Abstract

While cisplatin-based chemoradiotherapy regimens (gemcitabine-cisplatin [GP] and docetaxel-cisplatin-5-fluorouracil [TPF]) remain standard treatments for advanced nasopharyngeal carcinoma (NPC), 30-40% of patients exhibit intrinsic chemoresistance, resulting in therapeutic failure. The molecular underpinnings of this resistance are poorly characterized. Through integrative multi-omics profiling, we identified Mitochondrial Ribosomal Protein S7 (MRPS7) and Mitochondrial Ribosomal Protein S23 (MRPS23) as novel drivers of cisplatin resistance in NPC. Mechanistically, integrated single-cell RNA-seq (scRNA-seq) analysis, mass spectrometry, and functional studies revealed that MRPS7 and MRPS23 stabilized β-catenin by inhibiting its ubiquitination, thereby promoting β-catenin-mediated cancer stemness and epithelial-mesenchymal transition (EMT) to establish cisplatin resistance in NPC. Additionally, we identified Ubiquitin Specific Peptidase 10 (USP10) as a critical upstream regulator that protects MRPS7/23 from proteasomal degradation and sustaining their oncogenic activity. Notably, Spautin-1, a potent USP10 inhibitor, demonstrates synergistic therapeutic activity with cisplatin in diminished tumor growth and metastasis in NPC mice. This research established the USP10-MRPS7/MRPS23-β-catenin axis as a promising precision medicine strategy to combat metastatic dissemination and reverse cisplatin chemoresistance in advanced NPC, which offers a promising opportunity to develop cisplatin sensitizers for the clinical translation of NPC therapies.