USP10 Inhibits Ferroptosis via Deubiquinating POLR2A in Head and Neck Squamous Cell Carcinoma

Abstract Ferroptosis has become a new way to induce cell death in cancer therapy. Deubiquitinating enzymes (DUBs) contribute to cancer ferroptosis, but underlying mechanisms are not completely understood. Here, it is discovered that USP10 as a member of DUBs, is tightly associated with a poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC). Functionally, USP10 inhibits ferroptosis via transcriptionally upregulating the expression of SLC7A11 in HNSCC. Targeting USP10 via gene depletion and antagonist sensitizes HNSCC cells to ferroptosis inducers both in vitro and in vivo. Mechanistically, USP10 directly interacts with the largest RNA Polymerase II Subunit A (POLR2A), removes the K48‐ and K63‐linked ubiquitin chains of POLR2A through its deubiquitinase activity and prevents ubiquitin‐mediated degradation. Then, POLR2A transcriptionally activates SLC7A11 , eventually leading to the suppression of ferroptosis. Overall, the study indicates that a novel USP10‐POLR2A‐SLC7A11 axis regulates ferroptosis, positioning USP10 as a potential therapeutic target in patients with HNSCC.