Mechanistically, SLC16A1 activates signal transducer and activator of transcription 3 (STAT3) to transcriptionally upregulate SLC7A11 expression.<h4>Conclusion</h4>Our study defines a novel SLC16A1-STAT3-SLC7A11 signaling axis that promotes HNSCC progression by conferring robust resistance to ferroptosis. This evidence concerns the gene SLC16A1 and head and neck squamous cell carcinoma.