. The risk model, incorporating independent prognostic parameters such as risk score, age and pathological T stage, exhibited favorable diagnostic performance for CRC. Tumor immune microenvironment analysis showed higher dysfunction, exclusion, and tumor immune dysfunction and exclusion scores in the high-risk group compared to the low-risk group. Significant differences were observed in the 50% inhibitory concentration of 84 drugs between the two risk subgroups. ENCs and myeloid cells were regarded as key cells. Importantly, IL13RA2 exhibited higher expression in patients with CRC, while CLU was more highly expressed in normal samples. This study identified ATP6V0A4, CLU and IL13RA2 as potential biomarkers associated with lysosome-mediated cell death in CRC, providing insights for diagnosis and treatment.