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The role of regulated necrosis in diabetes and its complications

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Abstract

Morphologically, cell death can be divided into apoptosis and necrosis. Apoptosis, which is a type of regulated cell death, is well tolerated by the immune system and is responsible for hemostasis and cellular turnover under physiological conditions. In contrast, necrosis is defined as a form of passive cell death that leads to a dramatic inflammatory response (also referred to as necroinflammation) and causes organ dysfunction under pathological conditions. Recently, a novel form of cell death named regulated necrosis (such as necroptosis, pyroptosis, and ferroptosis) was discovered. Distinct from apoptosis, regulated necrosis is modulated by multiple internal or external factors, but meanwhile, it results in inflammation and immune response. Accumulating evidence has indicated that regulated necrosis is associated with multiple diseases, including diabetes. Diabetes is characterized by hyperglycemia caused by insulin deficiency and/or insulin resistance, and long-term high glucose leads to various diabetes-related complications. Here, we summarize the mechanisms of necroptosis, pyroptosis, and ferroptosis, and introduce recent advances in characterizing the associations between these three types of regulated necrosis and diabetes and its complications.

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References

  1. Galluzzi L, Bravo-San Pedro JM, Kepp O, Kroemer G (2016) Regulated cell death and adaptive stress responses. Cell Mol Life Sci 73(11–12):2405–2410

    Article  CAS  PubMed  Google Scholar 

  2. Nagata S (2010) Apoptosis and autoimmune diseases. Ann N Y Acad Sci 1209:10–16

    Article  CAS  PubMed  Google Scholar 

  3. Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature 417(6885):182–187

    Article  CAS  PubMed  Google Scholar 

  4. Rojas J, Bermudez V, Palmar J, Martinez MS, Olivar LC, Nava M et al (2018) Pancreatic beta cell death: novel potential mechanisms in diabetes therapy. J Diabetes Res 2018:9601801

    Article  PubMed  PubMed Central  Google Scholar 

  5. Tonnus W, Belavgeni A, Beuschlein F, Eisenhofer G, Fassnacht M, Kroiss M et al (2021) The role of regulated necrosis in endocrine diseases. Nat Rev Endocrinol 17(8):497–510

    Article  PubMed  PubMed Central  Google Scholar 

  6. Zhao Y, Scott NA, Fynch S, Elkerbout L, Wong WW, Mason KD et al (2015) Autoreactive T cells induce necrosis and not BCL-2-regulated or death receptor-mediated apoptosis or RIPK3-dependent necroptosis of transplanted islets in a mouse model of type 1 diabetes. Diabetologia 58(1):140–148

    Article  CAS  PubMed  Google Scholar 

  7. Eizirik DL, Pasquali L, Cnop M (2020) Pancreatic beta-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol 16(7):349–362

    Article  CAS  PubMed  Google Scholar 

  8. Xue L, Wang H, He Y, Sui M, Li H, Mei L et al (2022) Incidence and risk factors of diabetes mellitus in the Chinese population: a dynamic cohort study. BMJ Open 12(11):e060730

    Article  PubMed  PubMed Central  Google Scholar 

  9. Cao T, Ni R, Ding W, Ji X, Li L, Liao G et al (2022) MLKL-mediated necroptosis is a target for cardiac protection in mouse models of type-1 diabetes. Cardiovasc Diabetol 21(1):165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Qiu Z, Lei S, Zhao B, Wu Y, Su W, Liu M et al (2017) NLRP3 inflammasome activation-mediated pyroptosis aggravates myocardial ischemia/reperfusion injury in diabetic rats. Oxid Med Cell Longev 2017:9743280

    Article  PubMed  PubMed Central  Google Scholar 

  11. Feng X, Wang S, Sun Z, Dong H, Yu H, Huang M et al (2021) Ferroptosis enhanced diabetic renal tubular injury via HIF-1alpha/HO-1 pathway in db/db mice. Front Endocrinol (Lausanne) 12:626390

    Article  PubMed  Google Scholar 

  12. American Diabetes Association Professional Practice C. 2 (2022) Classification and diagnosis of diabetes: standards of medical care in diabetes-2022. Diabetes Care 45(Suppl 1):S17–S38

