iProXProteomicsJuan LinHomo Sapienshttp://www.iprox.org/page/project.html?id=IPX0013643000linjuan2020@xmu.edu.cSchool of Medicine, Xiamen UniversityiProXfalseUSP52 mediated deubiquitylation of RAB11FIP5 inhibits transferrin recycling to promote ferroptosis resistance in HNSCCFerroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, functions as an innate tumor suppression mechanism. However, the regulatory networks governing ferroptosis sensitivity in cancer cells remain incompletely elucidated. In this study, we identify RAB11FIP5 as a novel negative regulator of ferroptosis in head and neck squamous cell carcinoma (HNSCC) cells. Mechanistically, RAB11FIP5 competitively binds to RAB11A against RAB11FIP1, thereby inhibiting the recycling of transferrin (TF) and transferrin receptor (TFR), which are critical for cellular iron import. Furthermore, we demonstrate that USP52 acts as a deubiquitinase that stabilizes RAB11FIP5 by removing the K48 ubiquitin chains in ferroptosis-resistant HNSCC cells. In a subcutaneous xenograft model, knockout of RAB11FIP5 not only enhances the anti-tumor efficacy of the ferroptosis inducer IKE but also suppresses HNSCC tumor growth even in the absence of IKE treatment. Analysis of public databases and patient tissue samples reveals that high RAB11FIP5 expression in HNSCC tumors correlates with poor prognosis. Collectively, our findings elucidate a previously unrecognized mechanism by which RAB11FIP5 regulates ferroptosis through modulating TF/TFR recycling, highlighting its potential as both a prognostic marker and a therapeutic target for HNSCC.Sun Sep 28 00:00:00 BST 2025PXD0689169606