Potential Therapeutic Strategies Targeting CRELD1: Regulation of the Immune Microenvironment in Clear Cell Renal Cell Carcinoma

Background Clear cell renal cell carcinoma (ccRCC) is a highly aggressive kidney cancer subtype with poor survival rates, particularly in metastatic cases. While proteomics and immune dysregulation are implicated in ccRCC, the causal relationships between circulating proteins and ccRCC remain poorly understood. This study investigates the causal roles of circulating proteins in ccRCC pathogenesis and identifies potential therapeutic targets. Methods We conducted a two-sample Mendelian randomization (MR) analysis using cis-pQTL data from genome-wide association studies (GWAS) to identify causal relationships between circulating proteins and ccRCC. Colocalization analysis was performed to validate shared genetic loci influencing both protein levels and ccRCC susceptibility. Transcriptomic data and immune infiltration analysis explored protein expression and immune regulatory roles. Molecular docking analysis identified compounds targeting key proteins. Results Two proteins, CRELD1 and KDEL2, were identified as significantly associated with ccRCC (FDR < 0.05). CRELD1 emerged as a protective factor (OR = 0.909, 95% CI: 0.879–0.940), with consistent downregulation in ccRCC tissues. KDEL2 also demonstrated a protective association (OR = 0.747), though it was paradoxically upregulated in tumor tissues, suggesting a possible compensatory response to cellular stress. Colocalization analysis confirmed shared causal variants for CRELD1 and ccRCC susceptibility (PPH3 + PPH4 > 0.9). CRELD1 positively correlated with adaptive immune cells, including T-helper and regulatory T cells, highlighting its role in modulating the tumor immune microenvironment. Molecular docking identified Gentamicin as a promising compound targeting CRELD1, with a binding energy of -6.2 kcal/mol. Conclusions CRELD1 is a novel tumor suppressor and immune regulator in ccRCC, with potential as a diagnostic biomarker and therapeutic target. Gentamicin may offer a therapeutic strategy to upregulate CRELD1, improving immune responses and tumor suppression. These findings provide actionable insights for precision oncology in ccRCC.