Advances in the study of regulators of ferroptosis in head and neck squamous cell carcinoma (Review)

Abstract

Head and neck squamous cell carcinoma (HNSCC), a common malignancy of the head and neck, is associated with a rapid progression, a high mortality rate and unsatisfactory curative effects. The treatment efficacy is unsatisfactory due to chemotherapeutic drug resistance, the lack of ideal therapeutic agents, as well as the absence of clinical prognostic models. Thus, the identification of novel potential therapeutic targets for its diagnosis and treatment is vital. Ferroptosis is an iron‑dependent regulatory cell death mode different from traditional cell death modes, such as apoptosis and autophagy, and has notable therapeutic potential in cancer treatment. The study of ferroptosis in HNSCC is expected to solve this bottleneck problem. In the present review, the findings, characteristics and regulatory mechanisms of ferroptosis are summarized, with emphasis on the factors and drugs that regulate ferroptosis in HNSCC, in order to provide theoretical basis for the targeted therapy of ferroptosis in HNSCC.

Keywords: ferroptosis; head and neck squamous cell carcinoma; regulators; regulatory mechanisms.

Figure 1

Regulatory mechanisms of ferroptosis. The regulatory mechanisms of ferroptosis include the following: i) The regulation of iron metabolism which involves TF, TFR1, LIP and the Fenton reaction; ii) the regulation of the System Xc-/GSH/GPX4 antioxidant system which involves GSH, GPX4, ROS, α-KG and the TCA cycle; iii) the regulation of lipid peroxidation which involves PUFAs, ACSL4, PUFA CoA, LPCAT3, PL-PUFA, ALOX15, PL-PUFA-OOH. TF, transferrin; TFR1, transferrin 1; LIP, labile iron pool; Fenton reaction, Fe²⁺ +H₂O₂ → Fe³⁺+OH⁻ + ·OH; GSH, glutathione; GPX4, glutathione peroxidase 4; ROS, reactive oxygen species; α-KG, α-ketoglutarate; TCA cycle, tricarboxylic acid cycle. PUFAs, polyunsaturated fatty acids; ACSL4, long-chain acyl-CoA synthetase 4; PUFA CoA, polyunsaturated fatty acids acetyl CoA; LPCAT3, lysophosphatidylcholine acyl-transferase 3; PL-PUFA, phospholipid polyunsaturated fatty acids; ALOX15, arachidonate 15-lipoxygenase; PL-PUFA-OOH, lipid hydrogen peroxide.

Figure 2

Roles and functions of the listed regulators in the regulation of ferroptosis in head and neck cancers. NRF2, nuclear factor erythroid 2-related factor 2; SOCS1, suppressors of cytokine signaling 1; IL-6, interleukin-6; GPX4, glutathione peroxidase 4; RSL3, an inhibitor of GPX4; EMP1, epithelial membrane protein genes 1; PER1, circadian rhythm protein 1, period-1; Cav-1, caveolin-1; FTH1, ferritin heavy chain.