    Article  Google Scholar 

  13. Eizirik DL, Colli ML, Ortis F (2009) The role of inflammation in insulitis and beta-cell loss in type 1 diabetes. Nat Rev Endocrinol 5(4):219–226

    Article  CAS  PubMed  Google Scholar 

  14. Sims EK, DiMeglio LA (2019) Cause or effect? A review of clinical data demonstrating beta cell dysfunction prior to the clinical onset of type 1 diabetes. Mol Metab 27S(Suppl):S129–S138

    Article  PubMed  Google Scholar 

  15. Quan W, Jo EK, Lee MS (2013) Role of pancreatic beta-cell death and inflammation in diabetes. Diabetes Obes Metab 15(Suppl 3):141–151

    Article  CAS  PubMed  Google Scholar 

  16. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52(1):102–110

    Article  CAS  PubMed  Google Scholar 

  17. Talchai C, Xuan S, Lin HV, Sussel L, Accili D (2012) Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell 150(6):1223–1234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11(2):98–107

    Article  CAS  PubMed  Google Scholar 

  19. Ehses JA, Perren A, Eppler E, Ribaux P, Pospisilik JA, Maor-Cahn R et al (2007) Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56(9):2356–2370

    Article  CAS  PubMed  Google Scholar 

  20. Liu S, Tang G, Duan F, Zeng C, Gong J, Chen Y et al (2021) MiR-17-5p inhibits TXNIP/NLRP3 inflammasome pathway and suppresses pancreatic beta-cell pyroptosis in diabetic mice. Front Cardiovasc Med 8:768029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wei S, Qiu T, Yao X, Wang N, Jiang L, Jia X et al (2020) Arsenic induces pancreatic dysfunction and ferroptosis via mitochondrial ROS-autophagy-lysosomal pathway. J Hazard Mater 384:121390

    Article  CAS  PubMed  Google Scholar 

  22. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT et al (2011) Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12(5):408–415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL et al (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17(2):179–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N et al (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1(2):112–119

    Article  CAS  PubMed  Google Scholar 

  25. Li L, Tong A, Zhang Q, Wei Y, Wei X (2021) The molecular mechanisms of MLKL-dependent and MLKL-independent necrosis. J Mol Cell Biol 13(1):3–14

    Article  CAS  PubMed  Google Scholar 

  26. Dhuriya YK, Sharma D (2018) Necroptosis: a regulated inflammatory mode of cell death. J Neuroinflammation 15(1):199

    Article  PubMed  PubMed Central  Google Scholar 

  27. Festjens N, Vanden Berghe T, Cornelis S, Vandenabeele P (2007) RIP1, a kinase on the crossroads of a cell’s decision to live or die. Cell Death Differ 14(3):400–410

    Article  CAS  PubMed  Google Scholar 

  28. Newton K, Dugger DL, Wickliffe KE, Kapoor N, de Almagro MC, Vucic D et al (2014) Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343(6177):1357–1360

    Article  CAS  PubMed  Google Scholar 

  29. O’Donnell MA, Perez-Jimenez E, Oberst A, Ng A, Massoumi R, Xavier R et al (2011) Caspase 8 inhibits programmed necrosis by processing CYLD. Nat Cell Biol 13(12):1437–1442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Xie T, Peng W, Yan C, Wu J, Gong X, Shi Y (2013) Structural insights into RIP3-mediated necroptotic signaling. Cell Rep 5(1):70–78

    Article  CAS  PubMed  Google Scholar 

  31. Weber K, Roelandt R, Bruggeman I, Estornes Y, Vandenabeele P (2018) Nuclear RIPK3 and MLKL contribute to cytosolic necrosome formation and necroptosis. Commun Biol 1:6

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kaiser WJ, Upton JW, Mocarski ES (2013) Viral modulation of programmed necrosis. Curr Opin Virol 3(3):296–306

    Article  CAS  PubMed  Google Scholar 

  33. Mocarski ES, Upton JW, Kaiser WJ (2011) Viral infection and the evolution of caspase 8-regulated apoptotic and necrotic death pathways. Nat Rev Immunol 12(2):79–88

