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Cell death in multiple sclerosis

Cell Death & Differentiation volume 33, pages 433–446 (2026)Cite this article

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Abstract

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS) characterized by inflammatory demyelination and progressive neurodegeneration. Although current disease-modifying therapies modulate peripheral autoimmune responses, they are insufficient to fully prevent tissue specific neuroinflammation and long-term neuronal and oligodendrocyte loss. Growing evidence implicates various regulated cell death (RCD) pathways, including apoptosis, necroptosis, pyroptosis, and ferroptosis, not only as downstream consequences of chronic inflammation, but also as active drivers of demyelination, axonal injury, and glial dysfunction in MS. These RCD modalities contribute to MS pathology by disrupting cellular homeostasis and sustaining immune activation through the continuous release of damage-associated molecular patterns (DAMPs), thereby establishing a self-amplifying loop between cell death and inflammation. Furthermore, distinct RCD forms can co-occur within lesions, contributing to the complex cellular landscape of MS. This review summarizes current understanding of RCD mechanisms in MS, focusing on their contributions to neuroinflammation and neurodegeneration across different disease stages. We also discuss recent therapeutic advances targeting RCD, including approved drugs whose efficacy may be partially attributed to modulation of cell death, and emerging small-molecule inhibitors targeting key cell death components such as receptor-interacting protein kinase 1 (RIPK1) and NOD-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3). Targeting RCD in conjunction with inflammation may represent a more pragmatic approach for mitigating MS progression and neurodegeneration.

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Fig. 1: Differential susceptibility to apoptosis of T cells, B cells and oligodendrocyte in MS.
Fig. 2: Necroptosis in MS pathogenesis: dual roles in inflammation and cell death.
Fig. 3: Pyroptosis and inflammasome activation in MS pathogenesis.
Fig. 4: Ferroptosis and iron-dependent lipid peroxidation in MS.
Fig. 5: MS pathogenesis from cell death perspective.

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References

  1. Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O. Multiple sclerosis. Lancet. 2018;391:1622–36.

    Article  PubMed  Google Scholar 

  2. Absinta M, Sati P, Reich DS. Advanced MRI and staging of multiple sclerosis lesions. Nat Rev Neurol. 2016;12:358–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kuhlmann T, Moccia M, Coetzee T, Cohen JA, Correale J, Graves J, et al. Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol. 2023;22:78–88.

    Article  PubMed  Google Scholar 

  4. Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005;128:2705–12.

    Article  PubMed  Google Scholar 

  5. Zhang LJ, Tian DC, Yang L, Shi K, Liu Y, Wang Y, et al. White matter disease derived from vascular and demyelinating origins. Stroke Vasc Neurol. 2024;9:344–50.

  6. Shi K, Li H, Chang T, He W, Kong Y, Qi C, et al. Bone marrow hematopoiesis drives multiple sclerosis progression. Cell. 2022;185:2234–47.e17.

    Article  CAS  PubMed  Google Scholar 

  7. Schirmer L, Schafer DP, Bartels T, Rowitch DH, Calabresi PA. Diversity and function of glial cell types in multiple sclerosis. Trends Immunol. 2021;42:228–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15:545–58.

    Article  CAS  PubMed  Google Scholar 

  9. Kuhlmann T, Ludwin S, Prat A, Antel J, Bruck W, Lassmann H. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol. 2017;133:13–24.

    Article  CAS  PubMed  Google Scholar 

  10. Ai Y, Meng Y, Yan B, Zhou Q, Wang X. The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death. Mol Cell. 2024;84:170–9.

    Article  CAS  PubMed  Google Scholar 

  11. Okuda Y, Apatoff BR, Posnett DN. Apoptosis of T cells in peripheral blood and cerebrospinal fluid is associated with disease activity of multiple sclerosis. J Neuroimmunol. 2006;171:163–70.

    Article  CAS  PubMed  Google Scholar 

  12. Meuth SG, Herrmann AM, Simon OJ, Siffrin V, Melzer N, Bittner S, et al. Cytotoxic CD8+ T cell-neuron interactions: perforin-dependent electrical silencing precedes but is not causally linked to neuronal cell death. J Neurosci. 2009;29:15397–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B, DeWitt JP, et al. Activation of necroptosis in multiple sclerosis. Cell Rep. 2015;10:1836–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zelic M, Pontarelli F, Woodworth L, Zhu C, Mahan A, Ren Y, et al. RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis. Cell Rep. 2021;35:109112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. McKenzie BA, Mamik MK, Saito LB, Boghozian R, Monaco MC, Major EO, et al. Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis. Proc Natl Acad Sci USA. 2018;115:E6065–E74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Humphries F, Shmuel-Galia L, Ketelut-Carneiro N, Li S, Wang B, Nemmara VV, et al. Succination inactivates gasdermin D and blocks pyroptosis. Science. 2020;369:1633–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hu CL, Nydes M, Shanley KL, Morales Pantoja IE, Howard TA, Bizzozero OA. Reduced expression of the ferroptosis inhibitor glutathione peroxidase-4 in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neurochem. 2019;148:426–39.

