An integrative bioinformatics approach unveils fibrosis-driven prognostic signature and immunotherapeutic potential in kidney renal clear cell carcinoma

BACKGROUND: Fibrosis plays a significant role in tumor progression and modifies the immune microenvironment; however, its prognostic implications in kidney renal clear cell carcinoma (KIRC) warrant further investigation. This study develops a robust prognostic model that predicts patient outcomes and responsiveness to immunotherapy in KIRC based on fibrosis-related gene signatures. METHODS: Fibrosis-associated genes were curated from three reputable databases (GeneCards, CTD, and OMIM). RNA-sequencing datasets for KIRC were acquired from TCGA, ICGC, and E-MTAB-1980 cohorts. Comprehensive analyses, including differential gene expression, univariate Cox regression, and LASSO Cox regression, were employed to establish and validate a fibrosis-related signature (FRS). Functional enrichment analyses, genomic instability profiling, and assessments of immune cell infiltration were performed to elucidate the biological features of FRS. PDGFRA was examined through single-cell and pan-cancer analyses, with subsequent PDGFRA knockdown created in OS-RC-2 and Caki-1 cell lines. Co-culture experiments with HDF were conducted to evaluate the expression of MMP2 and MMP9. Cell proliferation, migration, and apoptosis were assessed using CCK8, Transwell assays, and Annexin V/PI staining, respectively, while an in vivo xenograft model was utilized to investigate PDGFRA's role in KIRC. RESULTS: The FRS, incorporating four genes (PDGFRA, SLC40A1, CXCL2, AGTR1), demonstrated strong prognostic capabilities. High-FRS patients experienced significantly worse survival rates, heightened genomic instability, and distinctive immune profiles characterized by increased immune cell infiltration and immune dysfunction. PDGFRA emerged as a significant prognosticator, exhibiting substantial clinical relevance. In vitro silencing of PDGFRA impeded cell proliferation and migration while promoting apoptosis and inhibiting MMP2 and MMP9 expression in HDF. Additionally, PDGFRA knockdown markedly reduced fibrosis and tumorigenicity in KIRC models in vivo. CONCLUSION: The fibrosis-related signature effectively stratifies KIRC patients according to prognosis and potential immunotherapy responses, enhancing our understanding of fibrosis-mediated tumor biology and enabling personalized therapeutic approaches in kidney cancer.