Ferroptosis is an iron-dependent form of programmed cell death characterized by excessive accumulation of lipid peroxides. It is extensively involved in various physiological processes and pathological injuries in the body, and is morphologically and biochemically distinct from other cell death modes such as apoptosis, necrosis, and autophagic cell death. The activation and progression of ferroptosis are precisely and synergistically regulated by intracellular iron metabolism, lipid metabolism, antioxidant systems, and multiple signaling pathways. Hypoxia is a typical common feature of the pathological microenvironments in various diseases, including solid tumors, ischemia-reperfusion injury, and neurodegenerative diseases, which remodel cellular metabolic patterns and mediate cellular stress responses by activating the hypoxia-inducible factor (HIF) signaling pathway. Existing studies have confirmed that hypoxia regulates the progression of ferroptosis via the HIF pathway, presenting complex and bidirectional regulatory characteristics. This review systematically summarizes the core regulatory network of ferroptosis, elaborates the molecular mechanisms underlying the crosstalk between hypoxia signaling and ferroptosis pathways, and focuses on analyzing the bidirectional regulatory effects of hypoxia on ferroptosis. It aims to provide a novel theoretical basis and potential therapeutic targets for the mechanistic research and clinical prevention and treatment of related diseases.

1. DixonSJ,LembergKM,LamprechtMR,et al.Ferroptosis: an iron-dependent form of nonapoptotic cell death[J].Cell,2012,149(5):1060-1072.doi：10.1016/j.cell.2012.03.042

2. DixonSJ,OlzmannJA.The cell biology of ferroptosis[J].Nat Rev Mol Cell Biol,2024,25(6):424-442.doi：10.1038/s41580-024-00703-5

3. ChenG,WuK,LiH,et al.Role of hypoxia in the tumor microenvironment and targeted therapy[J].Front Oncol,2022,12:961637.doi：10.3389/fonc.2022.961637

4. TaylorCT,ScholzCC.The effect of HIF on metabolism and immunity[J].Nat Rev Nephrol,2022,18(9):573-587.doi：10.1038/s41581-022-00587-8

5. LiuXQ,ShiMZ,BaiYT,et al.Hypoxia and ferroptosis[J].Cell Signal,2024,122:111328.doi：10.1016/j.cellsig.2024.111328

6. LiK,FanC,ChenJ,et al.Role of oxidative stress-induced ferroptosis in cancer therapy[J].J Cell Mol Med,2024,28(10):e18399.doi：10.1111/jcmm.18399

7. FrazerDM,AndersonGJ.The regulation of iron transport[J].Biofactors,2014,40(2):206-214.doi：10.1002/biof.1148

8. MayleKM,LeAM,KameiDT.The intracellular trafficking pathway of transferrin[J].Biochim Biophys Acta,2012,1820(3):264-281.doi：10.1016/j.bbagen.2011.09.009

9. YinS,LiZ,OuWB.Ferroptosis: mechanisms, comparison with cuproptosis and emerging horizons in therapeutics[J].Oncol Res,2025,34(1):8.doi：10.32604/or.2025.069049

10. XuH,LuJ,TangX,et al.Traditional Chinese medicine and ferroptosis in intracerebral hemorrhage: a potential therapeutic approach[J].Drug Des Devel Ther,2025,19:4789-4808.doi：10.2147/dddt.s513343

11. VogtACS,ArsiwalaT,MohsenM,et al.On iron metabolism and its regulation[J].Int J Mol Sci,2021,22(9):4591.doi：10.3390/ijms22094591

12. LiangD,MinikesAM,JiangX.Ferroptosis at the intersection of lipid metabolism and cellular signaling[J].Mol Cell,2022,82(12):2215-2227.doi：10.1016/j.molcel.2022.03.022

13. DollS,PronethB,TyurinaYY,et al.ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition[J].Nat Chem Biol,2017,13(1):91-98.doi：10.1038/nchembio.2239

14. MaheshwariS.Ferroptosis signaling pathways: Alzheimer's disease[J].Horm Metab Res,2023,55(12):819-826.doi：10.1055/a-2084-3561

