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While cisplatin (CDDP) remains the first\u2010line chemotherapeutic agent, treatment failure frequently occurs due to drug resistance. To address this challenge, the FTO inhibitor FB23\u20102 has emerged as a promising candidate to enhance therapeutic efficacy. Consequently, this study aims to evaluate the combined efficacy of CDDP and FB23\u20102 in HNSCC and investigate their synergistic mechanisms. Using CCK\u20108 assays, colony formation assays, and flow cytometry for proliferation and cell cycle analysis, we observed that the CDDP\u2010FB23\u20102 combination synergistically suppressed HNSCC proliferation. This treatment induced S\/G2 phase cell cycle arrest and subsequent mitotic catastrophe. We further validated these findings in\u00a0vivo using 4NQO\u2010induced HNSCC mouse models. Additionally, drug safety was assessed via H&amp;E staining of visceral organs, which revealed that a semi\u2010combined regimen reduced treatment\u2010related side effects. Mechanistic investigations involving immunofluorescence (IF), quantitative real\u2010time PCR (qRT\u2010PCR), co\u2010immunoprecipitation (Co\u2010IP), and western blot analyses demonstrated that FB23\u20102 potentiated CDDP\u2010induced DNA damage while inhibiting DNA repair mechanisms, thereby promoting apoptotic cell death. Specifically, FB23\u20102 blocked the assembly and nuclear translocation of XPF\/ERCC1 complexes in CDDP\u2010treated cells, directly increasing cellular sensitivity to CDDP. Collectively, our findings demonstrate that FB23\u20102 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.<\/jats:p>","DOI":"10.1111\/cas.70322","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T23:22:19Z","timestamp":1769037739000},"page":"1010-1025","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>FB23<\/scp>\n                    \u20102 and Cisplatin Synergize to Inhibit Head and Neck Squamous Cell Carcinoma by Targeting the\n                    <scp>XPF<\/scp>\n                    \/\n                    <scp>ERCC1<\/scp>\n                    Complex"],"prefix":"10.1111","volume":"117","author":[{"given":"Yaoqi","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery Hospital of Stomatology, 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