SWI/SNF subunit SMARCD1 deficiency promotes clear cell renal cell carcinoma progression via mitochondrial reprogramming

Clear cell renal cell carcinoma (ccRCC) remains a lethal malignancy driven in part by SWI/SNF dysfunction, yet the mechanistic basis of this link is unclear. We identify SMARCD1, a core SWI/SNF subunit, as a tumor suppressor progressively silenced by DNMT3B-mediated promoter hypermethylation in ccRCC. SMARCD1 loss enables DDX3X binding to the MAFF promoter, leading to transcriptional upregulation of MAFF, which in turn promotes ubiquitin-mediated degradation of the mitochondrial fusion protein MFN1. The SMARCD1–MAFF–MFN1 axis disrupts mitochondrial fusion, reprograms metabolism toward oxidative phosphorylation, and enhances metastatic potential. Therapeutically, pharmacological restoration of MFN1 with the FDA-approved immunosuppressant leflunomide reverses mitochondrial dysfunction and suppresses tumor progression in multiple preclinical models. In patient-derived xenografts, leflunomide also potentiates tyrosine kinase inhibitor and immune checkpoint blockade efficacy. These findings establish a direct link between chromatin remodeling defects and mitochondrial dysregulation and highlight leflunomide repurposing as a clinically actionable strategy in SMARCD1-deficient ccRCC. The SWI/SNF chromatin remodeling complex is associated with cancer. Here, the authors report that the SWI/SNF subunit SMARCD1 is a tumor suppressor in clear cell renal cell carcinoma through regulation of mitochondrial function.