15. PopeLE,DixonSJ.Regulation of ferroptosis by lipid metabolism[J].Trends Cell Biol,2023,33(12):1077-1087.doi：10.1016/j.tcb.2023.05.003

16. ZouY,LiH,GrahamET,et al.Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis[J].Nat Chem Biol,2020,16(3):302-309.doi：10.1038/s41589-020-0472-6

17. ConradM,PrattDA.The chemical basis of ferroptosis[J].Nat Chem Biol,2019,15(12):1137-1147.doi：10.1038/s41589-019-0408-1

18. XueQ,YanD,ChenX,et al.Copper-dependent autophagic degradation of GPX4 drives ferroptosis[J].Autophagy,2023,19(7):1982-1996.doi：10.1080/15548627.2023.2165323

19. JiangX,StockwellBR,ConradM.Ferroptosis: mechanisms, biology and role in disease[J].Nat Rev Mol Cell Biol,2021,22(4):266-282.doi：10.1038/s41580-020-00324-8

20. DollS,FreitasFP,ShahR,et al.FSP1 is a glutathione-independent ferroptosis suppressor[J].Nature,2019,575(7784):693-698.doi：10.1038/s41586-019-1707-0

21. KraftVAN,BezjianCT,PfeifferS,et al.GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling[J].ACS Cent Sci,2020,6(1):41-53.doi：10.1021/acscentsci.9b01063

22. SoulaM,WeberRA,ZilkaO,et al.Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers[J].Nat Chem Biol,2020,16(12):1351-1360.doi：10.1038/s41589-020-0613-y

23. LeeSH,GolinskaM,GriffithsJR.HIF-1-independent mechanisms regulating metabolic adaptation in hypoxic cancer cells[J].Cells,2021,10(9):2371.doi：10.3390/cells10092371

24. SemenzaGL.Hypoxia-inducible factors in physiology and medicine[J].Cell,2012,148(3):399-408.doi：10.1016/j.cell.2012.01.021

25. CowmanSJ,KohMY.Revisiting the HIF switch in the tumor and its immune microenvironment[J].Trends Cancer,2022,8(1):28-42.doi：10.1016/j.trecan.2021.10.004

26. HuW,CaiY,CaiD,et al.HIF-1α alleviates ferroptosis in ulcerative colitis by regulation of GPX4[J].Cell Death Dis,2025,16(1):542.doi：10.1038/s41419-025-07883-8

27. LuX,LiD,LinZ,et al.HIF-1α-induced expression of the m6A reader YTHDF1 inhibits the ferroptosis of nucleus pulposus cells by promoting SLC7A11 translation[J].Aging Cell,2024,23(9):e14210.doi：10.1111/acel.14210

28. YuanS,WeiC,LiuG,et al.Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF-1α/SLC7A11 pathway[J].Cell Prolif,2021,55(1):e13158.doi：10.1111/cpr.13158

29. PanG,XiaY,HaoM,et al.EZH2 suppresses IR-induced ferroptosis by forming a co-repressor complex with HIF-1α to inhibit ACSL4: targeting EZH2 enhances radiosensitivity in KDM6A-deficient esophageal squamous carcinoma[J].Cell Death Differ,2025,32(6):1026-1040.doi：10.1038/s41418-025-01451-5

30. WangY,ZhangM,BiR,et al.ACSL4 deficiency confers protection against ferroptosis-mediated acute kidney injury[J].Redox Biol,2022,51:102262.doi：10.1016/j.redox.2022.102262

31. YangL,LiuQ,LuQ,et al.Scavenger receptor class B type I deficiency induces iron overload and ferroptosis in renal tubular epithelial cells via hypoxia-inducible factor-1α/transferrin receptor 1 signaling pathway[J].Antioxid Redox Signal,2024,41(1-3):56-73.doi：10.1089/ars.2023.0380

32. SanguignoL,GuidaN,AnzilottiS,et al.Stroke by inducing HDAC9-dependent deacetylation of HIF-1 and Sp1, promotes TfR1 transcription and GPX4 reduction, thus determining ferroptotic neuronal death[J].Int J Biol Sci,2023,19(9):2695-2710.doi：10.7150/ijbs.80735