    Article  CAS  PubMed  Google Scholar 

  18. Li X, Chu Y, Ma R, Dou M, Li S, Song Y, et al. Ferroptosis as a mechanism of oligodendrocyte loss and demyelination in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2022;373:577995.

    Article  CAS  PubMed  Google Scholar 

  19. Picon C, Jayaraman A, James R, Beck C, Gallego P, Witte ME, et al. Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter. Acta Neuropathol. 2021;141:585–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. McKenzie BA, Fernandes JP, Doan MAL, Schmitt LM, Branton WG, Power C. Activation of the executioner caspases-3 and -7 promotes microglial pyroptosis in models of multiple sclerosis. J Neuroinflammation. 2020;17:253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Akizuki Y, Kaypee S, Ohtake F, Ikeda F. The emerging roles of non-canonical ubiquitination in proteostasis and beyond. J Cell Biol. 2024;223:e202311171.

  22. Czabotar PE, Garcia-Saez AJ. Mechanisms of BCL-2 family proteins in mitochondrial apoptosis. Nat Rev Mol Cell Biol. 2023;24:732–48.

    Article  CAS  PubMed  Google Scholar 

  23. Jiang X, Wang X. Cytochrome C-mediated apoptosis. Annu Rev Biochem. 2004;73:87–106.

    Article  CAS  PubMed  Google Scholar 

  24. Comi C, Leone M, Bonissoni S, DeFranco S, Bottarel F, Mezzatesta C, et al. Defective T cell Fas function in patients with multiple sclerosis. Neurology. 2000;55:921–7.

    Article  CAS  PubMed  Google Scholar 

  25. Seidi OA, Sharief MK. The expression of apoptosis-regulatory proteins in B lymphocytes from patients with multiple sclerosis. J Neuroimmunol. 2002;130:202–10.

    Article  CAS  PubMed  Google Scholar 

  26. Julia E, Edo MC, Horga A, Montalban X, Comabella M. Differential susceptibility to apoptosis of CD4+T cells expressing CCR5 and CXCR3 in patients with MS. Clin Immunol. 2009;133:364–74.

    Article  CAS  PubMed  Google Scholar 

  27. Cencioni MT, Santini S, Ruocco G, Borsellino G, De Bardi M, Grasso MG, et al. FAS-ligand regulates differential activation-induced cell death of human T-helper 1 and 17 cells in healthy donors and multiple sclerosis patients. Cell Death Dis. 2015;6:e1741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ramesh A, Schubert RD, Greenfield AL, Dandekar R, Loudermilk R, Sabatino JJ Jr., et al. A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis. Proc Natl Acad Sci USA. 2020;117:22932–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Prineas JW, Parratt JD. Oligodendrocytes and the early multiple sclerosis lesion. Ann Neurol. 2012;72:18–31.

    Article  PubMed  Google Scholar 

  30. Lloyd AF, Davies CL, Holloway RK, Labrak Y, Ireland G, Carradori D, et al. Central nervous system regeneration is driven by microglia necroptosis and repopulation. Nat Neurosci. 2019;22:1046–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lisak RP, Nedelkoska L, Benjamins JA, Schalk D, Bealmear B, Touil H, et al. B cells from patients with multiple sclerosis induce cell death via apoptosis in neurons in vitro. J Neuroimmunol. 2017;309:88–99.

    Article  CAS  PubMed  Google Scholar 

  32. Chong SY, Chan JR. Tapping into the glial reservoir: cells committed to remaining uncommitted. J Cell Biol. 2010;188:305–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kuhlmann T, Miron V, Wegner CuiQ, Antel C, Bruck J. W. Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain. 2008;131:1749–58.

    Article  CAS  PubMed  Google Scholar 

  34. Cui QL, Kuhlmann T, Miron VE, Leong SY, Fang J, Gris P, et al. Oligodendrocyte progenitor cell susceptibility to injury in multiple sclerosis. Am J Pathol. 2013;183:516–25.

