Work

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

Year: 2026

Type: article

Abstract: 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.

Source: Nature Communications

DOI: 10.1038/s41467-026-78285-3