Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Necroptotic cell death consequences and disease relevance

Nature Immunology volume 26, pages 1863–1876 (2025) Cite this article

Subjects

Abstract

Arguably one of the most surprising revelations in the field of cell death research was the discovery that cellular necrosis, a lytic and inherently messy cell death with far-reaching consequences for human physiology, can be genetically encoded. There is no single necrotic pathway either, as compelling evidence exists for distinct necrotic modalities such as pyroptosis, necroptosis and ferroptosis. The recent momentum of molecular, structural and disease-relevant findings has opened the door to targeting necrotic machinery to prevent collateral tissue damage and inflammatory diseases. In this Review, we evaluate the case for targeting the necrotic cell death pathway called necroptosis. We examine the organs and cell types where the human necroptotic machinery is expressed, identifying a lymphocytic ZBP1, RIPK1, RIPK3 and MLKL signature, review knowledge into the immunogenic consequences of necroptotic signaling and highlight building evidence that necroptosis is engaged in humans and can be triggered by ischemic injuries. Finally, we note several limitations of mouse studies due to fundamental differences with the human necroptotic apparatus and critically appraise the evidence for necroptosis being a disease-driving factor that, if successfully targeted, could be of clinical benefit.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Overview of necroptosis triggers and signaling pathway.
The alternative text for this image may have been generated using AI.
Fig. 2: Protein and transcript levels of necroptotic players in human tissue.
The alternative text for this image may have been generated using AI.
Fig. 3: The role of MLKL in autoimmune, inflammatory and infectious diseases.
The alternative text for this image may have been generated using AI.

Similar content being viewed by others

References

  1. Taabazuing, C. Y., Okondo, M. C. & Bachovchin, D. A. Pyroptosis and apoptosis pathways engage in bidirectional crosstalk in monocytes and macrophages. Cell Chem. Biol. 24, 507–514 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Oberst, A. et al. Catalytic activity of the caspase-8–FLIPL complex inhibits RIPK3-dependent necrosis. Nature 471, 363–367 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Newton, K. et al. Activity of caspase-8 determines plasticity between cell death pathways. Nature 575, 679–682 (2019).

    CAS  PubMed  Google Scholar 

  4. Fritsch, M. et al. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature 575, 683–687 (2019). Together with Newton et al. (2019), this study took the cell death field by surprise, showing the in vivo importance of caspase-8 for regulating the three main cell death pathways of apoptosis, necroptosis and pyroptosis.

    CAS  PubMed  Google Scholar 

  5. Lawlor, K. E., Murphy, J. M. & Vince, J. E. Gasdermin and MLKL necrotic cell death effectors: signaling and diseases. Immunity 57, 429–445 (2024).

    CAS  PubMed  Google Scholar 

  6. Paskiewicz, A., Niu, J. & Chang, C. Autoimmune lymphoproliferative syndrome: a disorder of immune dysregulation. Autoimmun. Rev. 22, 103442 (2023).

    CAS  PubMed  Google Scholar 

  7. Moyer, A., Tanaka, K. & Cheng, E. H. Apoptosis in cancer biology and therapy. Annu. Rev. Pathol. 20, 303–328 (2025).

    CAS  PubMed  Google Scholar 

  8. Oda, H., Annibaldi, A., Kastner, D. L. & Aksentijevich, I. Genetic regulation of cell death: insights from autoinflammatory diseases. Annu Rev. Immunol. 43, 313–342 (2025).

    CAS  PubMed  Google Scholar 

  9. Linkermann, A., Stockwell, B. R., Krautwald, S. & Anders, H. J. Regulated cell death and inflammation: an auto-amplification loop causes organ failure. Nat. Rev. Immunol. 14, 759–767 (2014).

    CAS  PubMed  Google Scholar 

  10. Pang, S. H. M. et al. Mesenchymal stromal cell apoptosis is required for their therapeutic function. Nat. Commun. 12, 6495 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Bergmann, A. & Steller, H. Apoptosis, stem cells, and tissue regeneration. Sci. Signal. 3, re8 (2010).

