Wogonin targets GATA1 to induce ferroptosis and potentiate cisplatin-mediated anti-tumor effects in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with a dismal prognosis, mainly due to cisplatin resistance and severe adverse effects of conventional therapies. Wogonin, a natural flavonoid, exhibits anticancer activity in several cancers, but its efficacy and potential molecular mechanisms in ESCC remain unclear. PURPOSE: Our study aimed to investigate the anticancer effect of wogonin in ESCC and elucidate its molecular mechanism, with a particular focus on ferroptosis regulation and synergy with cisplatin. METHODS: A series of experiments were conducted, including cell functional assays, key gene knockdown, RNA-seq, bioinformatics analyses, western blotting, qPCR, molecular docking, surface plasmon resonance (SPR), and in vivo xenograft models and ex vivo tumor explant assays. RESULTS: Wogonin could dose-dependently inhibit ESCC cell proliferation and cisplatin (DDP) resistance by inducing ferroptosis. Mechanistically, wogonin directly interacts with GATA-binding protein 1 (GATA1) to stabilize the protein and enhance its nuclear translocation. Nuclear-accumulated GATA1 upregulates the transcription of lysophosphatidylcholine acyltransferase 3 (LPCAT3) to exacerbate lipid peroxidation and elevates transferrin receptor 1 (TFRC) abundance to trigger intracellular iron overload. Wogonin synergizes with cisplatin to enhance anticancer efficacy via distinct ferroptotic pathways. In vivo, wogonin suppressed tumor growth without affecting mouse body weight and increased the expression of ferroptosis markers in tumor tissues. CONCLUSIONS: This study is the first to demonstrate that wogonin induces ferroptosis in ESCC by regulating GATA1. This highlights the potential of wogonin as a treatment candidate for ESCC, particularly in overcoming cisplatin resistance, and provides a novel synergistic strategy with cisplatin.