The USP46-MCM7-RAD51 axis confers oxaliplatin resistance in colon cancer by augmenting homologous recombination repair capacity

Chemoresistance remains a critical barrier to the efficacy of oxaliplatin in colon cancer treatment. While the deubiquitinating enzyme USP46 is implicated in multiple tumor progression pathways, its specific role in oxaliplatin resistance remains undetermined. Our analysis reveals that USP46 is significantly overexpressed in colon cancer tissues, with its elevated expression correlating with poor clinical outcomes in colon cancer patients. Silencing USP46 suppresses both the proliferation and metastatic potential of colon cancer cells while simultaneously enhancing cellular sensitivity to the DNA-damaging agent oxaliplatin. Mechanistically, overexpression of USP46 leads to upregulation of nuclear RAD51 expression and facilitates the assembly of RAD51 foci, thereby increasing homologous recombination repair (HRR) capacity and contributing to oxaliplatin resistance in colon cancer cells. MCM7 is identified as a bona fide substrate of USP46 by LC-MS/MS profiling. Subsequent experiments confirm that USP46 specifically removes K48-linked polyubiquitin chains from MCM7, thereby stabilizing its protein expression. Rescue assays validate that USP46 modulates RAD51 expression and HRR function in an MCM7-dependent manner. Collectively, our study uncovers a novel USP46-MCM7-RAD51 signaling cascade that confers oxaliplatin resistance in colon cancer via augmentation of HRR-dependent DNA repair, thereby establishing this axis as a promising therapeutic target for overcoming oxaliplatin resistance.