OCIAD2 Stabilizes Integrin β1 Signaling Through SNX17‐Mediated Endosomal Recycling to Lipid Rafts and Modulates Cisplatin Response in HNSCC

ABSTRACT While cisplatin is a widely used and effective chemotherapeutic agent in the treatment of head and neck squamous cell carcinoma (HNSCC), the molecular mechanisms underlying its resistance remain poorly understood. 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‐immunoprecipitation coupled with mass spectrometry, we demonstrate that OCIAD2 modulates integrin signaling by directly interacting with integrin β1. Mechanistic investigations reveal that OCIAD2 does not regulate integrin β1 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 β1, promoting its recycling to lipid raft‐enriched regions of the plasma membrane. By maintaining integrin β1 in these lipid raft compartments, OCIAD2 sustains the activation of the FAK–PI3K–AKT–mTOR signaling cascade, thereby fostering cellular resilience and resistance to cisplatin. Moreover, targeting OCIAD2, either through genetic silencing or RNA‐based therapies, significantly sensitizes tumors to cisplatin treatment in preclinical models. This study uncovers a previously unrecognized trafficking‐dependent mechanism of drug resistance, suggesting that OCIAD2 may serve as a novel therapeutic target to overcome chemoresistance in HNSCC.