MCM10 Modulates Lipid Metabolic Reprogramming via the USP7-FASN Axis to Accelerate Renal Cell Carcinoma Progression.

Abstract

Metabolic reprogramming, particularly dysregulated lipid metabolism, is a hallmark of clear cell renal cell carcinoma (ccRCC) progression. However, the upstream regulators responsible for lipid metabolic rewiring remain largely unknown. Here, we integrated single-cell RNA sequencing, spatial transcriptomics, and functional validation to identify MCM10 as a critical regulator of lipid metabolism in ccRCC. Single-cell and spatial analyses revealed that MCM10 was predominantly expressed in malignant epithelial cells and positively associated with lipid metabolic activity and poor clinical outcomes. Functional studies demonstrated that MCM10 promoted ccRCC cell proliferation, migration, and lipid accumulation in vitro and enhanced tumor growth and metastasis in vivo. Mechanistically, MCM10 interacted with c-Myc and increased its protein stability by facilitating USP7-mediated deubiquitination and suppressing FBW7-dependent ubiquitination. Stabilized c-Myc directly bound to the promoter region of fatty acid synthase (FASN) and transcriptionally activated FASN expression, thereby promoting de novo fatty acid synthesis and lipid metabolic reprogramming. Collectively, our study reveals a previously unrecognized role of MCM10 in regulating lipid metabolic remodeling through the USP7/c-Myc/FASN axis and provides new insights into the molecular mechanisms underlying ccRCC progression. These findings suggest that targeting the MCM10-mediated metabolic pathway may represent a potential therapeutic strategy for ccRCC.