Ferroptosis and cuproptosis are two novel metal-dependent regulated cell death modalities, which have recently become research hotspots in colorectal cancer (CRC). Ferroptosis is driven by iron-dependent lipid peroxidation and regulates the progression of CRC via multiple signaling pathways including the System Xc^--GSH-GPX4 axis, iron metabolism, and the p53 pathway, thereby inhibiting the proliferation and metastasis of CRC. In contrast, cuproptosis is triggered by abnormal intracellular copper accumulation, which disturbs the function of lipoylated proteins involved in the tricarboxylic acid cycle, induces mitochondrial proteotoxic stress, and ultimately suppresses the malignant growth of CRC cells. Ferroptosis and cuproptosis share core regulatory pathways in the occurrence and development of CRC, including glutathione metabolism, mitochondrial function modulation, and the p53 signaling network. This provides novel insights into overcoming therapeutic resistance and developing precise combination therapeutic strategies for CRC. This paper systematically reviews the mechanisms and interactions of ferroptosis and cuproptosis in CRC, and discusses their prospects for clinical translational application, aiming to provide a theoretical reference for further basic research and clinical practice of CRC.

1. BrayF,LaversanneM,SungH,et al.Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer J Clin,2024,74(3):229‑263.doi：10.3322/caac.21834

2. StorandtMH,SinicropeFA.Deficient mismatch repair/microsatellite instability‑high colorectal cancer: current treatment paradigms, limitations and future perspectives[J].BMJ Oncol,2026,5(1):e000980.doi：10.1136/bmjonc-2025-000980

3. ZhuXQ,GeBB,WenLC.Mechanisms and emerging strategies to overcome immunotherapy resistance in cold tumours of colorectal cancer[J].Onco Targets Ther,2026,19:621109.doi：10.2147/ott.s621109

4. YangQ,QuRZ,LuSY,et al.Biological and clinical characteristics of proximal colon cancer: far from its anatomical subsite[J].Int J Med Sci,2024,21(10):1824‑1839.doi：10.7150/ijms.97574

5. Duta‑IonSG,JuganaruIR,HotinceanuIA,et al.Redefining therapeutic approaches in colorectal cancer: targeting molecular pathways and overcoming resistance[J].Int J Mol Sci,2024,25(23):12507.doi：10.3390/ijms252312507

6. ZhuL,TanQM,WangYX,et al.Artemisitene triggers calcium‑dependent ferroptosis by disrupting the LSH‑EWSR1 interaction in colorectal cancer[J].Redox Biol,2026,89:103950.doi：10.1016/j.redox.2025.103950

7. ZhangLM,XieAH,MaJX,et al.Unveiling cuproptosis: mechanistic insights, roles, and leading advances in oncology[J].Biochim Biophys Acta Rev Cancer,2024,1879(6):189180.doi：10.1016/j.bbcan.2024.189180

8. YangHY,ChenX,HuangSQ,et al.A novel GSH depletor for simultaneous ferroptosis and cuproptosis activation in hepatocellular carcinoma[J].Biochem Pharmacol,2026,243(Pt 1):117488.doi：10.1016/j.bcp.2025.117488

9. SaezMA,Garcia‑MonteroC,Fraile‑MartinezO,et al.Differential expression of ferroptosis markers, circadian regulators, KLOTHO, and classical tumor suppressors in colorectal cancer according to tumor stage: influence of age, anatomical location, and correlation patterns[J].Histol Histopathol,2025,40(12):1985‑2009.

10. LiL,SunFY,KongFY,et al.Characterization of a cuproptosis‑related signature to evaluate immune features and predict prognosis in colorectal cancer[J].Front Oncol,2023,13:1083956.doi：10.3389/fonc.2023.1083956

11. 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

12. OdaK,LeeY,WiriyasermkulP,et al.Consensus mutagenesis approach improves the thermal stability of system XC‑transporter, xCT, and enables cryo‑EM analyses[J].Protein Sci,2020,29(12):2398‑2407.doi：10.1002/pro.3966

13. Friedmann AngeliJP,SchneiderM,PronethB,et al.Inactivation of the ferroptosis regulator GPX4 triggers acute renal failure in mice[J].Nat Cell Biol,2014,16(12):1180‑1191.doi：10.1038/ncb3064

