Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. By modulating iron metabolism, lipid peroxidation, and antioxidant defense systems, ferroptosis can effectively induce tumor cell death and suppress tumor proliferation and metastasis. Emerging research indicates that head and neck cancer (HNC) cells can evade ferroptosis by upregulating the expression of SLC7A11. Consequently, researchers have developed various ferroptosis inducers and explored their therapeutic potential in HNC. Notably, combining these inducers with chemotherapeutic agents or immune checkpoint inhibitors has been shown to significantly enhance antitumor efficacy. However, the specific regulatory mechanisms of ferroptosis across different HNC subtypes and their clinical applications require further investigation. This article reviews recent advances in the molecular mechanisms, regulatory networks, and clinical applications of ferroptosis in HNC, to provide insights for future research and accelerate its clinical  translation.

1. Hashim D, Genden E, Posner M, et al. Head and neck cancer prevention: from primary prevention to impact of clinicians on reducing burden[J]. Ann Oncol, 2019, 30(5): 744-756.

2. Li Q, Tie Y, Alu A, et al. Targeted therapy for head and neck cancer: signaling pathways and clinical studies[J]. Signal Transduct Target Ther, 2023, 8(1): 31.

3. Novoplansky O, Jagadeeshan S, Prasad M, et al. Dual inhibition of HERs and PD-1 counteract resistance in KRASG12C-mutant head and neck cancer[J]. J Exp Clin Cancer Res, 2024, 43(1): 308.

4. Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease[J]. Nat Rev Mol Cell Biol, 2021, 22(4): 266-282.

5. Chen X, Li J, Kang R, et al. Ferroptosis: machinery and regulation[J]. Autophagy, 2021, 17(9): 2054-2081.

6. Lei G, Zhuang L, Gan B. The roles of ferroptosis in cancer: tumor suppression, tumor microenvironment, and therapeutic interventions[J]. Cancer Cell, 2024, 42(4): 513-534.

7. Shin D, Lee J, You JH, et al. Dihydrolipoamide dehydrogenase regulates cystine deprivation-induced ferroptosis in head and neck cancer[J]. Redox Biol, 2020, 30: 101418.

8. Shin D, Kim EH, Lee J, et al. Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer[J]. Free Radic Biol Med, 2018, 129: 454-462.

9. Liao P, Wang W, Wang W, et al. CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4[J]. Cancer Cell, 2022, 40(4): 365-378. e6.

10. Wu J, Minikes AM, Gao M, et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling[J]. Nature, 2019, 572(7770): 402-406.

11. Henning Y, Blind US, Larafa S, et al. Hypoxia aggravates ferroptosis in RPE cells by promoting the Fenton reaction[J]. Cell Death Dis, 2022, 13(7): 662.

12. Wang Y, Hu M, Cao J, et al. ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization[J]. Cell, 2025, 188(2): 412-429. e27.

13. Wei Z, Hao C, Huangfu J, et al. Aging lens epithelium is susceptible to ferroptosis[J]. Free Radic Biol Med, 2021, 167: 94-108.

14. Li Y, Qian L, Yang Z, et al. Photothermal and ferroptosis synergistic therapy for liver cancer using iron-doped polydopamine nanozymes[J]. Colloids Surf B Biointerfaces, 2024, 239: 113911.

15. Doll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor[J]. Nature, 2019, 575(7784): 693-698.

16. Chu B, Kon N, Chen D, et al. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway[J]. Nat Cell Biol, 2019, 21(5): 579-591.

17. Yang Y, Tang H, Zheng J, et al. The PER1/HIF-1alpha negative feedback loop promotes ferroptosis and inhibits tumor progression in oral squamous cell carcinoma[J]. Transl Oncol, 2022, 18: 101360.

18. Lu X, Kang N, Ling X, et al. MiR-27a-3p promotes non-small cell lung cancer through SLC7A11-mediated-ferroptosis[J]. Front Oncol, 2021, 11: 759346.

19. Tuo QZ, Liu Y, Xiang Z, et al. Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion[J]. Signal Transduct Target Ther, 2022, 7(1): 59.

20. Lee J, Roh JL. Promotion of ferroptosis in head and neck cancer with divalent metal transporter 1 inhibition or salinomycin[J]. Hum Cell, 2023, 36(3): 1090-1098.  

21. Fan R, Deng A, Lin R, et al. A platinum(IV)-artesunate complex triggers ferroptosis by boosting cytoplasmic and mitochondrial lipid peroxidation to enhance tumor immunotherapy[J]. MedComm (2020), 2024, 5(6): e570.

