Targeting Ferroptosis in Nasopharyngeal Carcinoma: Mechanisms of Therapy Resistance and Therapeutic Opportunities

Abstract Nasopharyngeal carcinoma (NPC), an Epstein‐Barr virus (EBV)‐driven malignancy with geographic prevalence in Asia, faces therapeutic challenges due to acquired resistance. Ferroptosis—an iron‐dependent cell death pathway driven by lipid peroxidation—emerges as a critical regulator of NPC pathobiology. This review synthesizes how ferroptosis suppression promotes NPC tumor growth, metastasis, and therapy resistance. Key mechanisms include: 1. EBV‐mediated activation of p62‐Keap1‐NRF2/GPX4 and GPX4‐TAK1 axes conferring chemo/radioresistance; 2. Extracellular vesicle (EV)‐mediated transfer of ITGB3 or SCARB1 reprogramming tumor‐associated macrophages (TAMs) and inhibiting ferroptosis in circulating cells; 3. Metabolic rewiring (e.g., CAPRIN2/HMGCR, P4HA1/HMGCS1) enhancing metastasis. Additionally, ferroptosis induction via radiotherapy, natural compounds (solasodine, luteolin), repurposed drugs (disulfiram/copper), or nanotechnology synergizes with immunotherapy by promoting lipid peroxidation and reversing EBV‐mediated immune evasion. Targeting ferroptosis regulators (SLC7A11, GPX4, FTO, CD38) overcomes resistance, positioning ferroptosis modulation as a transformative strategy for NPC management.