Multi-omics analysis suggests ZDHHC18 as a potential risk factor for clear cell renal cell carcinoma linked to myeloid DC morphology

BACKGROUND: Protein palmitoylation, a key posttranslational modification, is involved in cell signaling, protein stability, and tumor immune microenvironment (TIME) regulation. ZDHHC3 is known to mediate clear cell renal cell carcinoma (ccRCC) immune evasion by enhancing PD-L1 stability, but the roles of other palmitoyltransferases in ccRCC remain unclear. In this study, we analyzed genomic and transcriptomic data via a multiomics approach to investigate the expression patterns and potential regulatory mechanisms of known palmitoylation enzymes in ccRCC. METHOD: By integrating multiple large-scale data sets from GEO, GWAS, and the eQTLGen Alliance, we systematically screened differentially expressed palmitoylated genes using differentially expressed genes (DEG) analysis, two-sample Mendelian randomization (MR) analysis, SMR analysis based on pooled data, mediated Mendelian randomization analysis, and single-cell RNA sequencing technology, and deeply analyzed their potential causal association with renal clear cell carcinoma (ccRCC) and its possible mediating factors. Finally, this study further explored the specific expression patterns of these genes in tumor tissues, providing new perspectives and potential targets for understanding the molecular mechanisms of ccRCC. RESULTS: DEG analysis revealed that 15 palmitoylation enzymes were abnormally expressed in ccRCC tissues. Both MR and SMR analyses suggested a potential causal association between higher ZDHHC18 expression and an increased risk of ccRCC. Mediation MR analysis further revealed that the forward scatter area (FSC-A) phenotype of myeloid dendritic cells (mDCs) was a potential mediating factor between ZDHHC18 and ccRCC (mediation effect: 12.3%). Single-cell RNA sequencing data indicated a high expression of ZDHHC18 in tumor-infiltrating dendritic cells. CONCLUSIONS: This multi-omics analysis shows the specific overexpression of ZDHHC18 in tumor tissue DCs and suggests it may function by potentially modulating the FSC-A phenotype of mDCs, thereby potentially contributing to ccRCC pathogenesis. These findings provide new directions for discovering novel therapeutic targets for ccRCC.