    Article  CAS  PubMed  Google Scholar 

  35. Neumann H, Schmidt H, Cavalie A, Jenne D, Wekerle H. Major histocompatibility complex (MHC) class I gene expression in single neurons of the central nervous system: differential regulation by interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. J Exp Med. 1997;185:305–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kroesen BJ, Jacobs S, Pettus BJ, Sietsma H, Kok JW, Hannun YA, et al. BcR-induced apoptosis involves differential regulation of C16 and C24-ceramide formation and sphingolipid-dependent activation of the proteasome. J Biol Chem. 2003;278:14723–31.

    Article  CAS  PubMed  Google Scholar 

  37. Qin J, Berdyshev E, Goya J, Natarajan V, Dawson G. Neurons and oligodendrocytes recycle sphingosine 1-phosphate to ceramide: significance for apoptosis and multiple sclerosis. J Biol Chem. 2010;285:14134–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. van Doorn R, Nijland PG, Dekker N, Witte ME, Lopes-Pinheiro MA, van het Hof B, et al. Fingolimod attenuates ceramide-induced blood-brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes. Acta Neuropathol. 2012;124:397–410.

    Article  CAS  PubMed  Google Scholar 

  39. Mc Guire C, Volckaert T, Wolke U, Sze M, de Rycke R, Waisman A, et al. Oligodendrocyte-specific FADD deletion protects mice from autoimmune-mediated demyelination. J Immunol. 2010;185:7646–53.

    Article  Google Scholar 

  40. Hovelmeyer N, Hao Z, Kranidioti K, Kassiotis G, Buch T, Frommer F, et al. Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis. J Immunol. 2005;175:5875–84.

    Article  PubMed  Google Scholar 

  41. He S, Wang L, Miao L, Wang T, Du F, Zhao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009;137:1100–11.

    Article  CAS  PubMed  Google Scholar 

  42. Sun L, Wang H, Wang Z, He S, Chen S, Liao D, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012;148:213–27.

    Article  CAS  PubMed  Google Scholar 

  43. Newton K, Wickliffe KE, Dugger DL, Maltzman A, Roose-Girma M, Dohse M, et al. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature. 2019;574:428–31.

    Article  CAS  PubMed  Google Scholar 

  44. Zhang T, Yin C, Boyd DF, Quarato G, Ingram JP, Shubina M, et al. Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis. Cell. 2020;180:1115–29.e13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, Li Y, et al. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science. 2016;353:603–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ko KW, Milbrandt J, DiAntonio A. SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration. J Cell Biol. 2020;219:e201912047.

  47. Sharma D, Kanneganti TD. The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation. J Cell Biol. 2016;213:617–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shi J, Gao W, Shao F. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem Sci. 2017;42:245–54.

    Article  CAS  PubMed  Google Scholar 

  49. Piancone F, Saresella M, Marventano I, La Rosa F, Santangelo MA, Caputo D, et al. Monosodium urate crystals activate the inflammasome in primary progressive multiple sclerosis. Front Immunol. 2018;9:983.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Keane RW, Dietrich WD, de Rivero Vaccari JP. Inflammasome proteins as biomarkers of multiple sclerosis. Front Neurol. 2018;9:135.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Inoue M, Williams KL, Gunn MD, Shinohara ML. NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA. 2012;109:10480–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Martin BN, Wang C, Zhang CJ, Kang Z, Gulen MF, Zepp JA, et al. T cell-intrinsic ASC critically promotes T(H)17-mediated experimental autoimmune encephalomyelitis. Nat Immunol. 2016;17:583–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Freeman L, Guo H, David CN, Brickey WJ, Jha S, Ting JP. NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J Exp Med. 2017;214:1351–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhang Y, Hou B, Liang P, Lu X, Wu Y, Zhang X, et al. TRPV1 channel mediates NLRP3 inflammasome-dependent neuroinflammation in microglia. Cell Death Dis. 2021;12:1159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yiu SPT, Zerbe C, Vanderwall D, Huttlin EL, Weekes MP, Gewurz BE. An Epstein-Barr virus protein interaction map reveals NLRP3 inflammasome evasion via MAVS UFMylation. Mol Cell. 2023;83:2367–86.e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Noroozi S, Meimand HAE, Arababadi MK, Nakhaee N, Asadikaram G. The effects of IFN-beta 1a on the expression of inflammasomes and apoptosis-associated speck-like proteins in multiple sclerosis patients. Mol Neurobiol. 2017;54:3031–7.

