<scp>FB23</scp> ‐2 and Cisplatin Synergize to Inhibit Head and Neck Squamous Cell Carcinoma by Targeting the <scp>XPF</scp> / <scp>ERCC1</scp> Complex

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy with a poor prognosis, often necessitating multimodal treatment approaches. While cisplatin (CDDP) remains the first-line chemotherapeutic agent, treatment failure frequently occurs due to drug resistance. To address this challenge, the FTO inhibitor FB23-2 has emerged as a promising candidate to enhance therapeutic efficacy. Consequently, this study aims to evaluate the combined efficacy of CDDP and FB23-2 in HNSCC and investigate their synergistic mechanisms. Using CCK-8 assays, colony formation assays, and flow cytometry for proliferation and cell cycle analysis, we observed that the CDDP-FB23-2 combination synergistically suppressed HNSCC proliferation. This treatment induced S/G2 phase cell cycle arrest and subsequent mitotic catastrophe. We further validated these findings in vivo using 4NQO-induced HNSCC mouse models. Additionally, drug safety was assessed via H&E staining of visceral organs, which revealed that a semi-combined regimen reduced treatment-related side effects. Mechanistic investigations involving immunofluorescence (IF), quantitative real-time PCR (qRT-PCR), co-immunoprecipitation (Co-IP), and western blot analyses demonstrated that FB23-2 potentiated CDDP-induced DNA damage while inhibiting DNA repair mechanisms, thereby promoting apoptotic cell death. Specifically, FB23-2 blocked the assembly and nuclear translocation of XPF/ERCC1 complexes in CDDP-treated cells, directly increasing cellular sensitivity to CDDP. Collectively, our findings demonstrate that FB23-2 enhances CDDP sensitivity in HNSCC by targeting the XPF/ERCC1 complex, providing a theoretical basis and experimental support for their clinical application in HNSCC treatment.