UFM1 regulates ferroptosis in oral squamous cell carcinoma by stabilizing SLC7A11

Oral squamous cell carcinoma (OSCC) is highly invasive malignancy with limited effective therapeutic strategies. Ubiquitin-fold modifier 1 (UFM1) is a ubiquitin-like molecule that has been implicated in several cancers; however, its role in ferroptosis within OSCC remains unclear. In this study, UFM1 was demonstrated to be upregulated in OSCC. UFM1 depletion suppressed proliferation and dissemination of OSCC cells and induced ferroptosis characterized by increased lipid peroxidation and Fe²⁺ accumulation. Mechanically, UFM1 deficiency significantly reduced SLC7A11 levels and sensitized cells to oxidative stress. Reintroduction of SLC7A11 rescued ferroptosis and restored cell survival in UFM1-deficient cells. In vivo, UFM1 depletion significantly inhibited tumor growth, reduced SLC7A11 expression, and increased lipid oxidation, as indicated by 4-hydroxynonenal (4-HNE) immunohistochemical staining. These findings suggest that UFM1 protects OSCC from ferroptosis by stabilizing SLC7A11 protein via UFMylation, thereby preventing its proteasomal degradation.