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In this study, we screened 1161 FDA\u2010approved compounds to identify agents that induce reactive oxygen species (ROS) accumulation in head and neck squamous cell carcinoma (HNSCC) cells. Pimozide, a dopamine D2 receptor antagonist, emerged as the most potent ROS inducer. It selectively suppresses the growth of HNSCC cells with high oxidative stress resistance while exhibiting only modest effects on less resistant cells and normal keratinocytes. Notably, pimozide exhibited anti\u2010tumor effects as a monotherapy and in combination with paclitaxel at clinically relevant doses. Mechanistic analysis revealed that pimozide rapidly induced ROS accumulation via a mechanism distinct from its known action on dopamine D2 receptors and STAT3\/5. To identify markers of ROS\u2010induced responses, we examined ROS\u2010responsive genes and found that early growth response 1 (EGR1) was selectively induced in sensitive cells and correlated with pimozide responsiveness. Functional analysis revealed that EGR1 knockdown suppressed pimozide\u2010induced cytotoxicity, suggesting its role as a functional pharmacodynamic marker of pimozide sensitivity. In a patient\u2010derived xenograft model of HNSCC, pimozide significantly reduced the tumor burden alone and in combination with paclitaxel. While tumor volume reduction in the combination group was not statistically greater than that in the monotherapy group, fluorescence immunohistochemistry revealed a marked decrease in undifferentiated tumor cells, indicating enhanced therapeutic effects of combination treatment. Taken together, these findings indicate that pimozide is a promising candidate for repurposing as a novel therapeutic agent against HNSCC.<\/jats:p>","DOI":"10.1111\/cas.70253","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T13:24:42Z","timestamp":1763645082000},"page":"511-521","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Drug Repurposing Screen Identifies Pimozide as a\n                    <scp>ROS<\/scp>\n                    \u2010Inducing Therapy With Anti\u2010Tumor Efficacy in\n                    <scp>HNSCC PDX<\/scp>\n                    Models"],"prefix":"10.1111","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2243-5140","authenticated-orcid":false,"given":"Shogo","family":"Okazaki","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology Nihon University School of Dentistry  Tokyo 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