Epigenetic activation of VEGFA by SMARCD1 mediates tumor progression and bevacizumab resistance in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is an aggressive malignancy characterized by strong invasiveness and treatment resistance. Although SMARCD1 has been studied in several cancers, its function in ccRCC and its regulatory relationship with the key angiogenic factor VEGFA remain unexplored. Clinical relevance of SMARCD1 was assessed through in vitro experiments and data analysis. Integrated in vivo and in vitro functional studies evaluated SMARCD1’s biological impact in ccRCC. SMARCD1-VEGFA epigenetic regulation was investigated via ChIP-qPCR, ATAC-qPCR, luciferase reporter assays, and HUVEC angiogenesis models. Bevacizumab-resistant cell lines and combination therapy models were established to validate SMARCD1’s role in drug resistance. SMARCD1 expression was significantly upregulated in ccRCC tissues and was strongly correlated with both disease progression and adverse clinical outcomes. Functionally, we have demonstrated that SMARCD1 promotes tumor proliferation, migration, and angiogenesis. Mechanistically, we have discovered that SMARCD1 binds directly to the VEGFA promoter, enhancing chromatin accessibility and modifying histone marks to activate transcriptional expression. The pro-tumor effects of SMARCD1 were found to be critically dependent on VEGFA. Furthermore, SMARCD1 knockdown sensitized bevacizumab-resistant ccRCC models to anti-angiogenic therapy. This study establishes that SMARCD1 promotes ccRCC progression and bevacizumab resistance by epigenetically remodeling the VEGFA promoter region. These findings provide a mechanistic foundation for novel precision therapies targeting the SMARCD1-VEGFA axis.