TRAPPC4 resists ferroptosis and promotes head and neck squamous cell carcinoma progression by regulating GPX4 protein stability via TRIM55

Ferroptosis resistance continues to be a major challenge in the treatment of head and neck squamous cell carcinoma (HNSCC), yet the molecular mechanisms driving this resistance remain inadequately understood. Here, we conducted an unbiased genome-wide CRISPR-Cas9 knockout library screen and identified TRAPPC4 as a key protein that resists ferroptosis in HNSCC. Moreover, we conducted experiments using HNSCC cell lines, patient-derived organoids, cell-derived xenograft, patient-derived xenograft, conditional knockout mouse models, and popliteal lymph node and lung metastasis models, which confirmed that TRAPPC4 promotes HNSCC progression by inhibiting ferroptosis. Mechanistically, TRAPPC4 inhibits chromatin accessibility at the TRIM55 promoter, blocking FOS driven TRIM55 transcription, reducing TRIM55-mediated GPX4 degradation, and promoting ferroptosis resistance. We further identified pitavastatin calcium as a TRAPPC4 inhibitor and found that its combination with RSL3 effectively suppressed HNSCC progression. This work reveals the critical role of TRAPPC4-mediated ferroptosis in promoting HNSCC progression and provides a promising therapeutic target for treating HNSCC.