    Article  CAS  PubMed  Google Scholar 

  57. Malhotra S, Hurtado-Navarro L, Pappolla A, Villar LMM, Rio J, Montalban X, et al. Increased NLRP3 Inflammasome Activation and Pyroptosis in Patients With Multiple Sclerosis With Fingolimod Treatment Failure. Neurol Neuroimmunol Neuroinflamm. 2023;10:e200100.

  58. Vidmar L, Maver A, Drulovic J, Sepcic J, Novakovic I, Ristic S, et al. Multiple sclerosis patients carry an increased burden of exceedingly rare genetic variants in the inflammasome regulatory genes. Sci Rep. 2019;9:9171.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Wang D, Zhang T, Shao Q, Wu X, Zhao X, Zhang H, et al. GSDME-mediated pyroptosis in microglia exacerbates demyelination and neuroinflammation in multiple sclerosis: insights from humans and cuprizone-induced demyelination model mice. Cell Death Differ. 2025. https://doi.org/10.1038/s41418-025-01537-0.

  60. Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014;13:1045–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. De Lury AD, Bisulca JA, Lee JS, Altaf MD, Coyle PK, Duong TQ. Magnetic resonance imaging detection of deep gray matter iron deposition in multiple sclerosis: a systematic review. J Neurol Sci. 2023;453:120816.

    Article  PubMed  Google Scholar 

  62. Popescu BF, Frischer JM, Webb SM, Tham M, Adiele RC, Robinson CA, et al. Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions. Acta Neuropathol. 2017;134:45–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tang C, Yang J, Zhu C, Ding Y, Yang S, Xu B, et al. Iron metabolism disorder and multiple sclerosis: a comprehensive analysis. Front Immunol. 2024;15:1376838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Dal-Bianco A, Grabner G, Kronnerwetter C, Weber M, Kornek B, Kasprian G, et al. Long-term evolution of multiple sclerosis iron rim lesions in 7 T MRI. Brain. 2021;144:833–47.

    Article  PubMed  Google Scholar 

  65. Santiago Gonzalez DA, Cheli VT, Wan R, Paez PM. Iron metabolism in the peripheral nervous system: the role of DMT1, ferritin, and transferrin receptor in schwann cell maturation and myelination. J Neurosci. 2019;39:9940–53.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Jhelum P, Zandee S, Ryan F, Zarruk JG, Michalke B, Venkataramani V, et al. Ferroptosis induces detrimental effects in chronic EAE and its implications for progressive MS. Acta Neuropathol Commun. 2023;11:121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sfagos C, Makis AC, Chaidos A, Hatzimichael EC, Dalamaga A, Kosma K, et al. Serum ferritin, transferrin and soluble transferrin receptor levels in multiple sclerosis patients. Mult Scler. 2005;11:272–5.

    Article  CAS  PubMed  Google Scholar 

  68. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yan B, Ai Y, Sun Q, Ma Y, Cao Y, Wang J, et al. Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol Cell. 2021;81:355–69.e10.

    Article  CAS  PubMed  Google Scholar 

  70. Fischer MT, Sharma R, Lim JL, Haider L, Frischer JM, Drexhage J, et al. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain. 2012;135:886–99.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Zhang D, Li Y, Du C, Sang L, Liu L, Li Y, et al. Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level. J Transl Med. 2022;20:363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Licht-Mayer S, Wimmer I, Traffehn S, Metz I, Bruck W, Bauer J, et al. Cell type-specific Nrf2 expression in multiple sclerosis lesions. Acta Neuropathol. 2015;130:263–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Woo MS, Brand J, Bal LC, Moritz M, Walkenhorst M, Vieira V, et al. The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis. Cell. 2025;188:4567–85.e32.

  74. Woo MS, Mayer C, Binkle-Ladisch L, Sonner JK, Rosenkranz SC, Shaposhnykov A, et al. STING orchestrates the neuronal inflammatory stress response in multiple sclerosis. Cell. 2024;187:4043–60.e30.

    Article  CAS  PubMed  Google Scholar 

  75. Rothammer N, Woo MS, Bauer S, Binkle-Ladisch L, Di Liberto G, Egervari K, et al. G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis. Sci Adv. 2022;8:eabm5500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Luoqian J, Yang W, Ding X, Tuo QZ, Xiang Z, Zheng Z, et al. Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis. Cell Mol Immunol. 2022;19:913–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Berglund R, Guerreiro-Cacais AO, Adzemovic MZ, Zeitelhofer M, Lund H, Ewing E, et al. Microglial autophagy-associated phagocytosis is essential for recovery from neuroinflammation. Sci Immunol. 2020;5:eabb5077.