14. LiuWW,LiuCQ,XiaoJ,et al.HTRA1 interacts with SLC7A11 to modulate colorectal cancer chemosensitivity by inhibiting ferroptosis[J].Cell Death Discov,2024,10(1):228.doi：10.1038/s41420-024-01993-6

15. LiR,WuYY,LiY,et al.Targeted regulated cell death with small molecule compounds in colorectal cancer: current perspectives of targeted therapy and molecular mechanisms[J].Eur J Med Chem,2024,265:116040.doi：10.1016/j.ejmech.2023.116040

16. HuangYZ,YangWC,YangL,et al.Nrf2 inhibition increases sensitivity to chemotherapy of colorectal cancer by promoting ferroptosis and pyroptosis[J].Sci Rep,2023,13(1):14359.doi：10.1038/s41598-023-41490-x

17. YangJW,MoJJ,DaiJJ,et al.Cetuximab promotes RSL3‑induced ferroptosis by suppressing the Nrf2/HO‑1 signalling pathway in KRAS mutant colorectal cancer[J].Cell Death Dis,2021,12(11):1079.doi：10.1038/s41419-021-04367-3

18. WangC,WangJY,XingF,et al.Synergistic effects of 5‑fluorouracil in combination with salinomycin promoted ferroptosis via inhibiting SLC7A11/GPX4 in colorectal cancer[J].Front Oncol,2025,15:1558290.doi：10.3389/fonc.2025.1558290

19. 罗寿,刘文杰,苏昊,等.结肠腺癌组织中谷胱甘肽过氧化物酶4的表达及其与患者临床病理特征和预后的关系[J].肿瘤研究与临床,2021,33(8):572-578.LuoS,LiuWJ,SuH,et al.Expression of glutathione peroxidases 4 in colon adenocarcinoma tissues and its relationship with clinicopathological features and prognosis of patients[J].Cancer Research and Clinic,2021,33(8):572-578.

20. OuYR,WuNQ,ShuLS,et al.The high expression of SLC7A11 and GPX4 are significantly correlated with β‑catenin in colorectal cancer[J].Cancer Manag Res,2024,16:1639‑1648.doi：10.2147/cmar.s483526

21. ZhangYY,HanY,LiWN,et al.Tumor iron homeostasis and immune regulation[J].Trends Pharmacol Sci,2024,45(2):145‑156.doi：10.1016/j.tips.2023.12.003

22. KimH,VillarealLB,LiuZL,et al.Transferrin receptor‑mediated iron uptake promotes colon tumorigenesis[J].Adv Sci (Weinh),2023,10(10):e2207693.doi：10.1002/advs.202207693

23. MarkopoulosGS,SimosYV,TsamisKI,et al.Beyond Iron: the roles of CD71 in the pathophysiology of cancer‑a comprehensive review[J].J Clin Med,2025,14(23):8265.doi：10.3390/jcm14238265

24. StockwellBR,Friedmann AngeliJP,BayirH,et al.Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease[J].Cell,2017,171(2):273‑285.doi：10.1016/j.cell.2017.09.021

25. ShenZN,ZhaoL,YooSA,et al.Emodin induces ferroptosis in colorectal cancer through NCOA4‑mediated ferritinophagy and NF‑κb pathway inactivation[J].Apoptosis,2024,29(9‑10):1810‑1823.doi：10.1007/s10495-024-01973-2

26. ChengJH,YangXX,ZhaoW.REV1‑targeting inhibitor JH‑RE‑06 induces ferroptosis via NCOA4‑mediated ferritinophagy in colorectal cancer cells[J].Oncol Rep,2025,54(6):159.doi：10.3892/or.2025.8992

27. YuanH,LiXM,ZhangXY,et al.Identification of ACSL4 as a biomarker and contributor of ferroptosis[J].Biochem Biophys Res Commun,2016,478(3):1338‑1343.doi：10.1016/j.bbrc.2016.08.124

28. ZengKX,LiWH,WangY,et al.Inhibition of CDK1 overcomes oxaliplatin resistance by regulating ACSL4‑mediated ferroptosis in colorectal cancer[J].Adv Sci (Weinh),2023,10(25):e2301088.doi：10.1002/advs.202301088

