Targeting ferroptosis: a novel pathway in oral, oropharyngeal, hypopharyngeal, and laryngeal cancers.

Malignancies of the oral cavity, oropharynx, hypopharynx, and larynx rank as the seventh most prevalent cancers globally, characterized by high morbidity and mortality. Despite advancements in conventional therapies, these cancers often demonstrate recurrence and treatment resistance. This review investigates ferroptosis, an iron-dependent regulated cell death mechanism, as a novel therapeutic target to overcome resistance and recurrence in these cancers. A narrative review study was conducted using online databases, including PubMed, Google Scholar, Scopus, and Web of Science. The search incorporated keywords such as "ferroptosis", "oral squamous cell carcinoma", "oropharyngeal cancer", "hypopharyngeal cancer", "laryngeal cancer", "iron metabolism", and "lipid peroxidation". Studies focusing on molecular mechanisms, ferroptosis regulation, and therapeutic applications were included. Key findings highlighted the involvement of genes like CA9, CAV1, and SLC7 A11 in oral squamous cell carcinoma (OSCC), contributing to progression and resistance. Ferroptosis inducers such as resveratrol and quercetin effectively promoted ferroptosis in OSCC by targeting pathways like p53/SLC7 A11. In hypopharyngeal and oropharyngeal cancers, agents like ascorbic acid and RSL3 enhanced lipid peroxidation, while laryngeal cancers showed resistance through molecules like SLC3 A2 and KPNA2, which could be counteracted with targeted therapies. Nanotechnology-based approaches, including photodynamic therapy and nanofiber membranes, offer potential for localized and effective ferroptosis induction. Ferroptosis holds promise as a therapeutic strategy for treating head and neck cancers by addressing treatment resistance and recurrence. Future research should focus on optimizing combination therapies, understanding molecular heterogeneity, and translating preclinical findings into clinical applications to improve patient outcomes.