Unveiling the comorbidity hub: WT1 drives renal cancer progression in chronic kidney disease and confers sirolimus vulnerability.

Chronic kidney disease (CKD) is epidemiologically linked to renal cell carcinoma (RCC); however, the biological mechanisms underlying this association remain unclear. In the present study, a meta-analysis confirmed CKD as a significant risk factor for incident RCC (pooled odds ratio, 2.55; 95% confidence interval, 1.80-3.59; P<0.00001), with a marked heterogeneity (I²=97%) that was largely explained by geography as North American studies showed stronger effects than East Asian studies (P=0.01). Integrating The Cancer Genome Atlas, Gene Expression Omnibus and immunogenic cell death-related genes, 17 CKD-associated genes (CKDGs) were found to be dysregulated in both RCC and CKD. Functional analyses implicated these genes in kinase signaling (MAPK/PI3K-Akt) and epithelial proliferation. Re-analysis of publicly available single-cell RNA-sequencing data revealed that CKDGs were enriched in tumor-infiltrating T cells, where high CKDG activity was correlated with enhanced cytotoxicity, reduced exhaustion and active ligand-receptor crosstalk. Unsupervised clustering of bulk tumor data defined two CKDG-based subtypes; the immune-rich Cluster 2 showed elevated checkpoint expression (programmed cell death protein 1, cytotoxic T-lymphocyte-associated protein 4 and lymphocyte-activation gene 3) and higher tumor immune dysfunction and exclusion scores, suggesting potential responsiveness to immunotherapy despite a poorer survival. From the CKDGs, an 8-gene prognostic signature that stratified patients by survival was built (P<0.0001). Phenome-wide association study singled out Wilms tumor 1 (WT1) as the only CKDG significantly associated with kidney cancer (P=0.039). Computational screening prioritized sirolimus as a high-affinity WT1 binder (ΔG= -122.89 kJ/mol). In vitro, sirolimus (IC50=15.09 µg/ml) dose-dependently suppressed UOK276 cell proliferation and invasion as well as induced apoptosis. Collectively, the present study identified WT1 as a molecular nexus in RCC-CKD comorbidity and provided mechanistic rationale for repurposing sirolimus in this context.