    Article  PubMed  PubMed Central  Google Scholar 

  34. Op de Beeck a, Eizirik DL (2016) Viral infections in type 1 diabetes mellitus--why the beta cells? Nat Rev Endocrinol 12(5):263–73

    Article  PubMed Central  Google Scholar 

  35. Nakamura H, Kinjo T, Arakaki W, Miyagi K, Tateyama M, Fujita J (2020) Serum levels of receptor-interacting protein kinase-3 in patients with COVID-19. Crit Care 24(1):484

    Article  PubMed  PubMed Central  Google Scholar 

  36. Hollstein T, Schulte DM, Schulz J, Gluck A, Ziegler AG, Bonifacio E et al (2020) Autoantibody-negative insulin-dependent diabetes mellitus after SARS-CoV-2 infection: a case report. Nat Metab 2(10):1021–1024

    Article  CAS  PubMed  Google Scholar 

  37. Wu CT, Lidsky PV, Xiao Y, Lee IT, Cheng R, Nakayama T et al (2021) SARS-CoV-2 infects human pancreatic beta cells and elicits beta cell impairment. Cell Metab 33(8):1565-76e5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hildebrand JM, Lo B, Tomei S, Mattei V, Young SN, Fitzgibbon C et al (2021) A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes. Cell Death Dis 12(4):345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Song S, Ding Y, Dai GL, Zhang Y, Xu MT, Shen JR et al (2021) Sirtuin 3 deficiency exacerbates diabetic cardiomyopathy via necroptosis enhancement and NLRP3 activation. Acta Pharmacol Sin 42(2):230–241

    Article  CAS  PubMed  Google Scholar 

  40. Sun L, Chen Y, Luo H, Xu M, Meng G, Zhang W (2019) Ca(2+)/calmodulin-dependent protein kinase II regulation by inhibitor 1 of protein phosphatase 1 alleviates necroptosis in high glucose-induced cardiomyocytes injury. Biochem Pharmacol 163:194–205

    Article  CAS  PubMed  Google Scholar 

  41. Chen Y, Li X, Hua Y, Ding Y, Meng G, Zhang W (2021) RIPK3-mediated necroptosis in diabetic cardiomyopathy requires CaMKII activation. Oxid Med Cell Longev 2021:6617816

    PubMed  PubMed Central  Google Scholar 

  42. Drummond K, Mauer M (2002) International Diabetic Nephropathy Study G. The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes. Diabetes 51(5):1580–7

    Article  CAS  PubMed  Google Scholar 

  43. Garg P (2018) A review of podocyte biology. Am J Nephrol 47(Suppl 1):3–13

    Article  CAS  PubMed  Google Scholar 

  44. Xu Y, Gao H, Hu Y, Fang Y, Qi C, Huang J et al (2019) High glucose-induced apoptosis and necroptosis in podocytes is regulated by UCHL1 via RIPK1/RIPK3 pathway. Exp Cell Res 382(2):111463

    Article  CAS  PubMed  Google Scholar 

  45. Gao S, Huang X, Zhang Y, Bao L, Wang X, Zhang M (2021) Investigation on the expression regulation of RIPK1/RIPK3 in the retinal ganglion cells (RGCs) cultured in high glucose. Bioengineered 12(1):3947–3956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wei J, Zhao Y, Liang H, Du W, Wang L (2022) Preliminary evidence for the presence of multiple forms of cell death in diabetes cardiomyopathy. Acta Pharm Sin B 12(1):1–17

    Article  CAS  PubMed  Google Scholar 

  47. Bergsbaken T, Fink SL, Cookson BT (2009) Pyroptosis: host cell death and inflammation. Nat Rev Microbiol 7(2):99–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Christgen S, Kanneganti TD (2020) Inflammasomes and the fine line between defense and disease. Curr Opin Immunol 62:39–44

