TRIB3 promotes malignancy of head and neck squamous cell carcinoma (HNSCC) by inhibiting ferroptosis. TRIB3, a novel oncogene, was found to suppress ferroptosis by forming a heterotrimeric complex with TCF4 and β-catenin, which directly interacts with the ALOXE3 promoter, reducing its activation. This interaction leads to partial neutralization of ferroptosis, as shown by ALOXE3 knockdown. The molecular inhibitor hesperidin, targeting TRIB3, reduced cell malignancy and induced ferroptosis, thereby suppressing tumor growth. TRIB3 silencing significantly promoted cell death by inducing ferroptosis, while TRIB3 overexpression increased cell proliferation. TRIB3 knockdown cells showed increased lipid peroxidation, Fe²⁺, and MDA levels, indicating enhanced ferroptosis. TRIB3 inhibition also led to reduced tumor growth in vivo, with TRIB3 knockdown cells showing lower tumor growth and Ki67-positive cells. TRIB3 interacts with β-catenin and TCF4 to form a heterotrimeric complex, which negatively regulates ALOXE3 expression, thereby inhibiting ferroptosis. ALOXE3 is a lipoxygenase involved in lipid peroxidation, and its suppression by TRIB3-β-catenin-TCF4 complex reduces ferroptosis. Hesperidin, a TRIB3 inhibitor, inhibited cell growth and migration in HNSCC cells and promoted ferroptosis. These findings suggest that TRIB3 is a potential therapeutic target for HNSCC, as targeting TRIB3 could enhance ferroptosis and inhibit tumor progression. The study highlights the role of TRIB3 in HNSCC progression through ferroptosis inhibition and identifies hesperidin as a promising therapeutic agent.TRIB3 promotes malignancy of head and neck squamous cell carcinoma (HNSCC) by inhibiting ferroptosis. TRIB3, a novel oncogene, was found to suppress ferroptosis by forming a heterotrimeric complex with TCF4 and β-catenin, which directly interacts with the ALOXE3 promoter, reducing its activation. This interaction leads to partial neutralization of ferroptosis, as shown by ALOXE3 knockdown. The molecular inhibitor hesperidin, targeting TRIB3, reduced cell malignancy and induced ferroptosis, thereby suppressing tumor growth. TRIB3 silencing significantly promoted cell death by inducing ferroptosis, while TRIB3 overexpression increased cell proliferation. TRIB3 knockdown cells showed increased lipid peroxidation, Fe²⁺, and MDA levels, indicating enhanced ferroptosis. TRIB3 inhibition also led to reduced tumor growth in vivo, with TRIB3 knockdown cells showing lower tumor growth and Ki67-positive cells. TRIB3 interacts with β-catenin and TCF4 to form a heterotrimeric complex, which negatively regulates ALOXE3 expression, thereby inhibiting ferroptosis. ALOXE3 is a lipoxygenase involved in lipid peroxidation, and its suppression by TRIB3-β-catenin-TCF4 complex reduces ferroptosis. Hesperidin, a TRIB3 inhibitor, inhibited cell growth and migration in HNSCC cells and promoted ferroptosis. These findings suggest that TRIB3 is a potential therapeutic target for HNSCC, as targeting TRIB3 could enhance ferroptosis and inhibit tumor progression. The study highlights the role of TRIB3 in HNSCC progression through ferroptosis inhibition and identifies hesperidin as a promising therapeutic agent.