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Esophageal squamous cell carcinoma (ESCC) remains treatment-resistant; we explored Elbasvir, an NS5A inhibitor, as a ferroptosis inducer. Cell viability was assessed by CCK-8 assays. Apoptosis and cell cycle were analyzed via flow cytometry, and key markers via Western blotting. In vivo efficacy was evaluated using BALB/c nude mouse xenografts. Proteomic analysis was conducted by mass spectrometry. Ferroptosis induction was verified via TEM, JC-1, FerroOrange, DCFH-DA, MDA assays, and Western blotting of NCOA4, Ferritin, and FTH1. Binding to NCOA4 was confirmed by surface plasmon resonance (SPR) and drug affinity responsive target stability (DARTS) assays. Elbasvir (40 µM, 48 h) suppressed KYSE150/TE1 viability, induced apoptosis/G0/G1 arrest, and inhibited xenograft growth without toxicity. Proteomics identified ferroptosis as the top pathway. SPR/DARTS confirmed NCOA4 binding. NCOA4 knockdown reduced ferroptosis; overexpression enhanced it. Elbasvir triggered NCOA4-mediated ferritinophagy, FTH1 degradation, iron accumulation, and lipid peroxidation. Elbasvir targets NCOA4-FTH1 to induce ferroptosis, offering a repurpose strategy for ESCC. Its safety profile supports clinical translation, with potential applications in iron metabolism-dependent cancers.