33. XiongJ,NieM,FuC,et al.Hypoxia enhances HIF1α transcription activity by upregulating KDM4A and mediating H3K9me3, thus inducing ferroptosis resistance in cervical cancer cells[J].Stem Cells Int,2022,2022:1608806.doi：10.1155/2022/1608806

34. ZouY,PalteMJ,DeikAA,et al.A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis[J].Nat Commun,2019,10(1):1617.doi：10.1038/s41467-019-09277-9

35. WangC,ChuQ,DongW,et al.Microbial metabolite deoxycholic acid-mediated ferroptosis exacerbates high-fat diet-induced colonic inflammation[J].Mol Metab,2024,84:101944.doi：10.1016/j.molmet.2024.101944

36. JingX,WangW,HeX,et al.HIF-2α/TFR1 mediated iron homeostasis disruption aggravates cartilage endplate degeneration through ferroptotic damage and mtDNA release: a new mechanism of intervertebral disc degeneration[J].J Orthop Translat,2024,46:65-78.doi：10.1016/j.jot.2024.03.005

37. SchwantesA,WickertA,BeckerS,et al.Tumor associated macrophages transfer ceruloplasmin mRNA to fibrosarcoma cells and protect them from ferroptosis[J].Redox Biol,2024,71:103093.doi：10.1016/j.redox.2024.103093

38. JiangJ,ZhengZ,ChenS,et al.Hypoxia inducible factor (HIF) 3α prevents COPD by inhibiting alveolar epithelial cell ferroptosis via the HIF-3α-GPx4 axis[J].Theranostics,2024,14(14):5512-5527.doi：10.7150/thno.99237

39. SiesH.Oxidative stress: a concept in redox biology and medicine[J].Redox Biol,2015,4:180-183.doi：10.1016/j.redox.2015.01.002

40. YangS,LianG.ROS and diseases: role in metabolism and energy supply[J].Mol Cell Biochem,2020,467(1-2):1-12.doi：10.1007/s11010-019-03667-9

41. CheungEC,VousdenKH.The role of ROS in tumour development and progression[J].Nat Rev Cancer,2022,22(5):280-297.doi：10.1038/s41568-021-00435-0

42. BaeT,HallisSP,KwakMK.Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer[J].Exp Mol Med,2024,56(3):501-514.doi：10.1038/s12276-024-01180-8

43. BairdL,YamamotoM.The molecular mechanisms regulating the KEAP1-NRF2 pathway[J].Mol Cell Biol,2020,40(13):e00099-20.doi：10.1128/mcb.00099-20

44. SunX,OuZ,ChenR,et al.Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells[J].Hepatology,2016,63(1):173-184.doi：10.1002/hep.28251

45. BellezzaI,GiambancoI,MinelliA,et al.Nrf2-Keap1 signaling in oxidative and reductive stress[J].Biochim Biophys Acta Mol Cell Res,2018,1865(5):721-733.doi：10.1016/j.bbamcr.2018.02.010

46. MachadoSE,SpanglerD,StacksDA,et al.Counteraction of myocardial ferritin heavy chain deficiency by heme oxygenase-1[J].Int J Mol Sci,2022,23(15):8300.doi：10.3390/ijms23158300

47. ZhangDD.Thirty years of NRF2: advances and therapeutic challenges[J].Nat Rev Drug Discov,2025,24(6):421-444.doi：10.1038/s41573-025-01145-0

48. BiZ,ZhangQ,FuY,et al.Nrf2 and HIF1α converge to arsenic-induced metabolic reprogramming and the formation of the cancer stem-like cells[J].Theranostics,2020,10(9):4134-4149.doi：10.7150/thno.42903

49. ZhengJ,KimSJ,SaeidiS,et al.Overactivated NRF2 induces pseudohypoxia in hepatocellular carcinoma by stabilizing HIF-1α[J].Free Radic Biol Med,2023,194:347-356.doi：10.1016/j.freeradbiomed.2022.11.039