    Article  CAS  PubMed  Google Scholar 

  49. Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10(2):417–426

    Article  CAS  PubMed  Google Scholar 

  50. Gritsenko A, Yu S, Martin-Sanchez F, Diaz-Del-Olmo I, Nichols EM, Davis DM et al (2020) Priming is dispensable for NLRP3 inflammasome activation in human monocytes in vitro. Front Immunol 11:565924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S et al (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526(7575):666–671

    Article  CAS  PubMed  Google Scholar 

  52. Vigano E, Diamond CE, Spreafico R, Balachander A, Sobota RM, Mortellaro A (2015) Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes. Nat Commun 6:8761

    Article  CAS  PubMed  Google Scholar 

  53. Sarhan J, Liu BC, Muendlein HI, Li P, Nilson R, Tang AY et al (2018) Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. Proc Natl Acad Sci USA 115(46):E10888–E10897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhou B, Zhang JY, Liu XS, Chen HZ, Ai YL, Cheng K et al (2018) Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis. Cell Res 28(12):1171–1185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sun X, Pang H, Li J, Luo S, Huang G, Li X et al (2020) The NLRP3 inflammasome and its role in T1DM. Front Immunol 11:1595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hu C, Ding H, Li Y, Pearson JA, Zhang X, Flavell RA et al (2015) NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets. Proc Natl Acad Sci USA 112(36):11318–11323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Carlos D, Costa FR, Pereira CA, Rocha FA, Yaochite JN, Oliveira GG et al (2017) Mitochondrial DNA activates the NLRP3 inflammasome and predisposes to type 1 diabetes in murine model. Front Immunol 8:164

    Article  PubMed  PubMed Central  Google Scholar 

  58. Ma H, Jeppesen JF, Jaenisch R (2020) Human T cells expressing a CD19 CAR-T receptor provide insights into mechanisms of human CD19-positive beta cell destruction. Cell Rep Med 1(6):100097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Giordano A, Murano I, Mondini E, Perugini J, Smorlesi A, Severi I et al (2013) Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis. J Lipid Res 54(9):2423–2436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lin Y, Hu Y, Hu X, Yang L, Chen X, Li Q et al (2020) Ginsenoside Rb2 improves insulin resistance by inhibiting adipocyte pyroptosis. Adipocyte 9(1):302–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chen C, Ma X, Yang C, Nie W, Zhang J, Li H et al (2018) Hypoxia potentiates LPS-induced inflammatory response and increases cell death by promoting NLRP3 inflammasome activation in pancreatic beta cells. Biochem Biophys Res Commun 495(4):2512–2518

    Article  CAS  PubMed  Google Scholar 

  62. Li X, Bai C, Wang H, Wan T, Li Y (2022) LncRNA MEG3 regulates autophagy and pyroptosis via FOXO1 in pancreatic beta-cells. Cell Signal 92:110247

    Article  CAS  PubMed  Google Scholar 

  63. Xing Y, He Y, Zhang Y, Wang H, Peng S, Xie C et al (2022) Emodin alleviates high-glucose-induced pancreatic beta-cell pyroptosis by inhibiting NLRP3/GSDMD signaling. Evid Based Complement Alternat Med 2022:5276832

    Article  PubMed  PubMed Central  Google Scholar 

  64. Wu M, Lu L, Guo K, Lu J, Chen H (2022) Vitamin D protects against high glucose-induced pancreatic beta-cell dysfunction via AMPK-NLRP3 inflammasome pathway. Mol Cell Endocrinol 547:111596

    Article  CAS  PubMed  Google Scholar 

  65. Minutoli L, Puzzolo D, Rinaldi M, Irrera N, Marini H, Arcoraci V et al (2016) ROS-mediated NLRP3 inflammasome activation in brain, heart, kidney, and testis ischemia/reperfusion injury. Oxid Med Cell Longev 2016:2183026

    Article  PubMed  PubMed Central  Google Scholar 

  66. Luo B, Li B, Wang W, Liu X, Xia Y, Zhang C et al (2014) NLRP3 gene silencing ameliorates diabetic cardiomyopathy in a type 2 diabetes rat model. PLoS ONE 9(8):e104771

