Role of Ferroptosis in Anticancer Drug Resistance in Head and Neck Squamous Cell Carcinoma: A Systematic Review of Preclinical Studies
Abstract
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.
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BibTeX
@article{marques2026role,
title = {{Role of Ferroptosis in Anticancer Drug Resistance in Head and Neck Squamous Cell Carcinoma: A Systematic Review of Preclinical Studies}},
author = {Cintia Marques and Everton Morais and Nicolly Felipe-Moreira and Bruno Costa and Lilianny Oliveira and Edgard Graner and Ahmed Al-Samadi and Ricardo Coletta},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219622},
url = {https://www.mdpi.com/1422-0067/27/21/9622},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Role of Ferroptosis in Anticancer Drug Resistance in Head and Neck Squamous Cell Carcinoma: A Systematic Review of Preclinical Studies
AU - Cintia Marques
AU - Everton Morais
AU - Nicolly Felipe-Moreira
AU - Bruno Costa
AU - Lilianny Oliveira
AU - Edgard Graner
AU - Ahmed Al-Samadi
AU - Ricardo Coletta
PY - 2026
DA - 2026/10/27
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219622
UR - https://www.mdpi.com/1422-0067/27/21/9622
AB - 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.
SN - 1422-0067
ER -