Ferroptosis in head and neck squamous cell carcinoma: from pathogenesis to treatment

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignant tumor worldwide, with high morbidity and mortality. Surgery and postoperative chemoradiotherapy have largely reduced the recurrence and fatality rates for most HNSCCs. Nonetheless, these therapeutic approaches result in poor prognoses owing to severe adverse reactions and the development of drug resistance. Ferroptosis is a kind of programmed cell death which is non-apoptotic. Ferroptosis of tumor cells can inhibit tumor development. Ferroptosis involves various biomolecules and signaling pathways, whose expressions can be adjusted to modulate the sensitivity of cells to ferroptosis. As a tool in the fight against cancer, the activation of ferroptosis is a treatment that has received much attention in recent years. Therefore, understanding the molecular mechanism of ferroptosis in HNSCC is an essential strategy with therapeutic potential. The most important thing to treat HNSCC is to choose the appropriate treatment method. In this review, we discuss the molecular and defense mechanisms of ferroptosis, analyze the role and mechanism of ferroptosis in the inhibition and immunity against HNSCC, and explore the therapeutic strategy for inducing ferroptosis in HNSCC including drug therapy, radiation therapy, immunotherapy, nanotherapy and comprehensive treatment. We find ferroptosis provides a new target for HNSCC treatment.

Keywords: GSH; GXP4; ferroptosis; head and neck squamous cell carcinoma; pathogenesis; treatment.

FIGURE 1

Mechanism of ferroptosis. Iron metabolism: extracellular Fe²⁺ can be oxidized to Fe³⁺, and Fe³⁺ binds to TF to form TF-Fe³⁺ and then binds to the TFR. Fe³⁺ is reduced to Fe²⁺ by STEAP3, and DMT1 transports reduced Fe²⁺ into the cytoplasm. Excess iron is stored in ferritin or the LIP. Free ferrous iron can cause lipid peroxidation through the Fenton reaction. FPN1 is the only channel through which intracellular Fe²⁺ is transported from cells. HEPC can bind to and degrade FPN1. CISD2 reduces free iron concentrations. NCOA4 promotes ferritin degradation while releasing free iron. Amino acid metabolism: Transport system x_c ⁻ exteriorizes intracellular glutamate while internalizing cystine, which is then reduced to cysteine in the cytoplasm. Cysteine is involved in the synthesis of GSH. GPX4 converts PLOOHs into PLOHs and converts GSH to GSSG. GPX4 can inhibit lipid peroxidation. Lipid metabolism: ACSL4 links free PUFAs to CoA to generate PUFA-CoA, which is then induced by LPCAT3 to form PL-PUFAs. PL-PUFAs can be further oxidized by LOXs to form lipid hydroperoxides and finally induce ferroptosis in cells. Mitochondria: Mitochondria also have an iron pool that causes a significant accumulation of mitoROS. MitoROS can react with PUFAs in the mitochondrial membrane, resulting in mitochondrial lipid peroxidation. Abbreviations: TFR, transferrin receptor; STEAP3, six transmembrane epithelial antigens of the prostate; DMT1, divalent metal transporter 1; LIP, labile iron pool; FPN1, ferroportin 1; HEPC, hepcidin; CISD2, CDGSH Iron Sulfur Domain 2; NCOA4, nuclear receptor coactivator 4; GSH, glutathione; GPX4, glutathione peroxidase 4; PLOOH, phospholipid hydroperoxide; PLOH, phospholipid-alcohol; GSSG, oxidized glutathione; ACSL4, long-chain lipid-CoA ligase 4; PUFA, polyunsaturated fatty acid; LPCAT3, lysophosphatidylcholine transferase 3; LOX, lipoxygenase; mitoROS, mitochondrial ROS.

FIGURE 2

Regulatory pathway of ferroptosis. ① GSH–GPX4 system: Inhibition of SLC7A11 inhibits cysteine uptake and reduces GSH synthesis, and GSH depletion results in GPX4 inactivation, ROS accumulation, and ferroptosis in cancer cells. ② FSP1–CoQ system: FSP1 is an oxidoreductase that reduces CoQ to CoQH2. Moreover, CoQH2 can sequester lipid peroxidation free radicals, thereby inhibiting ferroptosis by inhibiting lipid peroxidation. ③ DHODH system: DHODH is an enzyme localized on the mitochondrial inner membrane. It can reduce CoQ to CoQH2 on the mitochondrial inner membrane, which can compensate for the loss of GPX4, thereby decreasing mitochondrial lipid peroxidation. ④ GCH1–BH4 system: GCH1 is the rate-limiting enzyme for BH4 synthesis. BH4 can promote the formation of CoQ and block lipid peroxidation, thereby inhibiting ferroptosis. Abbreviations: GSH, glutathione; GPX4, glutathione peroxidase 4; SLC7A11, solute carrier family 7 member 11; ROS, reactive oxygen species; FSP1, ferroptosis suppressor protein 1; CoQ, ubiquinone; CoQH2, ubiquinol; DHODH, dihydroorotate dehydrogenase; GCH1, GTP cyclic hydrolase 1; BH4, tetrahydrobiopterin; CAV1, caveolin-1; NRF2, nuclear factor erythroid 2-related factor 2; KEAP1, Kelch-like ECH-associated protein 1; IL-6, interleukin 6; HSPB1, heat shock protein B1.