29. ChenCC,YangYB,GuoYG,et al.CYP1B1 inhibits ferroptosis and induces anti‑PD‑1 resistance by degrading ACSL4 in colorectal cancer[J].Cell Death Dis,2023,14(4):271.doi：10.1038/s41419-023-05803-2

30. DaiGL,WangD,MaST,et al.ACSL4 promotes colorectal cancer and is a potential therapeutic target of emodin[J].Phytomedicine,2022,102:154149.doi：10.1016/j.phymed.2022.154149

31. YangH,SunWS,BiT,et al.ZNF8‑miR‑552‑5p axis modulates ACSL4‑mediated ferroptosis in hepatocellular carcinoma[J].DNA Cell Biol,2023,42(6):336‑347.doi：10.1089/dna.2022.0582

32. ImJ,NamSK,LeeHS.MicroRNA‑552 expression in colorectal cancer and its clinicopathological significance[J].J Pathol Transl Med,2021,55(2):125‑131.doi：10.4132/jptm.2021.01.17

33. MaCY,ChenRX,WangHX,et al.Actinidia chinensis planch root extracts trigger ferroptosis in colorectal cancer via the p53/SLC7A11/GPX4 axis[J].Front Pharmacol,2026,17:1724983.doi：10.3389/fphar.2026.1724983

34. OuY,WangSJ,LiDW,et al.Activation of SAT1 engages polyamine metabolism with p53‑mediated ferroptotic responses[J].Proc Natl Acad Sci U S A,2016,113(44):E6806‑E6812.doi：10.1073/pnas.1607152113

35. 李智育,王松玲,张雯,等.基于转录组学和细胞实验验证探究药根碱对结直肠癌细胞SAT1介导的铁死亡的调控作用[J].中国中药杂志,2026,51(1):153‑162.LiZY,WangSL,ZhangW,et al.Transcriptomics and cell experiments reveal regulatory effect of jatrorrhizine on SAT1‑mediated ferroptosis in colorectal cancer cell[J].Zhongguo Zhong Yao Za Zhi,2026,51(1):153‑162.

36. TongJ,HanT,DengJ,et al.p53 and fatty acids collaborate to trigger ferroptosis via the FBXO2‑FABP5 axis in colorectal cancer[J].Redox Biol,2026,90:104043.doi：10.1016/j.redox.2026.104043

37. JiangL,KonN,LiTY,et al.Ferroptosis as a p53‑mediated activity during tumour suppression[J].Nature,2015,520(7545):57‑62.doi：10.1038/nature14344

38. TsvetkovP,CoyS,PetrovaB,et al.Copper induces cell death by targeting lipoylated TCA cycle proteins[J].Science,2022,375(6586):1254‑1261.doi：10.1126/science.abf0529

39. HuangCZ,WangMJ,WangJJ,et al.Suppression MGP inhibits tumor proliferation and reverses oxaliplatin resistance in colorectal cancer[J].Biochem Pharmacol,2021,189:114390.doi：10.1016/j.bcp.2020.114390

40. GaoW,HuangZ,DuanJF,et al.Elesclomol induces copper‑dependent ferroptosis in colorectal cancer cells via degradation of ATP7A[J].Mol Oncol,2021,15(12):3527‑3544.doi：10.1002/1878-0261.13079

41. O'ConnellE,ReynoldsIS,SalvucciS,et al.Mucinous and non‑mucinous colorectal cancers show differential expression of chemotherapy metabolism and resistance genes[J].Pharmacogenomics J,2021,21(4):510‑519.doi：10.1038/s41397-021-00229-5

42. Martinez‑BalibreaE,Martínez‑CardúsA,MusulénE,et al.Increased levels of copper efflux transporter ATP7B are associated with poor outcome in colorectal cancer patients receiving oxaliplatin‑based chemotherapy[J].Int J Cancer,2009,124(12):2905‑2910.doi：10.1002/ijc.24273

43. YangWC,WangYX,HuangYZ.4‑octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to promote cuproptosis in colorectal cancer[J].Biomed Pharmacother,2023,159:114301.doi：10.1016/j.biopha.2023.114301

44. WangYH,PeiP,YangK,et al.Copper in colorectal cancer: from copper‑related mechanisms to clinical cancer therapies[J].Clin Transl Med,2024,14(6):e1724.doi：10.1002/ctm2.1724

