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Life sciences · Journal article
Frontiers in Oncology · October 14, 2026
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Purpose Clear cell renal cell carcinoma (ccRCC) accounts for more than 75% of renal cell carcinomas and is characterized by high metastatic potential and resistance to therapy. Fibronectin 1 (FN1), a major extracellular matrix glycoprotein, is overexpressed in various cancers and promotes tumor progression; however, its precise molecular mechanisms in RCC remain unclear. Methods We analyzed the expression level of FN1 and its clinical relevance in ccRCC using TCGA database. Subsequently, FN1 was knocked down in ACHN cells, followed by functional assays, RNA sequencing, and Western blot validation. Furthermore, we integrated FN1-interacting proteins from the BioGRID and STRING databases and combined this information with differentially expressed genes to identify key downstream effectors of FN1. Results FN1 was significantly upregulated in ccRCC and strongly associated with lymph node metastasis, distant metastasis, and poor overall survival. FN1 knockdown markedly suppressed invasion of ACHN cells, induced transcriptomic alterations, and downregulated key oncogenes, including CSF2, SOX9, and LAMC2. Pathway analysis revealed significant inhibition of the PI3K–Akt signaling axis. Integrating FN1-interacting proteins with the DEGs identified YWHAZ—a known regulator of the PI3K–Akt pathway—as a critical downstream effector of FN1, whose expression was markedly reduced upon FN1 knockdown. Rescue experiments further showed that YWHAZ overexpression substantially restored FN1 knockdown-impaired invasion but only modestly and non-significantly affected Akt phosphorylation. Conclusion FN1 promotes invasion in RCC cells at least in part through YWHAZ-dependent mechanisms, with partial involvement of PI3K-Akt signaling and additional pathways likely contributing. These findings suggest that the FN1/YWHAZ axis may serve as a candidate prognostic marker and a potential target for future preclinical investigation in RCC.