    PubMed  PubMed Central  Google Scholar 

  12. Broz, P. Pyroptosis: molecular mechanisms and roles in disease. Cell Res. 35, 334–344 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Berndt, C. et al. Ferroptosis in health and disease. Redox Biol. 75, 103211 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Vercammen, D. et al. Dual signaling of the Fas receptor: initiation of both apoptotic and necrotic cell death pathways. J. Exp. Med. 188, 919–930 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Vercammen, D. et al. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J. Exp. Med. 187, 1477–1485 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Holler, N. et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1, 489–495 (2000).

    CAS  PubMed  Google Scholar 

  17. Degterev, A. et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 4, 313–321 (2008). Together with Degterev et al. (2005), this article marked the beginning of drugging RIPK1 and the necroptotic machinery, with clinical trials now evaluating the efficacy of RIPK1 inhibitors in diverse diseases.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1–RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009). This paper, together with He et al. (2009) and Zhang et al. (2009), identified RIPK3 as a core necroptotic signaling component 9 years after the role of RIPK1 was identified and reinvigorated the quest to fully map the necroptotic pathway.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell 137, 1100–1111 (2009).

    CAS  PubMed  Google Scholar 

  20. Zhang, D. W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 (2009).

    CAS  PubMed  Google Scholar 

  21. Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213–227 (2012). This landmark study discovered MLKL as the substrate of RIPK3 that is required for necroptosis and identified necrosulfonamide, the first MLKL inhibitor.

    CAS  PubMed  Google Scholar 

  22. Murphy, J. M. et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39, 443–453 (2013). This paper reported the first structure of MLKL and the first gene-targeted mouse, proving that MLKL is essential for necroptotic cell death.

    CAS  PubMed  Google Scholar 

  23. Najjar, M. et al. RIPK1 and RIPK3 kinases promote cell-death-independent inflammation by Toll-like receptor 4. Immunity 45, 46–59 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Saleh, D. et al. Kinase activities of RIPK1 and RIPK3 can direct IFN-β synthesis induced by lipopolysaccharide. J. Immunol. 198, 4435–4447 (2017).

    CAS  PubMed  Google Scholar 

  25. Kang, T. B., Jeong, J. S., Yang, S. H., Kovalenko, A. & Wallach, D. Caspase-8 deficiency in mouse embryos triggers chronic RIPK1-dependent activation of inflammatory genes, independently of RIPK3. Cell Death Differ. 25, 1107–1117 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Peng, R. et al. Human ZBP1 induces cell death-independent inflammatory signaling via RIPK3 and RIPK1. EMBO Rep. 23, e55839 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Alvarez-Diaz, S. et al. The pseudokinase MLKL and the kinase RIPK3 have distinct roles in autoimmune disease caused by loss of death-receptor-induced apoptosis. Immunity 45, 513–526 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Lawlor, K. E. et al. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat. Commun. 6, 6282 (2015). This paper is one of the first reports showing how RIPK3 can signal cell death and potent inflammatory responses independent of MLKL. This opened the door to future studies examining the non-necroptotic functions of RIPK3 in health and disease.

    CAS  PubMed  Google Scholar 

  29. Vince, J. E. et al. Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 36, 215–227 (2012).

    CAS  PubMed  Google Scholar 

  30. Amusan, O. T. et al. RIPK1 is required for ZBP1-driven necroptosis in human cells. PLoS Biol. 23, e3002845 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Lin, J. et al. RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation. Nature 540, 124–128 (2016). RIPK1 is required for death receptor-induced necroptosis. Surprisingly, this study and Newton et al. (2016) demonstrated that mouse RIPK1 actually inhibits RIPK3 binding to ZBP1 and thereby blocks ZBP1-mediated lethal necroptotic signaling.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Newton, K. et al. RIPK1 inhibits ZBP1-driven necroptosis during development. Nature 540, 129–133 (2016).