  78. Al-Kuraishy HM, Jabir MS, Al-Gareeb AI, Saad HM, Batiha GE, Klionsky DJ. The beneficial role of autophagy in multiple sclerosis: Yes or No?. Autophagy. 2024;20:259–74.

    Article  CAS  PubMed  Google Scholar 

  79. Hassanpour M, Cheraghi O, Laghusi D, Nouri M, Panahi Y. The relationship between ANT1 and NFL with autophagy and mitophagy markers in patients with multiple sclerosis. J Clin Neurosci. 2020;78:307–12.

    Article  CAS  PubMed  Google Scholar 

  80. Chen L, Shen Q, Liu Y, Zhang Y, Sun L, Ma X, et al. Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases. Signal Transduct Target Ther. 2025;10:31.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Offen D, Gilgun-Sherki Y, Barhum Y, Benhar M, Grinberg L, Reich R, et al. A low molecular weight copper chelator crosses the blood-brain barrier and attenuates experimental autoimmune encephalomyelitis. J Neurochem. 2004;89:1241–51.

    Article  CAS  PubMed  Google Scholar 

  82. Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022;375:1254–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Orning P, Weng D, Starheim K, Ratner D, Best Z, Lee B, et al. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science. 2018;362:1064–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang Y, Gao W, Shi X, Ding J, Liu W, He H, et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017;547:99–103.

    Article  CAS  PubMed  Google Scholar 

  85. Deng B, Wang J, Yang T, Deng Z, Yuan J, Zhang B, et al. TNF and IFNgamma-induced cell death requires IRF1 and ELAVL1 to promote CASP8 expression. J Cell Biol. 2024;223:e202305026.

  86. Karki R, Sharma BR, Tuladhar S, Williams EP, Zalduondo L, Samir P, et al. Synergism of TNF-alpha and IFN-gamma triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes. Cell. 2021;184:149–68.e17.

    Article  CAS  PubMed  Google Scholar 

  87. Centonze D, Muzio L, Rossi S, Furlan R, Bernardi G, Martino G. The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis. Cell Death Differ. 2010;17:1083–91.

    Article  CAS  PubMed  Google Scholar 

  88. Hernandez-Pedro N, Magana-Maldonado R, Ramiro AS, Perez-De la Cruz V, Rangel-Lopez E, Sotelo J, et al. PAMP-DAMPs interactions mediates development and progression of multiple sclerosis. Front Biosci (Sch Ed). 2016;8:13–28.

    Article  Google Scholar 

  89. Paudel YN, Angelopoulou E, Piperi CBK, Othman C. I. High mobility group box 1 (HMGB1) protein in Multiple Sclerosis (MS): mechanisms and therapeutic potential. Life Sci. 2019;238:116924.

    Article  CAS  PubMed  Google Scholar 

  90. Amorini AM, Petzold A, Tavazzi B, Eikelenboom J, Keir G, Belli A, et al. Increase of uric acid and purine compounds in biological fluids of multiple sclerosis patients. Clin Biochem. 2009;42:1001–6.

    Article  CAS  PubMed  Google Scholar 

  91. Kayagaki N, Kornfeld OS, Lee BL, Stowe IB, O’Rourke K, Li Q, et al. NINJ1 mediates plasma membrane rupture during lytic cell death. Nature. 2021;591:131–6.

    Article  CAS  PubMed  Google Scholar 

  92. Ahn BJ, Le H, Shin MW, Bae SJ, Lee EJ, Wee HJ, et al. Ninjurin1 deficiency attenuates susceptibility of experimental autoimmune encephalomyelitis in mice. J Biol Chem. 2014;289:3328–38.

    Article  CAS  PubMed  Google Scholar 

  93. Zang YC, Li S, Rivera VM, Hong J, Robinson RR, Breitbach WT, et al. Increased CD8+ cytotoxic T cell responses to myelin basic protein in multiple sclerosis. J Immunol. 2004;172:5120–7.

    Article  CAS  PubMed  Google Scholar 

  94. Medana IM, Gallimore A, Oxenius A, Martinic MM, Wekerle H, Neumann H. MHC class I-restricted killing of neurons by virus-specific CD8+ T lymphocytes is effected through the Fas/FasL, but not the perforin pathway. Eur J Immunol. 2000;30:3623–33.

    Article  CAS  PubMed  Google Scholar 

  95. Wang C, Zhang CJ, Martin BN, Bulek K, Kang Z, Zhao J, et al. IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression. Nat Commun. 2017;8:15508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ramaglia V, Sheikh-Mohamed S, Legg K, Park C, Rojas OL, Zandee S, et al. Multiplexed imaging of immune cells in staged multiple sclerosis lesions by mass cytometry. Elife. 2019;8:e48051.

