Quetiapine inhibits the oxidative phosphorylation in head and neck squamous cell carcinoma through suppressing...

N4-acetylcytidine (ac4C) is an RNA epigenetic modification, newly discovered to be catalyzed by the enzyme N-acetyltransferase 10 (NAT10). This study aimed to elucidate the functional role and regulatory mechanism of NAT10-mediated ac4C RNA modification in head and neck squamous cell carcinoma (HNSCC), and to explore its potential as a druggable target.

Bioinformatics analysis of The Cancer Genome Atlas (TCGA) data was performed to assess NAT10 expression and its clinical correlation in HNSCC. Gene set enrichment analysis (GSEA) was conducted on differentially expressed genes from NAT10-high versus NAT10-low patients. The L1000 FireWorks Display (L1000FWD) platform was utilized to predict potential NAT10-targeting drugs. The anti-tumor effects and mechanisms of the top candidate, quetiapine, were validated through in vitro experiments, including binding assays, functional phenotyping (proliferation, migration, and apoptosis), and assessment of mitochondrial function via oxygen consumption rate (OCR) measurements.

NAT10 was significantly upregulated in HNSCC, and its high expression was correlated with advanced tumor stage, higher grade, poor overall survival, and specific immune cell infiltration patterns. GSEA revealed a strong association between NAT10 and the oxidative phosphorylation (OXPHOS) pathway. Quetiapine was identified as a top candidate targeting the NAT10-associated signature. In vitro experiments confirmed that quetiapine directly bound to NAT10, inhibited its expression, and reduced global ac4C levels. Quetiapine treatment potently suppressed HNSCC cell proliferation and migration, while promoting apoptosis. Mechanistically, quetiapine-mediated NAT10 inhibition downregulated key OXPHOS components and substantially decreased cellular OCR, indicating impaired mitochondrial respiration.

NAT10 functions as a critical oncoprotein in HNSCC, potentially by enhancing OXPHOS-driven energy metabolism. The repurposed drug quetiapine suppresses tumor growth by targeting the NAT10/ac4C axis and disrupting mitochondrial respiratory function, positioning it as a promising therapeutic agent for HNSCC.