    CAS  PubMed  Google Scholar 

  33. Kaiser, W. J. et al. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J. Biol. Chem. 288, 31268–31279 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Cook, W. D. et al. RIPK1- and RIPK3-induced cell death mode is determined by target availability. Cell Death Differ. 21, 1600–1612 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Samson, A. L. et al. MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis. Nat. Commun. 11, 3151 (2020). This paper showed that the redistribution of activated MLKL to the plasma membrane is an active trafficking event. This foundational work is key for defining the specific route (and detours) activated MLKL takes to reach the plasma membrane, which may present with new strategies to therapeutically intervene in necroptosis signaling.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Hildebrand, J. M. et al. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc. Natl Acad. Sci. USA 111, 15072–15077 (2014). This paper, together with Dondelinger et al. (2014) and Wang et al. (2014), indicates that MLKL binds to and disrupts lipid membranes directly, suggesting that it is the terminal necroptotic effector.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Garnish, S. E. et al. Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis. Nat. Commun. 12, 2211 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Meng, Y. et al. Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization. Nat. Commun. 14, 6804 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Dondelinger, Y. et al. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep. 7, 971–981 (2014).

    CAS  PubMed  Google Scholar 

  40. Wang, H. et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54, 133–146 (2014).

    CAS  PubMed  Google Scholar 

  41. Wang, Y. et al. MLKL as an emerging machinery for modulating organelle dynamics: regulatory mechanisms, pathophysiological significance, and targeted therapeutics. Front. Pharmacol. 16, 1512968 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kayagaki, N. et al. NINJ1 mediates plasma membrane rupture during lytic cell death. Nature 591, 131–136 (2021). This paper took the cell death field by storm showing that membrane rupture downstream of pyroptosis, apoptosis and necrosis requires NINJ1. However, in a surprising twist, NINJ1 was not vital for necroptosis-induced plasma membrane rupture.

    CAS  PubMed  Google Scholar 

  43. Su, L. et al. A plug release mechanism for membrane permeation by MLKL. Structure 22, 1489–1500 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kaiser, W. J. et al. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471, 368–372 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Solon, M. et al. ZBP1 and TRIF trigger lethal necroptosis in mice lacking caspase-8 and TNFR1. Cell Death Differ. 31, 672–682 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Newton, K. et al. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature 574, 428–431 (2019).

    CAS  PubMed  Google Scholar 

  47. Martinez Lagunas, K. et al. Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair. Sci. Adv. 9, eadg2829 (2023).

    PubMed  PubMed Central  Google Scholar 

  48. Lalaoui, N. et al. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature 577, 103–108 (2020). Caspases have hundreds of substrates, yet this study, alongside Newton et al. (2019) and Tao et al. (2020), identifies the catastrophic consequences in mice and humans that result from the inability of caspases to process just one remarkable substrate, RIPK1 containing just a single amino acid change.

    CAS  PubMed  Google Scholar 

  49. Tran, H. T. et al. RIPK3 cleavage is dispensable for necroptosis inhibition but restricts NLRP3 inflammasome activation. Cell Death Differ. 31, 662–671 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Newton, K. et al. Caspase cleavage of RIPK3 after Asp333 is dispensable for mouse embryogenesis. Cell Death Differ. 31, 254–262 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Yu, X. et al. A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis. Blood 141, 1070–1086 (2023).

    CAS  PubMed  Google Scholar 

  52. Daniels, B. P. et al. RIPK3 restricts viral pathogenesis via cell death-independent neuroinflammation. Cell 169, 301–313 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Estevez, I. et al. The kinase RIPK3 promotes neuronal survival by suppressing excitatory neurotransmission during central nervous system viral infection. Immunity 58, 666–682 (2025).