  97. Kukanja P, Langseth CM, Rubio Rodriguez-Kirby LA, Agirre E, Zheng C, Raman A, et al. Cellular architecture of evolving neuroinflammatory lesions and multiple sclerosis pathology. Cell. 2024;187:1990–2009.e19.

    Article  CAS  PubMed  Google Scholar 

  98. Zrzavy T, Hametner S, Wimmer I, Butovsky O, Weiner HL, Lassmann H. Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis. Brain. 2017;140:1900–13.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Prineas JW, Parratt JDE. Multiple sclerosis: microglia, monocytes, and macrophage-mediated demyelination. J Neuropathol Exp Neurol. 2021;80:975–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Travers BS, Tsang BK, Barton JL. Multiple sclerosis: diagnosis, disease-modifying therapy and prognosis. Aust J Gen Pr. 2022;51:199–206.

    Article  Google Scholar 

  101. Shi FD, Yong VW. Neuroinflammation across neurological diseases. Science. 2025;388:eadx0043.

    Article  CAS  PubMed  Google Scholar 

  102. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358:676–88.

    Article  CAS  PubMed  Google Scholar 

  103. Ceronie B, Jacobs BM, Baker D, Dubuisson N, Mao Z, Ammoscato F, et al. Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells. J Neurol. 2018;265:1199–209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Spencer CM, Crabtree-Hartman EC, Lehmann-Horn K, Cree BA, Zamvil SS. Reduction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm. 2015;2:e76.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Tur C, Carbonell-Mirabent P, Cobo-Calvo A, Otero-Romero S, Arrambide G, Midaglia L, et al. Association of early progression independent of relapse activity with long-term disability after a first demyelinating event in multiple sclerosis. JAMA Neurol. 2023;80:151–60.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Piehl F. Current and emerging disease-modulatory therapies and treatment targets for multiple sclerosis. J Intern Med. 2021;289:771–91.

    Article  CAS  PubMed  Google Scholar 

  107. Maggi P, Bulcke CV, Pedrini E, Bugli C, Sellimi A, Wynen M, et al. B cell depletion therapy does not resolve chronic active multiple sclerosis lesions. EBioMedicine. 2023;94:104701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Jeffery DR, Rammohan KW, Hawker K, Fox E. Fingolimod: a review of its mode of action in the context of its efficacy and safety profile in relapsing forms of multiple sclerosis. Expert Rev Neurother. 2016;16:31–44.

    Article  CAS  PubMed  Google Scholar 

  109. Kocot J, Kosa P, Ashida S, Pirjanian NA, Goldbach-Mansky R, Peterson K, et al. Clemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis. J Clin Investig. 2025;135:e183941.

  110. Kassiotis G, Kollias G. Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: implications for pathogenesis and therapy of autoimmune demyelination. J Exp Med. 2001;193:427–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Gao H, Danzi MC, Choi CS, Taherian M, Dalby-Hansen C, Ellman DG, et al. Opposing functions of microglial and macrophagic TNFR2 in the pathogenesis of experimental autoimmune encephalomyelitis. Cell Rep. 2017;18:198–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Pegoretti V, Bauer J, Fischer R, Paro I, Douwenga W, Kontermann RE, et al. Sequential treatment with a TNFR2 agonist and a TNFR1 antagonist improves outcomes in a humanized mouse model for MS. J Neuroinflammation. 2023;20:106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hincelin-Mery A, Nicolas X, Cantalloube C, Pomponio R, Lewanczyk P, Benamor M, et al. Safety, pharmacokinetics, and target engagement of a brain penetrant RIPK1 inhibitor, SAR443820 (DNL788), in healthy adult participants. Clin Transl Sci. 2024;17:e13690.

    Article  CAS  PubMed  Google Scholar 

  114. Gonen OM, Porter T, Wang B, Xue F, Ma Y, Song L, et al. Safety, pharmacokinetics and target engagement of a novel brain penetrant ripk1 inhibitor (SIR9900) in healthy adults and elderly participants. Clin Transl Sci. 2025;18:e70151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Malhotra S, Costa C, Eixarch H, Keller CW, Amman L, Martinez-Banaclocha H, et al. NLRP3 inflammasome as prognostic factor and therapeutic target in primary progressive multiple sclerosis patients. Brain. 2020;143:1414–30.

    Article  PubMed  Google Scholar 

  116. Vijiaratnam N, Simuni T, Bandmann O, Morris HR, Foltynie T. Progress towards therapies for disease modification in Parkinson’s disease. Lancet Neurol. 2021;20:559–72.

