Shared inflammatory-metabolic transcriptional effects in tubulointerstitial fibrosis and clear cell renal cell carcinoma

BACKGROUND: Renal tubulointerstitial fibrosis and clear cell renal cell carcinoma (ccRCC) are distinct diseases that both exhibit inflammatory and metabolic remodeling. We investigated whether independently analyzed human fibrosis and ccRCC transcriptomes show reproducible disease-associated transcriptional overlap. METHODS: TCGA-KIRC (533 primary tumors and 72 solid-tissue normal samples) and GSE12682 (23 fibrosis and 13 healthy tubulointerstitial samples) were analyzed independently before gene-symbol alignment. Shared effects required FDR < 0.05, absolute log2 fold change ≥ 0.5, and concordant disease-associated direction. GSE328575 (65,770 cells) was used for descriptive single-cell localization. Species-resolved RT-qPCR assessed HADHA, ACSL4, PPARA, and PPARGC1A in TGF-β1-treated HK-2 and NRK-52E cells and in 786-O versus HK-2 cells. RESULTS: Among 11,805 aligned genes, 6690 (56.7%) showed concordant directions and 64 met the full shared-effect criteria, including 51 shared-upregulated and 13 shared-downregulated genes. Genome-wide effects were modestly but significantly correlated (Spearman ρ=0.224, P = 1.05×10⁻¹³³). Both diseases showed increased inflammatory and reduced fatty-acid-oxidation programs; S100A9 was the only independently shared member of the curated candidate panel. RT-qPCR showed decreased HADHA, PPARA, and PPARGC1A and increased ACSL4 across both TGF-β1-treated tubular models and 786-O versus HK-2 cells. CONCLUSIONS: Human bulk-tissue analyses identified a reproducible but limited inflammatory-metabolic overlap between fibrosis and ccRCC, with experimental mRNA-level validation of selected metabolic genes. The findings do not establish causality, direct HADHA-ACSL4 regulation, ferroptosis execution, or treatment efficacy.