Role of Ferroptosis in Anticancer Drug Resistance in Head and Neck Squamous Cell Carcinoma: A Systematic Review of Preclinical Studies

Head and neck squamous cell carcinomas (HNSCC) frequently develop anticancer drug resistance, limiting treatment efficacy. Ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid peroxidation, is dysregulated in drug-resistant HNSCC cells and may contribute to tumor survival. This systematic review synthesized preclinical evidence on the role of ferroptosis in HNSCC anticancer drug resistance. The review followed PRISMA 2020 guidelines and was registered in PROSPERO (CRD420261286567). PubMed/MEDLINE, Embase, Scopus, and ScienceDirect were searched without language or date restrictions, and preclinical studies evaluating ferroptosis in HNSCC drug resistance were included. Study selection, data extraction, and risk-of-bias assessment were independently performed by two reviewers. Out of 1870 records, 22 studies published between 2016 and 2026 met the inclusion criteria. Most used acquired cisplatin-resistant cell lines. Resistant cells consistently exhibited enhanced antioxidant defenses and reduced lipid peroxidation, primarily involving the SLC7A11/xCT–GSH–GPX4 axis and KEAP1–NRF2 signaling. Pharmacological or genetic inhibition of these defenses restored drug sensitivity in several models. Causal evidence was strongest in studies using ferroptosis-inhibitor rescue or in vivo validation, although methodological reporting was frequently insufficient. In conclusion, ferroptosis suppression contributes to HNSCC drug resistance, supporting ferroptosis induction as a potential resensitization strategy. Clinical translation requires validation in clinically relevant models.