    Article  CAS  PubMed  Google Scholar 

  117. Hissaria P, Kansagra K, Patel H, Momin T, Ghoghari A, Patel H, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of ZY-IL1 in three patients with cryopyrin-associated periodic syndromes. Clinical Pharmacol Drug Dev. 2024;13:152–9.

    Article  CAS  Google Scholar 

  118. Lynch SG, Peters K, LeVine SM. Desferrioxamine in chronic progressive multiple sclerosis: a pilot study. Mult Scler. 1996;2:157–60.

    Article  CAS  PubMed  Google Scholar 

  119. Lynch SG, Fonseca T, LeVine SM. A multiple course trial of desferrioxamine in chronic progressive multiple sclerosis. Cell Mol Biol. 2000;46:865–9.

    CAS  PubMed  Google Scholar 

  120. Ayton S, Barton D, Brew B, Brodtmann A, Clarnette R, Desmond P, et al. Deferiprone in Alzheimer disease: a randomized clinical trial. JAMA Neurol. 2025;82:11–8.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Bier J, Steiger SM, Reichardt HM, Luhder F. Protection of antigen-primed effector T cells from glucocorticoid-induced apoptosis in cell culture and in a mouse model of multiple sclerosis. Front Immunol. 2021;12:671258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Carlstrom KE, Zhu K, Ewing E, Krabbendam IE, Harris RA, Falcao AM, et al. Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis. Nat Commun. 2020;11:4071.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Aybar F, Julia Perez M, Silvina Marcora M, Eugenia Samman M, Marrodan M, Maria Pasquini J, et al. 2-Chlorodeoxyadenosine (Cladribine) preferentially inhibits the biological activity of microglial cells. Int Immunopharmacol. 2022;105:108571.

    Article  CAS  PubMed  Google Scholar 

  124. Durelli L, Conti L, Clerico M, Boselli D, Contessa G, Ripellino P, et al. T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta. Ann Neurol. 2009;65:499–509.

    Article  CAS  PubMed  Google Scholar 

  125. Haindl MT, Üçal M, Klaus B, Tögl L, Dohrmann J, Adzemovic MZ, et al. Anti-CD20 treatment effectively attenuates cortical pathology in a rat model of widespread cortical demyelination. J Neuroinflammation. 2021;18:138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Gurrea-Rubio M, Wang Q, Mills EA, Wu Q, Pitt D, Tsou PS, et al. Siponimod attenuates neuronal cell death triggered by neuroinflammation via NFkappaB and mitochondrial pathways. Int J Mol Sci. 2024;25:2454.

  127. Zehntner SP, Bourbonnière L, Moore CS, Morris SJ, Methot D, St Jean M, et al. X-linked inhibitor of apoptosis regulates T cell effector function. J Immunol. 2007;179:7553–60.

    Article  CAS  PubMed  Google Scholar 

  128. Ingwersen J, De Santi L, Wingerath B, Graf J, Koop B, Schneider R, et al. Nimodipine confers clinical improvement in two models of experimental autoimmune encephalomyelitis. J Neurochem. 2018;146:86–98.

  129. Schampel A, Volovitch O, Koeniger T, Scholz CJ, Jörg S, Linker RA, et al. Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis. Proc Natl Acad Sci USA. 2017;114:E3295–e304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Chen Y, Podojil JR, Kunjamma RB, Jones J, Weiner M, Lin W, et al. Sephin1, which prolongs the integrated stress response, is a promising therapeutic for multiple sclerosis. Brain. 2019;142:344–61.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Montalban X, Kuhle J, Fox R, Vartanian T, Horakova D, Filippi M, et al. Effect of RIPK1 inhibitor, SAR443820, on serum neurofilament light levels in patients with multiple sclerosis: a phase 2 trial design (P6-3.011). Neurology. 2023;100:2178.

    Article  Google Scholar 

  132. Zhang S, Su Y, Ying Z, Guo D, Pan C, Guo J, et al. RIP1 kinase inhibitor halts the progression of an immune-induced demyelination disease at the stage of monocyte elevation. Proc Natl Acad Sci USA. 2019;116:5675–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Yoshikawa M, Saitoh M, Katoh T, Seki T, Bigi SV, Shimizu Y, et al. Discovery of 7-Oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine derivatives as potent, orally available, and brain-penetrating receptor interacting protein 1 (RIP1) kinase inhibitors: analysis of structure-kinetic relationships. J Med Chem. 2018;61:2384–409.