45. ZhaoRY,WangXY,WangJQ,et al.Rewiring metal‑dependent cell death to unlock immunotherapy in colorectal cancer[J].Nano Lett,2026,26(14):4755‑4765.doi：10.1021/acs.nanolett.6c00449

46. WangC,GuoJJ,ZhangY,et al.Cuproptosis‑related gene FDX1 suppresses the growth and progression of colorectal cancer by retarding EMT progress[J].Biochem Genet,2025,63(1):775‑788.doi：10.1007/s10528-024-10784-8

47. TaoXY,WangHR,WangQ,et al.Marine natural product chagosendine C induces cuproptosis in colorectal cancer cells by targeting FDX1[J].J Am Chem Soc,2025,147(41):37089‑37103.

48. EkmekciuI,ZuchaDM,ChristmannJ,et al.Exploring the molecular profile of localized colon cancer: insights from the AIO colopredict plus registry[J].Front Oncol,2024,14:1434791.doi：10.3389/fonc.2024.1434791

49. SuwaraJ,HartmanML.Balancing between cuproplasia and copper‑dependent cell death: molecular basis and clinical implications of ATOX1 in cancer[J].J Exp Clin Cancer Res,2025,44(1):222.doi：10.1186/s13046-025-03486-5

50. TsymbalS,RefeldA,ZatsepinV,et al.The p53 protein is a suppressor of ATOX1 copper chaperon in tumor cells under genotoxic effects[J].PLoS One,2023,18(12):e0295944.doi：10.1371/journal.pone.0295944

51. LiaoQ,DengJ,TongJ,et al.p53 induces circFRMD4A to suppress cancer development through glycolytic reprogramming and cuproptosis[J].Mol Cell,2025,85(1):132‑149.e7.doi：10.1016/j.molcel.2024.11.013

52. LiHJ,LiYC,YuYH,et al.GSH exhaustion via inhibition of xCT‑GSH‑GPX4 pathway synergistically enhanced DSF/Cu‑induced cuproptosis in myelodysplastic syndromes[J].Free Radic Biol Med,2024,222:130‑148.doi：10.1016/j.freeradbiomed.2024.06.006

53. WangSH,ZhuL,WangYB,et al.ILF3 promotes colorectal cancer cell resistance to ferroptosis by enhancing cysteine uptake and GSH synthesis via stabilizing SLC3A2 mRNA[J].Cell Death Dis,2025,16(1):549.doi：10.1038/s41419-025-07872-x

54. JiangJ,YeFZ,WangJY,et al.Targeting SLC7A11 sensitizes colorectal cancer cells to elesclomol‑Cu‑induced cuproptosis via the GSH‑GPX4 axis[J].Biochem Biophys Res Commun,2026,799:153177.doi：10.1016/j.bbrc.2025.153177

55. BaiCS,HuaJL,MengDH,et al.Glutaminase‑1 mediated glutaminolysis to glutathione synthesis maintains redox homeostasis and modulates ferroptosis sensitivity in cancer cells[J].Cell Prolif,2025,58(11):e70036.doi：10.1111/cpr.70036

56. LuanMH,ZhuWS,FengZT,et al.MTF1 attenuates ferroptosis and cuproptosis synergistic potentiation in gastric cancer[J].Cell Death Differ,2026,33(6):1103-1119.doi：10.1038/s41418-025-01641-1

57. MaJ,ZhengLY,FangSJ,et al.Triptonide stabilizes BIM to enhance oxaliplatin‑induced ferroptosis and apoptosis in colorectal cancer[J].Transl Oncol,2025,60:102491.doi：10.1016/j.tranon.2025.102491

58. SongCH,ChoiY,KimNY,et al.Sex‑specific molecular markers NRF2 and PD‑L1 in colon carcinogenesis: implications for right‑sided colon cancer[J].Cancer Res Treat,2025,57(4):1090‑1103.doi：10.4143/crt.2024.818

59. LiuSL,WuJH,HuangH,et al.Effects of solamargine in hepatic metastasis of colorectal cancer: induction of ferroptosis and elimination of cancer stem cells[J].Chin Med,2025,20(1):110.doi：10.1186/s13020-025-01171-5