    Article  PubMed  PubMed Central  Google Scholar 

  67. Wang X, Pan J, Liu H, Zhang M, Liu D, Lu L et al (2019) AIM2 gene silencing attenuates diabetic cardiomyopathy in type 2 diabetic rat model. Life Sci 221:249–258

    Article  CAS  PubMed  Google Scholar 

  68. Meng L, Lin H, Huang X, Weng J, Peng F, Wu S (2022) METTL14 suppresses pyroptosis and diabetic cardiomyopathy by downregulating TINCR lncRNA. Cell Death Dis 13(1):38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yang F, Qin Y, Lv J, Wang Y, Che H, Chen X et al (2018) Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy. Cell Death Dis 9(10):1000

    Article  PubMed  PubMed Central  Google Scholar 

  70. Zou R, Nie C, Pan S, Wang B, Hong X, Xi S et al (2022) Co-administration of hydrogen and metformin exerts cardioprotective effects by inhibiting pyroptosis and fibrosis in diabetic cardiomyopathy. Free Radic Biol Med 183:35–50

    Article  CAS  PubMed  Google Scholar 

  71. Qu XF, Zhai BZ, Hu WL, Lou MH, Chen YH, Liu YF et al (2022) Pyrroloquinoline quinone ameliorates diabetic cardiomyopathy by inhibiting the pyroptosis signaling pathway in C57BL/6 mice and AC16 cells. Eur J Nutr 61(4):1823–1836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hong L, Zha Y, Wang C, Qiao S, An J (2021) Folic acid alleviates high glucose and fat-induced pyroptosis via inhibition of the hippo signal pathway on H9C2 cells. Front Mol Biosci 8:698698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Liu Y, Xu Z, Ma F, Jia Y, Wang G (2018) Knockdown of TLR4 attenuates high glucose-induced podocyte injury via the NALP3/ASC/Caspase-1 signaling pathway. Biomed Pharmacother 107:1393–1401

    Article  CAS  PubMed  Google Scholar 

  74. An X, Zhang Y, Cao Y, Chen J, Qin H, Yang L (2020) Punicalagin protects diabetic nephropathy by inhibiting pyroptosis based on TXNIP/NLRP3 pathway. Nutrients 12(5)

  75. Zhan JF, Huang HW, Huang C, Hu LL, Xu WW (2020) Long non-coding RNA NEAT1 regulates pyroptosis in diabetic nephropathy via mediating the miR-34c/NLRP3 axis. Kidney Blood Press Res 45(4):589–602

    Article  CAS  PubMed  Google Scholar 

  76. Cheng Q, Pan J, Zhou ZL, Yin F, Xie HY, Chen PP et al (2021) Caspase-11/4 and gasdermin D-mediated pyroptosis contributes to podocyte injury in mouse diabetic nephropathy. Acta Pharmacol Sin 42(6):954–963

    Article  CAS  PubMed  Google Scholar 

  77. Gan J, Huang M, Lan G, Liu L, Xu F (2020) High glucose induces the loss of retinal pericytes partly via NLRP3-Caspase-1-GSDMD-mediated pyroptosis. Biomed Res Int 2020:4510628

    Article  PubMed  PubMed Central  Google Scholar 

  78. Gu C, Draga D, Zhou C, Su T, Zou C, Gu Q et al (2019) miR-590-3p inhibits pyroptosis in diabetic retinopathy by targeting NLRP1 and inactivating the NOX4 signaling pathway. Invest Ophthalmol Vis Sci 60(13):4215–4223

    Article  CAS  PubMed  Google Scholar 

  79. Zha X, Xi X, Fan X, Ma M, Zhang Y, Yang Y (2020) Overexpression of METTL3 attenuates high-glucose induced RPE cell pyroptosis by regulating miR-25-3p/PTEN/Akt signaling cascade through DGCR8. Aging (Albany NY) 12(9):8137–8150

    Article  CAS  PubMed  Google Scholar 

  80. Huang C, Qi P, Cui H, Lu Q, Gao X (2022) CircFAT1 regulates retinal pigment epithelial cell pyroptosis and autophagy via mediating m6A reader protein YTHDF2 expression in diabetic retinopathy. Exp Eye Res 222:109152

