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This study evaluated whether brief, intravesical\u2010like ARI exposure could induce cytotoxic effects in bladder cancer cells while preserving normal bladder structure and function. RT4 and T24 bladder cancer cells, together with non\u2010malignant UROtsa urothelial cells, were exposed to ARI (1\u2013300\u2009\u03bcM) for 30\u2009min or 2\u2009h, and viability was assessed at 24, 48 and 72\u2009h. Reactive oxygen species (ROS) generation was measured in RT4 and T24 cells after 2\u2009h pretreatment, while caspase\u20103 activity and stress\u2010associated protein expression were examined in T24 cells. In parallel, an ex\u00a0vivo porcine bladder model was used to assess the effects of luminal ARI pretreatment (300\u2009\u03bcM, 2\u2009h) on urothelial thickness, ATP and acetylcholine release, detrusor contractility, \u03b2\u2010adrenergic relaxation, and nerve\u2010evoked responses. ARI reduced viability in a concentration\u2010dependent manner in RT4, T24 and UROtsa cells, with greater cytotoxicity after 2\u2009h pretreatment. In bladder cancer cells, ROS increased only at higher concentrations, whereas ARI increased caspase\u20103 activity at lower concentrations and altered multiple stress\u2010related proteins in T24 cells. In porcine bladder, ARI preserved urothelial structure and mediator release, maintained detrusor and neurogenic function, and enhanced the inhibitory influence attributed to urothelium\u2010derived inhibitory factor (UDIF). Collectively, these findings identify ARI as a mechanistically active yet bladder\u2010sparing candidate for intravesical repurposing and support its further evaluation as a potential therapy for bladder cancer.<\/jats:p>","DOI":"10.1002\/prp2.70260","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T04:16:46Z","timestamp":1778041006000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Antipsychotic Aripiprazole Induces Cytotoxicity in Bladder Cancer Cells While Preserving Urothelial and Bladder Function"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0938-4720","authenticated-orcid":false,"given":"Liam A.","family":"O'Callaghan","sequence":"first","affiliation":[{"name":"Faculty of Health Sciences and Medicine Bond University  Robina Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5950-3038","authenticated-orcid":false,"given":"Katie","family":"Powell","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences and Medicine Bond University  Robina Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7991-4117","authenticated-orcid":false,"given":"Russ","family":"Chess\u2010Williams","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences and Medicine Bond University  Robina Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3118-3084","authenticated-orcid":false,"given":"Catherine","family":"McDermott","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences and Medicine Bond University  Robina Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,5]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjgh-2020-004128"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00345-019-02984-4"},{"issue":"19","key":"e_1_2_13_4_1","first-page":"5144","article-title":"Pharmacokinetics of Intravesical Mitomycin C in Superficial Bladder Cancer Patients1","volume":"51","author":"Dalton J. 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