Overall, the findings of this study provide deep insight into the important role of SLC16A1 in the pathological processes of HNSCC and reveal that the SLC16A1 mediated ferroptosis resistance and tumor growth, and combining SLC16A1 inhibition with ferroptosis-inducers is an effective therapeutic strategy for patients with HNSCC. The gene discussed is SLC16A1; the disease is head and neck squamous cell carcinoma.