22. Belvin BR, Lewis JP. Ferroportin depletes iron needed for cell cycle progression in head and neck squamous cell carcinoma[J]. Front Oncol, 2023, 12: 1025434.  

23. Wu S, Zhou Y, Liang J, et al. Upregulation of NF-κB by USP24 aggravates ferroptosis in diabetic cardiomyopathy[J]. Free Radic Biol Med, 2024, 210: 352-366.

24. Allevato MM, Trinh S, Koshizuka K, et al. A genome-wide CRISPR screen reveals that antagonism of glutamine metabolism sensitizes head and neck squamous cell carcinoma to ferroptotic cell death[J]. Cancer Lett, 2024, 598: 217089.

25. Schroeder CP, Yang P, Newman RA, et al. Eicosanoid metabolism in squamous cell carcinoma cell lines derived from primary and metastatic head and neck cancer and its modulation by celecoxib[J]. Cancer Biol Ther, 2004, 3(9): 847-852.

26. Li B, Cheng B, Huang H, et al. Darolutamide-mediated phospholipid remodeling induces ferroptosis through the SREBP1-FASN axis in prostate cancer[J]. Int J Biol Sci, 2024, 20(12): 4635-4653.

27. Xu X, Mao Y, Feng Z, et al. SENP1 inhibits ferroptosis and promotes head and neck squamous cell carcinoma by regulating ACSL4 protein stability via SUMO1[J]. Oncol Rep, 2024, 51(2): 34.

28. Yang J, Gu Z. Ferroptosis in head and neck squamous cell carcinoma: from pathogenesis to treatment[J]. Front Pharmacol, 2024, 15: 1283465.

29. Fang X, Cai Z, Wang H, et al. Loss of cardiac ferritin H facilitates cardiomyopathy via SLC7A11-mediated ferroptosis[J]. Circ Res, 2020, 127(4): 486-501.

30. Yang XC, Jin YJ, Ning R, et al. Electroacupuncture attenuates ferroptosis by promoting Nrf2 nuclear translocation and activating Nrf2/SLC7A11/GPX4 pathway in ischemic stroke[J]. Chin Med, 2025, 20(1): 4.

31. Su Z, Kon N, Yi J, et al. Specific regulation of BACH1 by the hotspot mutant p53 R175H reveals a distinct gain-of-function mechanism[J]. Nat Cancer, 2023, 4(4): 564-581.

32. Bersuker K, Hendricks JM, Li Z, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis[J]. Nature, 2019, 575(7784): 688-692.

33. Xu T, Yang Y, Chen Z, et al. TNFAIP2 confers cisplatin resistance in head and neck squamous cell carcinoma via KEAP1/NRF2 signaling[J]. J Exp Clin Cancer Res, 2023, 42(1): 190.

34. Zhang L, Xu Y, Cheng Z, et al. The EGR1/miR-139/NRF2 axis orchestrates radiosensitivity of non-small-cell lung cancer via ferroptosis[J]. Cancer Lett, 2024, 595: 217000.

35. Liu L, Wen T, Xiao Y, et al. Sea buckthorn extract mitigates chronic obstructive pulmonary disease by suppression of ferroptosis via scavenging ROS and blocking p53/MAPK pathways[J]. J Ethnopharmacol, 2025, 336: 118726.

36. Xiang J, Jiang M, Du X. The role of Hippo pathway in ferroptosis[J]. Front Oncol, 2023, 12: 1107505.

37. Yang YF, Chang YC, Tsai KW, et al. UBE2C triggers HIF-1α-glycolytic flux in head and neck squamous cell carcinoma[J]. J Cell Mol Med, 2022, 26(13): 3716-3725.

38. Ouyang S, Li H, Lou L, et al. Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer[J]. Redox Biol, 2022, 52: 102317.

39. Chen LH, Hsu WL, Tseng YJ, et al. Involvement of DNMT 3B promotes epithelial-mesenchymal transition and gene expression profile of invasive head and neck squamous cell carcinomas cell lines[J]. BMC Cancer, 2016, 16(1): 595.

40. Mohanty S, Mohapatra P, Shriwas O, et al. CRISPR-based kinome-screening revealed MINK1 as a druggable player to rewire 5FU-resistance in OSCC through AKT/MDM2/p53 axis[J]. Oncogene, 2022, 41(45): 4929-4940.

