Abstract

Ferroptosis is an iron-dependent, lipid-peroxidation-driven cell death mechanism with tumor-suppressive potential, yet its regulatory networks in head and neck squamous cell carcinoma (HNSCC) remain elusive. Here, we identify RAB11FIP5 as a critical negative regulator of ferroptosis in HNSCC cell lines. Mechanistically, RAB11FIP5 competitively sequesters RAB11A to antagonize RAB11FIP1-mediated transferrin and transferrin receptor recycling, thereby restricting iron uptake. We further demonstrate that the deubiquitinase USP52 stabilizes RAB11FIP5 by specifically cleaving K48-linked ubiquitin chains at lysine residues 583 and 586. In addition to ferroptosis, RAB11FIP5 deletion impairs long-term proliferative capacity in vitro . In subcutaneous xenografts, RAB11FIP5 knockout suppresses tumor growth in both the presence and absence of the ferroptosis inducer IKE, operating through both ferroptosis-dependent and -independent mechanisms. Collectively, these findings establish RAB11FIP5 as a dual regulator of ferroptosis and proliferative capacity, representing a promising therapeutic target in HNSCC.