Exploring the functional role of palmitoylation genes in clear cell renal cell carcinoma and their impact on tumor microenvironment.

OBJECTIVE

The current work focused on elucidating the regulatory mechanisms of palmitoylation-related genes (PRGs) in influencing the occurrence and development of clear cell renal cell carcinoma (ccRCC), and identifying possible biomarkers and therapeutic targets.

METHODS

Integrative analyses were performed using multiple databases. Two-sample Mendelian randomization (MR) was first applied for identifying PRGs causally associated with ccRCC. Findings were then validated by summary-data-based Mendelian randomization (SMR), bioinformatics analyses, and experimental verification. Functional enrichment and molecular docking were used to predict target interactions, while single-cell transcriptomic analysis was performed for assessing the relations of key PRGs with the tumor microenvironment (TME). Mediation analysis further explored upstream and downstream regulatory mechanisms.

RESULTS

In total, 22 PRGs associated with ccRCC were identified. Among these, ZDHHC18 emerged as a significant risk factor based on both MR and SMR results. Bioinformatics, molecular docking, and laboratory assays revealed that ZDHHC18 was upregulated and validated LYPLA2 as its downstream palmitoylation target. Pathway enrichment and single-cell analyses indicated that ZDHHC18 might shape immune heterogeneity in ccRCC by influencing multiple immune cell populations within the TME. Mediation analysis suggested that mitochondrial DNA copy number (mtDNA-cn) regulated ZDHHC18 expression, which in turn promoted ccRCC progression through four specific immune cell traits.

CONCLUSION

This study defines an mtDNA-cn-ZDHHC18-immune cell traits axis that mechanistically links mitochondrial function, palmitoylation, and immune modulation in ccRCC. These findings expand the current understanding of palmitoylation in renal cancer biology and identify ZDHHC18 as a potential metabolic-immune regulator and therapeutic target.

CLINICAL TRIAL NUMBER: Not applicable.