41. Liu H, Xu X, Wu R, et al. Antioral squamous cell carcinoma effects of carvacrol via inhibiting inflammation, proliferation, and migration related to Nrf2/Keap1 pathway[J]. Biomed Res Int, 2021, 2021: 6616547.

42. Foy JP, Bertolus C, Michallet MC, et al. The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade[J]. Ann Oncol, 2017, 28(8): 1934-1941.

43. Zhi Y, Wang Q, Zi M, et al. Spatial transcriptomic and metabolomic landscapes of oral submucous fibrosis-derived oral squamous cell carcinoma and its tumor microenvironment[J]. Adv Sci (Weinh), 2024, 11(12): e2306515.

44. Zheng Q, Xing J, Li X, et al. PRDM16 suppresses ferroptosis to protect against sepsis-associated acute kidney injury by targeting the NRF2/GPX4 axis[J]. Redox Biol, 2024, 78: 103417.

45. Wu F, Xiong G, Chen Z, et al. SLC3A2 inhibits ferroptosis in laryngeal carcinoma via mTOR pathway[J]. Hereditas, 2022, 159(1): 6.

46. Liang Y, Zhong H, Zhao Y, et al. Epigenetic mechanism of RBM15 in affecting cisplatin resistance in laryngeal carcinoma cells by regulating ferroptosis[J]. Biol Direct, 2024, 19(1): 57.

47. Wang D, Tang L, Chen M, et al. Nanocarriers targeting circular RNA ADARB1 boost radiosensitivity of nasopharyngeal carcinoma through synergically promoting ferroptosis[J]. ACS Nano, 2024, 18(45): 31055-31075.

48. Yuan L, Li S, Chen Q, et al. EBV infection-induced GPX4 promotes chemoresistance and tumor progression in nasopharyngeal carcinoma[J]. Cell Death Differ, 2022, 29(8): 1513-1527.

49. Li W, Huang G, Wei J, et al. ALKBH5 inhibits thyroid cancer progression by promoting ferroptosis through TIAM1-Nrf2/HO-1 axis[J]. Mol Cell Biochem, 2023, 478(4): 729-741.

50. Liu X, Wang L, Xi X, et al. Targeting ferroptosis: a novel insight into thyroid cancer therapy[J]. Front Endocrinol (Lausanne), 2025, 16: 1527693.

51. Li J, Liu J, Xu Y, et al. Tumor heterogeneity in autophagy-dependent ferroptosis[J]. Autophagy, 2021, 17(11): 3361-3374.

52. Mapuskar KA, Vasquez Martinez G, Pulliam CF, et al. Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: an exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients[J]. Redox Biol, 2023, 60: 102599.

53. Song A, Wu L, Zhang BX, et al. Glutamine inhibition combined with CD47 blockade enhances radiotherapy-induced ferroptosis in head and neck squamous cell carcinoma[J]. Cancer Lett, 2024, 588: 216727.

54. Zhou J, Pathak JL, Wu L, et al. Downregulated GPX4 in salivary gland epithelial cells contributes to salivary secretion dysfunction in Sjogren's syndrome via lipid ROS/pSTAT4/AQP5 axis[J]. Free Radic Biol Med, 2024, 218: 1-15.

55. Weng X, Wang S, Wang Q, et al. Melatonin inhibits salivary gland epithelial cell ferroptosis via the NRF2/HO-1/GPX4 signaling pathway in primary Sjögren's syndrome[J]. Inflamm Res, 2025, 74(1): 84.

56. Mu M, Chen B, Li H, et al. Augmented the sensitivity of photothermal-ferroptosis therapy in triple-negative breast cancer through mitochondria-targeted nanoreactor[J]. J Control Release, 2024, 375: 733-744.

57. Zhai Q, Wang Z, Tang H, et al. Identification of ferroptosis-associated tumor antigens as the potential targets to prevent head and neck squamous cell carcinoma[J]. Genes Dis, 2024, 11(6): 101212.

58. Anandhan A, Dodson M, Shakya A, et al. NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8[J]. Sci Adv, 2023, 9(5): eade9585.

59. Li Y, Ran Q, Duan Q, et al. 7-Dehydrocholesterol dictates ferroptosis sensitivity[J]. Nature, 2024, 626(7998): 411-418.

60. Cai F, Xu H, Song S, et al. Knockdown of ubiquitin-conjugating enzyme E2 T abolishes the progression of head and neck squamous cell carcinoma by inhibiting NF-κb signaling and inducing ferroptosis[J]. Curr Protein Pept Sci, 2024, 25(7): 577-585.