Research progress on ferroptosis in head and neck squamous cell carcinoma

Ferroptosis, a regulated iron-dependent cell death pathway driven by lipid peroxidation and mitochondrial dysfunction, has emerged as a critical player in diseases characterized by dysregulated iron metabolism and redox imbalance. In recent years, its therapeutic potential has garnered significant attention in head and neck squamous cell carcinoma (HNSCC), a malignancy notorious for its high incidence, frequent recurrence, and poor prognosis. This review systematically delineates the molecular underpinnings of ferroptosis in HNSCC pathogenesis and therapy, focusing on four interconnected axes: (1) iron homeostasis disruption, exemplified by dysregulation of the iron efflux channel ferroportin (FPN); (2) lipid peroxidation dynamics, mediated through key regulators such as SLC7A11; (3) mitochondrial remodeling, including structural and functional alterations during ferroptosis execution; and (4) critical signaling cascades, notably the PI3K-AKT-mTOR pathway, which orchestrates cellular survival and death decisions. Therapeutic exploration has identified ferroptosis inducers (e.g., erastin) as promising agents to disrupt redox equilibrium in HNSCC cells, while pharmacological inhibitors offer potential for mitigating off-target toxicity. Notably, combination strategies integrating ferroptosis modulation with conventional therapies or other programmed cell death mechanisms demonstrate synergistic efficacy, highlighting a paradigm shift in precision oncology. This study aims to provide a mechanistic framework for ferroptosis in HNSCC, bridging preclinical insights with translational opportunities. By elucidating context-dependent regulatory networks and optimizing therapeutic targeting, we propose novel strategies to overcome treatment resistance, ultimately improving clinical outcomes and quality of life for HNSCC patients.