A renal cyst-clear cell renal cell carcinoma comorbidity analysis identifies a FOXM1-positive epithelial COL6A1-CD44 axis that remodels fibroblasts

Background Renal cystic conditions are heterogeneous. We used a broad renal cyst-associated disease-gene framework to identify molecular programs shared with clear cell renal cell carcinoma (ccRCC), without modeling a specific cystic disorder or direct cyst-to-cancer progression.Methods We identified 237 shared genes between renal cyst disease and ccRCC (TCGA-KIRC), performed functional enrichment, Mendelian randomization, and built a random survival forest (RSF) risk score benchmarked against published signatures and immunotherapy cohorts. Single-cell (Scissor, SCENIC, scTenifoldKnk virtual FOXM1 knockout) and spatial transcriptomics (RCTD, CellChat) were integrated with fibroblast subclustering and oncoPredict drug screening. Candidate FOXM1 inhibitors were prioritized by docking and 100-ns molecular dynamics, with isovitexin validated functionally.Results The shared program was enriched for epithelial development and ECM remodeling. Two direction-specific Mendelian randomization analyses supported associations between genetic liability to kidney cancer and related renal cystic phenotypes. The RSF score showed robust prognostic discrimination across cohorts and separated immunotherapy outcomes. High-risk tumors were enriched for Tregs, B cells, and fibroblasts. FOXM1+ malignant epithelium represented the high-risk state, with elevated CNV burden and regulon activity; virtual FOXM1 knockout identified COL6A1 and CD44 among 129 significant non-target perturbation hits. Convergent single-cell and spatial analyses nominated a COL6A1-CD44 communication axis associated with fibroblast remodeling, with F5_SFRP2+ fibroblasts as the most plausible receiving state. These fibroblasts showed ECM-remodeling, adverse prognosis, and pathway activation. Isovitexin emerged as a lead FOXM1-targeting compound, significantly suppressing ccRCC proliferation, migration, and invasion.Conclusions These findings support a testable communication model involving FOXM1+ epithelium, COL6A1-CD44 and F5_SFRP2+ fibroblasts. The in vitro results also support further evaluation of isovitexin in ccRCC.