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

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.