Integrative omics profiling of CRELD2 in ccRCC: a nexus of genetics, prognosis, and tumor microenvironment.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive form of renal malignancy. Although therapeutic strategies such as targeted agents and immune checkpoint inhibitors have progressed, the prognosis for patients with advanced ccRCC remains unsatisfactory. Cysteine-rich epidermal growth factor-like domain 2 (CRELD2), a protein localized to the endoplasmic reticulum, is involved in several biological processes, yet its function in ccRCC has not been clearly characterized. METHODS: We conducted an integrative multi-omics study to investigate the role of CRELD2 in ccRCC. The study incorporated mendelian randomization (MR), bulk and single-cell RNA sequencing, immunohistochemistry, immune infiltration analysis, and spatial transcriptomics to explore expression patterns, prognostic value, cellular distribution, and potential biological implications of CRELD2. RESULTS: MR and summary-data-based MR analyses identified CRELD2 as a genetically supported candidate associated with RCC susceptibility. Elevated CRELD2 expression was confirmed at both mRNA and protein levels in ccRCC and correlated with worse overall survival independently. Single-cell analysis revealed preferential CRELD2 enrichment in endothelial and B-cell compartments, with CRELD2-high subsets showing shared enrichment of TNFA/NFκB, MTORC1, ROS, and oxidative phosphorylation pathways. Immune infiltration analysis linked CRELD2 expression to a B-cell-related immune infiltration profile, while spatial transcriptomics showed CRELD2 enrichment in tertiary lymphoid structure (TLS)-associated regions. Across single-cell and spatial analyses, TNFA/NFκB-related immune-inflammatory signaling represented a recurrent CRELD2-associated pathway feature. CONCLUSION: This study pointed out the CRELD2-centered TLS-associated immune-inflammatory conceptual axis, linking CRELD2 expression, endothelial/B-cell cellular contexts, B-cell-related immune infiltration, TLS-associated spatial localization, and recurrent TNFA/NFκB pathway enrichment via multi-omics and supporting it as a candidate therapeutic biomarker in ccRCC for further functional investigations.