50. SullivanLB,Garcia-MartinezE,NguyenH,et al.The proto-oncometabolite fumarate binds glutathione to amplify ROS dependent signaling[J].Mol Cell,2013,51(2):236-248.doi：10.1016/j.molcel.2013.05.003

51. EarlyJO,MenonD,WyseCA,et al.Circadian clock protein BMAL1 regulates IL-1β in macrophages via NRF2[J].Proc Natl Acad Sci U S A,2018,115(36):E8460-E8468.doi：10.1073/pnas.1800431115

52. LiaoC,HuL,ZhangQ.Von Hippel-Lindau protein signalling in clear cell renal cell carcinoma[J].Nat Rev Urol,2024,21(11):662-675.doi：10.1038/s41585-024-00876-w

53. DengQ,JiY,LiuJ,et al.Lipid reprogramming and ferroptosis crosstalk in clear cell renal cell carcinoma: metabolic vulnerabilities and therapeutic targeting[J].Mol Cancer,2025,24(1):236.doi：10.1186/s12943-025-02457-w

54. LiD,ZhangM,LiuJ,et al.Potential therapies for HCC involving targeting the ferroptosis pathway[J].Am J Cancer Res,2024,14(4):1446-1465.doi：10.62347/sigp9279

55. YousefEH,El GayarAM,El-MagdNFA.Insights into Sorafenib resistance in hepatocellular carcinoma: mechanisms and therapeutic aspects[J].Crit Rev Oncol Hematol,2025,212:104765.doi：10.1016/j.critrevonc.2025.104765

56. WangF,WangL,BaiY.Research progress of ferroptosis in cervical cancer treatment[J].Ann Med,2026,58(1):2611208.doi：10.1080/07853890.2025.2611208

57. TangS,ChenL.The recent advancements of ferroptosis of gynecological cancer[J].Cancer Cell Int,2024,24(1):351.doi：10.1186/s12935-024-03537-5

58. LiW,LiaoY,ChenJ,et al.Ischemia-reperfusion injury: a roadmap to precision therapies[J].Mol Aspects Med,2025,104:101382.doi：10.1016/j.mam.2025.101382

59. XiangQ,YiX,ZhuXH,et al.Regulated cell death in myocardial ischemia-reperfusion injury[J].Trends Endocrinol Metab,2024,35(3):219-234.doi：10.1016/j.tem.2023.10.010

60. LiuX,XieC,WangY,et al.Ferritinophagy and ferroptosis in cerebral ischemia reperfusion injury[J].Neurochem Res,2024,49(8):1965-1979.doi：10.1007/s11064-024-04161-5

61. ChenY,YangL.Cellular senescence in renal ischemia-reperfusion injury[J].Chin Med J,2025,138(15):1794-1806.doi：10.1097/cm9.0000000000003698

62. ZhangM,LiuQ,MengH,et al.Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets[J].Signal Transduct Target Ther,2024,9(1):12.doi：10.1038/s41392-023-01688-x

63. LongD,MaoC,HuangY,et al.Ferroptosis in ulcerative colitis: potential mechanisms and promising therapeutic targets[J].Biomed Pharmacother,2024,175:116722.doi：10.1016/j.biopha.2024.116722

64. HeDL,FanYG,WangZY.Energy crisis links to autophagy and ferroptosis in Alzheimer's disease: current evidence and future avenues[J].Curr Neuropharmacol,2023,21(1):67-86.doi：10.2174/1570159x20666220817140737

65. WangZL,YuanL,LiW,et al.Ferroptosis in Parkinson's disease: glia-neuron crosstalk[J].Trends Mol Med,2022,28(4):258-269.doi：10.1016/j.molmed.2022.02.003

66. YangY,NawabiAQ,YaoY,et al.Ferroptosis of smooth muscle cells in vascular diseases: from basic principles to clinical translation[J].Cell Death Discov,2026,12(1):140.doi：10.1038/s41420-026-02950-1

67. ZhangY,QianT,JiangW,et al.Integrated bioinformatics identifies ferroptosis biomarkers and therapeutic targets in idiopathic pulmonary arterial hypertension[J].Sci Rep,2025,15(1):25187.doi：10.1038/s41598-025-11066-y