    Article  CAS  PubMed  Google Scholar 

  81. Wang JJ, Chen ZL, Wang DD, Wu KF, Huang WB, Zhang LQ (2022) linc00174 deteriorates the pathogenesis of diabetic retinopathy via miR-26a-5p/PTEN/Akt signalling cascade-mediated pyroptosis. Biochem Biophys Res Commun 630:92–100

    Article  CAS  PubMed  Google Scholar 

  82. Li W, Yang S, Chen G, He S (2022) MiR-200c-3p regulates pyroptosis by targeting SLC30A7 in diabetic retinopathy. Hum Exp Toxicol 41:9603271221099588

    Article  CAS  PubMed  Google Scholar 

  83. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lei G, Zhuang L, Gan B (2022) Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer 22(7):381–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. He J, Li Z, Xia P, Shi A, FuChen X, Zhang J et al (2022) Ferroptosis and ferritinophagy in diabetes complications. Mol Metab 60:101470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bridges R, Lutgen V, Lobner D, Baker DA (2012) Thinking outside the cleft to understand synaptic activity: contribution of the cystine-glutamate antiporter (System xc-) to normal and pathological glutamatergic signaling. Pharmacol Rev 64(3):780–802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Seibt TM, Proneth B, Conrad M (2019) Role of GPX4 in ferroptosis and its pharmacological implication. Free Radic Biol Med 133:144–152

    Article  CAS  PubMed  Google Scholar 

  88. Liu X, Zhang Y, Zhuang L, Olszewski K, Gan B (2021) NADPH debt drives redox bankruptcy: SLC7A11/xCT-mediated cystine uptake as a double-edged sword in cellular redox regulation. Genes Dis 8(6):731–745

    Article  CAS  PubMed  Google Scholar 

  89. Shen Z, Liu T, Li Y, Lau J, Yang Z, Fan W et al (2018) Fenton-reaction-acceleratable magnetic nanoparticles for ferroptosis therapy of orthotopic brain tumors. ACS Nano 12(11):11355–11365

    Article  CAS  PubMed  Google Scholar 

  90. Torti SV, Torti FM (2013) Iron and cancer: more ore to be mined. Nat Rev Cancer 13(5):342–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS et al (2017) Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 13(1):81–90

    Article  CAS  PubMed  Google Scholar 

  92. Lemasters JJ (2017) Evolution of voltage-dependent anion channel function: from molecular sieve to governator to actuator of ferroptosis. Front Oncol 7:303

    Article  PubMed  PubMed Central  Google Scholar 

  93. Kang R, Kroemer G, Tang D (2019) The tumor suppressor protein p53 and the ferroptosis network. Free Radic Biol Med 133:162–168

    Article  CAS  PubMed  Google Scholar 

  94. Santana-Codina N, Mancias JD (2018) The role of NCOA4-mediated ferritinophagy in health and disease. Pharmaceuticals (Basel) 11(4)

  95. Hayano M, Yang WS, Corn CK, Pagano NC, Stockwell BR (2016) Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ 23(2):270–278

    Article  CAS  PubMed  Google Scholar 

  96. Kuang F, Liu J, Tang D, Kang R (2020) Oxidative damage and antioxidant defense in ferroptosis. Front Cell Dev Biol 8:586578

    Article  PubMed  PubMed Central  Google Scholar 

  97. Sun X, Ou Z, Xie M, Kang R, Fan Y, Niu X et al (2015) HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene 34(45):5617–5625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Dodson M, Castro-Portuguez R, Zhang DD (2019) NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol 23:101107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bruni A, Pepper AR, Pawlick RL, Gala-Lopez B, Gamble AF, Kin T et al (2018) Ferroptosis-inducing agents compromise in vitro human islet viability and function. Cell Death Dis 9(6):595

    Article  PubMed  PubMed Central  Google Scholar 

  100. Krummel B, Plotz T, Jorns A, Lenzen S, Mehmeti I (2021) The central role of glutathione peroxidase 4 in the regulation of ferroptosis and its implications for pro-inflammatory cytokine-mediated beta-cell death. Biochim Biophys Acta Mol Basis Dis 1867(6):166114

