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In this study, we identify OCIA domain containing 2 (OCIAD2) as a central mediator of chemoresistance and tumor progression in HNSCC. Through transcriptomic analysis and Co\u2010immunoprecipitation coupled with mass spectrometry, we demonstrate that OCIAD2 modulates integrin signaling by directly interacting with integrin \u03b21. Mechanistic investigations reveal that OCIAD2 does not regulate integrin \u03b21 at the transcriptional level, but instead stabilizes its protein expression by preventing lysosomal degradation and enhancing its recycling. Importantly, OCIAD2 binds to SNX17 and enhances its association with integrin \u03b21, promoting its recycling to lipid raft\u2010enriched regions of the plasma membrane. By maintaining integrin \u03b21 in these lipid raft compartments, OCIAD2 sustains the activation of the FAK\u2013PI3K\u2013AKT\u2013mTOR signaling cascade, thereby fostering cellular resilience and resistance to cisplatin. Moreover, targeting OCIAD2, either through genetic silencing or RNA\u2010based therapies, significantly sensitizes tumors to cisplatin treatment in preclinical models. This study uncovers a previously unrecognized trafficking\u2010dependent mechanism of drug resistance, suggesting that OCIAD2 may serve as a novel therapeutic target to overcome chemoresistance in HNSCC.<\/jats:p>","DOI":"10.1002\/advs.202515452","type":"journal-article","created":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T17:59:47Z","timestamp":1770573587000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["OCIAD2 Stabilizes Integrin \u03b21 Signaling Through SNX17\u2010Mediated Endosomal Recycling to Lipid Rafts and Modulates Cisplatin Response in HNSCC"],"prefix":"10.1002","volume":"13","author":[{"given":"Li","family":"Cui","sequence":"first","affiliation":[{"name":"Stomatological Hospital School of Stomatology Southern Medical University  Guangzhou Guangdong China"},{"name":"School of Dentistry University of California  Los Angeles California 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