TRIBbles pseudokinase 3 (TRIB3) has been identified as a novel oncogene in several cancers, including head and neck squamous cell carcinoma (HNSCC). This study investigates the role of TRIB3 in HNSCC and its mechanism of action. The findings show that TRIB3 silencing promotes cell death by inducing ferroptosis, a form of iron-dependent cell death. TRIB3 interacts with Transcription Factor 4 (TCF4) and β-catenin to form a heterotrimeric complex, which negatively regulates the ALOXE3 promoter, thereby inhibiting ferroptosis. The study also demonstrates that hesperidin, a molecular inhibitor targeting TRIB3, reduces cell malignancy and induces ferroptosis, suppressing tumor growth. These results suggest that targeting TRIB3 could be an innovative therapeutic strategy for HNSCC.TRIBbles pseudokinase 3 (TRIB3) has been identified as a novel oncogene in several cancers, including head and neck squamous cell carcinoma (HNSCC). This study investigates the role of TRIB3 in HNSCC and its mechanism of action. The findings show that TRIB3 silencing promotes cell death by inducing ferroptosis, a form of iron-dependent cell death. TRIB3 interacts with Transcription Factor 4 (TCF4) and β-catenin to form a heterotrimeric complex, which negatively regulates the ALOXE3 promoter, thereby inhibiting ferroptosis. The study also demonstrates that hesperidin, a molecular inhibitor targeting TRIB3, reduces cell malignancy and induces ferroptosis, suppressing tumor growth. These results suggest that targeting TRIB3 could be an innovative therapeutic strategy for HNSCC.