    Article  PubMed  Google Scholar 

  101. Hao L, Mi J, Song L, Guo Y, Li Y, Yin Y et al (2021) SLC40A1 mediates ferroptosis and cognitive dysfunction in type 1 diabetes. Neuroscience 463:216–226

    Article  CAS  PubMed  Google Scholar 

  102. Wang Y, Wang S, Xin Y, Zhang J, Wang S, Yang Z et al (2021) Hydrogen sulfide alleviates the anxiety-like and depressive-like behaviors of type 1 diabetic mice via inhibiting inflammation and ferroptosis. Life Sci 278:119551

    Article  CAS  PubMed  Google Scholar 

  103. Bazinet RP, Laye S (2014) Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci 15(12):771–785

    Article  CAS  PubMed  Google Scholar 

  104. Zhang S, Liu X, Wang J, Yuan F, Liu Y (2022) Targeting ferroptosis with miR-144-3p to attenuate pancreatic beta cells dysfunction via regulating USP22/SIRT1 in type 2 diabetes. Diabetol Metab Syndr 14(1):89

    Article  PubMed  PubMed Central  Google Scholar 

  105. Eitel K, Staiger H, Brendel MD, Brandhorst D, Bretzel RG, Haring HU et al (2002) Different role of saturated and unsaturated fatty acids in beta-cell apoptosis. Biochem Biophys Res Commun 299(5):853–856

    Article  CAS  PubMed  Google Scholar 

  106. Krummel B, von Hanstein AS, Plotz T, Lenzen S, Mehmeti I (2022) Differential effects of saturated and unsaturated free fatty acids on ferroptosis in rat beta-cells. J Nutr Biochem 106:109013

    Article  PubMed  Google Scholar 

  107. Grau-Perez M, Kuo CC, Spratlen M, Thayer KA, Mendez MA, Hamman RF et al (2017) The association of arsenic exposure and metabolism with type 1 and type 2 diabetes in youth: the SEARCH case-control study. Diabetes Care 40(1):46–53

    Article  PubMed  Google Scholar 

  108. Sun L, Zong G, Pan A, Ye X, Li H, Yu Z et al (2013) Elevated plasma ferritin is associated with increased incidence of type 2 diabetes in middle-aged and elderly Chinese adults. J Nutr 143(9):1459–1465

    Article  CAS  PubMed  Google Scholar 

  109. Basuli D, Stevens RG, Torti FM, Torti SV (2014) Epidemiological associations between iron and cardiovascular disease and diabetes. Front Pharmacol 5:117

    PubMed  PubMed Central  Google Scholar 

  110. Fernandez-Real JM, Penarroja G, Castro A, Garcia-Bragado F, Hernandez-Aguado I, Ricart W (2002) Blood letting in high-ferritin type 2 diabetes: effects on insulin sensitivity and beta-cell function. Diabetes 51(4):1000–1004

    Article  CAS  PubMed  Google Scholar 

  111. Houschyar KS, Ludtke R, Dobos GJ, Kalus U, Broecker-Preuss M, Rampp T et al (2012) Effects of phlebotomy-induced reduction of body iron stores on metabolic syndrome: results from a randomized clinical trial. BMC Med 10:54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Song JX, An JR, Chen Q, Yang XY, Jia CL, Xu S et al (2022) Liraglutide attenuates hepatic iron levels and ferroptosis in db/db mice. Bioengineered 13(4):8334–8348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Li W, Li W, Leng Y, Xiong Y, Xia Z (2020) Ferroptosis is involved in diabetes myocardial ischemia/reperfusion injury through endoplasmic reticulum stress. DNA Cell Biol 39(2):210–225

    Article  CAS  PubMed  Google Scholar 

  114. Wang X, Chen X, Zhou W, Men H, Bao T, Sun Y et al (2022) Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways. Acta Pharm Sin B 12(2):708–722