    Article  CAS  PubMed  Google Scholar 

  134. Ma XR, Yang SY, Zheng SS, Yan HH, Gu HM, Wang F, et al. Inhibition of RIPK1 by ZJU-37 promotes oligodendrocyte progenitor proliferation and remyelination via NF-kappaB pathway. Cell Death Discov. 2022;8:147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21:248–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Gerzanich V, Makar TK, Guda PR, Kwon MS, Stokum JA, Woo SK, et al. Salutary effects of glibenclamide during the chronic phase of murine experimental autoimmune encephalomyelitis. J Neuroinflammation. 2017;14:177.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Lamkanfi M, Mueller JL, Vitari AC, Misaghi S, Fedorova A, Deshayes K, et al. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J Cell Biol. 2009;187:61–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sánchez-Fernández A, Skouras DB, Dinarello CA, López-Vales R. OLT1177 (Dapansutrile), a selective NLRP3 inflammasome inhibitor, ameliorates experimental autoimmune encephalomyelitis pathogenesis. Front Immunol. 2019;10:2578.

    Article  PubMed  PubMed Central  Google Scholar 

  139. He H, Jiang H, Chen Y, Ye J, Wang A, Wang C, et al. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nat Commun. 2018;9:2550.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Guo C, Fulp JW, Jiang Y, Li X, Chojnacki JE, Wu J, et al. Development and characterization of a hydroxyl-sulfonamide analogue, 5-chloro-N-[2-(4-hydroxysulfamoyl-phenyl)-ethyl]-2-methoxy-benzamide, as a novel NLRP3 inflammasome inhibitor for potential treatment of multiple sclerosis. ACS Chem Neurosci. 2017;8:2194–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Motawi TK, El-Maraghy SA, Kamel AS, Said SE, Kortam MA. Modulation of p38 MAPK and Nrf2/HO-1/NLRP3 inflammasome signaling and pyroptosis outline the anti-neuroinflammatory and remyelinating characters of Clemastine in EAE rat model. Biochem Pharm. 2023;209:115435.

    Article  CAS  PubMed  Google Scholar 

  142. Green AJ, Gelfand JM, Cree BA, Bevan C, Boscardin WJ, Mei F, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390:2481–9.

    Article  CAS  PubMed  Google Scholar 

  143. Hu JJ, Liu X, Xia S, Zhang Z, Zhang Y, Zhao J, et al. FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nat Immunol. 2020;21:736–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Zhao M, Sun D, Guan Y, Wang Z, Sang D, Liu M, et al. Disulfiram and diphenhydramine hydrochloride upregulate miR-30a to suppress IL-17-associated autoimmune inflammation. J Neurosci. 2016;36:9253–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Van San E, Debruyne AC, Veeckmans G, Tyurina YY, Tyurin VA, Zheng H, et al. Ferroptosis contributes to multiple sclerosis and its pharmacological targeting suppresses experimental disease progression. Cell Death Differ. 2023;30:2092–103.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Rayatpour A, Foolad F, Heibatollahi M, Khajeh K, Javan M. Ferroptosis inhibition by deferiprone, attenuates myelin damage and promotes neuroprotection in demyelinated optic nerve. Sci Rep. 2022;12:19630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank all colleagues Beijing-Tianjin Center for Neuroinflammation (BTCN) for support; E. Shi for editorial assistance. We apologize to those whose important contributions could not be cited due to space limitations. BY and F-DS are supported by the National Natural Science Foundation of China (Grant No. 22477095, 22307139, 82320108007, 81830038).

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  1. These authors contributed equally: Shuzhen Guan, Huimin Zhu.

Authors and Affiliations

  1. Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China

    Shuzhen Guan, Huimin Zhu, Fu-Dong Shi & Bo Yan

  2. Department of Neurology, China National Clinical Research Center for Neurological Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

    Mengting Zhang & Fu-Dong Shi

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  1. Shuzhen Guan
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  2. Huimin Zhu
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  4. Fu-Dong Shi
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Contributions

B Yan and F-D Shi conceived the project, formulated the manuscript structure and coordinated compiling, synthesizing, and drafting the text based on input from all co-authors. S Guan wrote the section on regulated cell death in MS and edited all figures. H Zhu contributed the section on therapeutic targeting, and M Zhang wrote the section on disease overview. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Fu-Dong Shi or Bo Yan.

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Guan, S., Zhu, H., Zhang, M. et al. Cell death in multiple sclerosis. Cell Death Differ 33, 433–446 (2026). https://doi.org/10.1038/s41418-025-01576-7

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