60. EguchiK,YaoT,KonomotoT,et al.Discordance of p53 mutations of synchronous colorectal carcinomas[J].Mod Pathol,2000,13(2):131‑139.doi：10.1038/modpathol.3880024

61. UmansRA,MartinJ,HarriganME,et al.Transcriptional regulation of amino acid transport in glioblastoma multiforme[J].Cancers (Basel),2021,13(24):6169.doi：10.3390/cancers13246169

62. LuJA,HeR,LiuY,et al.Exploiting cell death and tumor immunity in cancer therapy: challenges and future directions[J].Front Cell Dev Biol,2024,12:1416115.doi：10.3389/fcell.2024.1416115

63. LiJH,ZhangG,SunZ,et al.Immunogenic cuproptosis in cancer immunotherapy via an in situ cuproptosis‑inducing system[J].Biomaterials,2025,319:123201.doi：10.1016/j.biomaterials.2025.123201

64. RuanYH,ZhuangHL,ZengXM,et al.Engineered microbial nanohybrids for tumor‑mediated NIR II photothermal enhanced ferroptosis/cuproptosis and immunotherapy[J].Adv Healthc Mater,2024,13(4):e2302537.doi：10.1002/adhm.202470025

65. WangZY,DiYQ,YeLL,et al.NANS suppresses NF‑κB signaling to promote ferroptosis by perturbing iron homeostasis[J].Cell Rep,2025,44(5):115701.doi：10.1016/j.celrep.2025.115701

66. ChenYC,WangYJ,ZhangRT,et al.In situ transformable fibrillar clusters disrupt intracellular copper metabolic homeostasis by comprehensive blockage of cuprous ions efflux[J].Small,2025,21(1):e2406802.doi：10.1002/smll.202406802

67. RahB,ShafarinJ,KarimA,et al.Iron overloading potentiates the antitumor activity of 5‑fluorouracil by promoting apoptosis and ferroptosis in colorectal cancer cells[J].Cell Biochem Biophys,2024,82(4):3763‑3780.doi：10.1007/s12013-024-01463-x

68. XieYC,KangR,KlionskyDJ,et al.GPX4 in cell death, autophagy, and disease[J].Autophagy,2023,19(10):2621‑2638.doi：10.1080/15548627.2023.2218764

69. XiangY,ZhengJY,ZhaoXL,et al.Sodium butyrate enhances sorafenib‑induced ferroptosis and immunogenic cell death by modulating IRF2‑Oasl2‑cGAS pathway in colorectal cancer[J].Mater Today Bio,2025,35:102498.doi：10.1016/j.mtbio.2025.102498

70. 暴启颖.NDUFS2通过铁死亡调控人结直肠癌细胞HCT116对索拉非尼的敏感性[D].长春:吉林大学,2025.BaoQY.NDUFS2 regulates the sensitivity of human colorectal cancer cell HCT116 to sorafenib via ferroptosis[D].Changchun:Jilin University,2025.

71. WangL,WangJ,ChenL.TIMP1 represses sorafenib‑triggered ferroptosis in colorectal cancer cells by activating the PI3K/Akt signaling pathway[J].Immunopharmacol Immunotoxicol,2023,45(4):419‑425.doi：10.1080/08923973.2022.2160731

72. DaiX,DingWJ,HeYS,et al.Refractory microsatellite stable metastatic colorectal cancer with ERBB2/ERBB3 mutation may be preferred population for regorafenib plus PD‑1 inhibitor therapy: a real‑world study[J].Front Oncol,2023,13:1227644.doi：10.3389/fonc.2023.1227644

73. HuangJ,YangMJ,ZhouXY,et al.DDTC‑Cu(I) Nano‑MOF induces ferroptosis by targeting SLC7A11/GPX4 signal in colorectal cancer[J].ACS Biomater Sci Eng,2025,11(7):4468‑4480.doi：10.1021/acsbiomaterials.5c00680

74. XueXN,ZhangZB,ZhangQY,et al.Copper/iron‑based intelligent nanoparticles self‑amplify apoptosis/ferroptosis/cuproptosis in colorectal cancer[J].Mater Today Bio,2026,36:102732.doi：10.1016/j.mtbio.2025.102732