    Article  PubMed  Google Scholar 

  115. Chen QM, Maltagliati AJ (2018) Nrf2 at the heart of oxidative stress and cardiac protection. Physiol Genomics 50(2):77–97

    Article  CAS  PubMed  Google Scholar 

  116. Wei Z, Shaohuan Q, Pinfang K, Chao S (2022) Curcumin attenuates ferroptosis-induced myocardial injury in diabetic cardiomyopathy through the Nrf2 pathway. Cardiovasc Ther 2022:3159717

    Article  PubMed  PubMed Central  Google Scholar 

  117. Wu S, Zhu J, Wu G, Hu Z, Ying P, Bao Z et al (2022) 6-Gingerol alleviates ferroptosis and inflammation of diabetic cardiomyopathy via the Nrf2/HO-1 pathway. Oxid Med Cell Longev 2022:3027514

    Article  PubMed  PubMed Central  Google Scholar 

  118. Zang H, Wu W, Qi L, Tan W, Nagarkatti P, Nagarkatti M et al (2020) Autophagy inhibition enables Nrf2 to exaggerate the progression of diabetic cardiomyopathy in mice. Diabetes 69(12):2720–2734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wang Y, Bi R, Quan F, Cao Q, Lin Y, Yue C et al (2020) Ferroptosis involves in renal tubular cell death in diabetic nephropathy. Eur J Pharmacol 888:173574

    Article  CAS  PubMed  Google Scholar 

  120. Kim S, Kang SW, Joo J, Han SH, Shin H, Nam BY et al (2021) Characterization of ferroptosis in kidney tubular cell death under diabetic conditions. Cell Death Dis 12(2):160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Li S, Zheng L, Zhang J, Liu X, Wu Z (2021) Inhibition of ferroptosis by up-regulating Nrf2 delayed the progression of diabetic nephropathy. Free Radic Biol Med 162:435–449

    Article  CAS  PubMed  Google Scholar 

  122. Jin T, Chen C (2022) Umbelliferone delays the progression of diabetic nephropathy by inhibiting ferroptosis through activation of the Nrf-2/HO-1 pathway. Food Chem Toxicol 163:112892

    Article  CAS  PubMed  Google Scholar 

  123. Wu Y, Zhao Y, Yang HZ, Wang YJ, Chen Y (2021) HMGB1 regulates ferroptosis through Nrf2 pathway in mesangial cells in response to high glucose. Biosci Rep 41(2)

  124. Shao J, Bai Z, Zhang L, Zhang F (2022) Ferrostatin-1 alleviates tissue and cell damage in diabetic retinopathy by improving the antioxidant capacity of the Xc(-)-GPX4 system. Cell Death Discov 8(1):426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Fritsch M, Gunther SD, Schwarzer R, Albert MC, Schorn F, Werthenbach JP et al (2019) Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature 575(7784):683–687

    Article  CAS  PubMed  Google Scholar 

  126. Huang J, Jones D, Luo B, Sanderson M, Soto J, Abel ED et al (2011) Iron overload and diabetes risk: a shift from glucose to Fatty Acid oxidation and increased hepatic glucose production in a mouse model of hereditary hemochromatosis. Diabetes 60(1):80–87

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Key R&D Program of China (grant number 2018YFE0114500), the National Natural Science Foundation of China (grant numbers 82070813 and 81820108007), and the Hunan Province Natural Science Foundation of China (grant numbers 2022JJ30858, 2021JC0003 and 2020JJ2053).

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  1. National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China

    Haipeng Pang, Gan Huang, Zhiguo Xie & Zhiguang Zhou

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  1. Haipeng Pang
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  2. Gan Huang
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H.P. searched references, wrote the first draft of the paper, and revised the text. G.H. and Z.X. critically revised the text and provided substantial scientific contributions. Z.X. and Z.Z. proposed the project and revised the manuscript. All the authors approved the final version of the manuscript.

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Correspondence to Zhiguo Xie or Zhiguang Zhou.

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Pang, H., Huang, G., Xie, Z. et al. The role of regulated necrosis in diabetes and its complications. J Mol Med 102, 495–505 (2024). https://doi.org/10.1007/s00109-024-02421-z

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