Advances in ferroptosis mechanisms and therapeutic potential in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a biologically aggressive malignancy characterized by late diagnosis, frequent recurrence, and poor response to conventional therapies. Cisplatin-based chemoradiotherapy remains the standard of care, yet widespread chemoresistance limits head and neck squamous cell carcinoma (HNSCC) clinical efficacy. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising mechanism to overcome drug resistance. Recent studies elucidate multiple ferroptosis-related pathways in HNSCC, including SLC7A11-mediated cystine/glutamate transport, GPX4 and glutathione metabolism, Nrf2-ARE antioxidant signaling, iron and sulfur metabolism, HDAC and EMT modulation, and TP53 mutations. Pharmacologic inducers such as erastin, RSL3, sulfasalazine, dihydroartemisinin, and HDAC inhibitors effectively trigger ferroptosis and suppress tumor growth, both in vitro and in vivo, while combination strategies with photodynamic therapy or mutant TP53 modulation further enhance antitumor effects. Emerging predictive models incorporating ferroptosis-related genes, miRNAs, and lncRNAs enable prognostic stratification and may guide individualized therapy. This review highlights ferroptosis as a therapeutic vulnerability in HNSCC, offering new avenues to overcome chemoresistance and improve patient outcomes.