    CAS  PubMed  Google Scholar 

  54. Sarhan, J. et al. Constitutive interferon signaling maintains critical threshold of MLKL expression to license necroptosis. Cell Death Differ. 26, 332–347 (2019).

    CAS  PubMed  Google Scholar 

  55. Tanzer, M. C. et al. Combination of IAP antagonist and IFNγ activates novel caspase-10- and RIPK1-dependent cell death pathways. Cell Death Differ. 24, 481–491 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Ros, U. et al. MLKL activity requires a splicing-regulated, druggable intramolecular interaction. Mol. Cell. 85, 1589–1605 (2025).

    CAS  PubMed  Google Scholar 

  57. Kelepouras K. et al. STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD. Nature https://doi.org/10.1038/s41586-025-09536-4 (2025).

  58. Chiou, S. et al. An immunohistochemical atlas of necroptotic pathway expression. EMBO Mol. Med. 16, 1717–1749 (2024). This study outlines key protocols that enable the detection of necroptotic pathway expression and activation in both mice and humans and highlights their application to detect necroptosis in the context of IBD.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Wang, D. et al. A deep proteome and transcriptome abundance atlas of 29 healthy human tissues. Mol. Syst. Biol. 15, e8503 (2019). This study presents a comprehensive dataset profiling the proteome and transcriptome across 29 healthy human tissues, offering a valuable resource for future studies investigating tissue-specific gene and protein expression.

    PubMed  PubMed Central  Google Scholar 

  60. CZI Cell Science Program et al. CZ CELLxGENE Discover: a single-cell data platform for scalable exploration, analysis and modeling of aggregated data. Nucleic Acids Res. 53, D886–D900 (2025).

    Google Scholar 

  61. Ch’en, I. L., Tsau, J. S., Molkentin, J. D., Komatsu, M. & Hedrick, S. M. Mechanisms of necroptosis in T cells. J. Exp. Med. 208, 633–641 (2011).

    PubMed  PubMed Central  Google Scholar 

  62. Pang J. et al. A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease. Preprint at bioRxiv https://doi.org/10.1101/2024.11.13.623307 (2024).

  63. Pierdomenico, M. et al. Necroptosis is active in children with inflammatory bowel disease and contributes to heighten intestinal inflammation. Am. J. Gastroenterol. 109, 279–287 (2014).

    CAS  PubMed  Google Scholar 

  64. Caccamo, A. et al. Necroptosis activation in Alzheimer’s disease. Nat. Neurosci. 20, 1236–1246 (2017).

    CAS  PubMed  Google Scholar 

  65. Lee, J. M. et al. Involvement of alveolar epithelial cell necroptosis in idiopathic pulmonary fibrosis pathogenesis. Am. J. Respir. Cell Mol. Biol. 59, 215–224 (2018).

    CAS  PubMed  Google Scholar 

  66. Lu, Z. et al. Necroptosis signaling promotes inflammation, airway remodeling, and emphysema in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 204, 667–681 (2021).

    CAS  PubMed  Google Scholar 

  67. Freund, L. et al. IFNγ causes keratinocyte necroptosis in acute graft-versus-host disease. J. Invest. Dermatol. 143, 1746–1756 (2023).

    CAS  PubMed  Google Scholar 

  68. Koo, G. B. et al. Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Res. 25, 707–725 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Preston, S. P. et al. Epigenetic silencing of RIPK3 in hepatocytes prevents MLKL-mediated necroptosis from contributing to liver pathologies. Gastroenterology 163, 1643–1657 (2022).

    CAS  PubMed  Google Scholar 

  70. Yu, X. et al. Necroptosis in bacterial infections. Front. Immunol. 15, 1394857 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Meng, Y., Sandow, J. J., Czabotar, P. E. & Murphy, J. M. The regulation of necroptosis by post-translational modifications. Cell Death Differ. 28, 861–883 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Laurien, L. et al. Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation. Nat. Commun. 11, 1747 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Meng, Y. et al. Human RIPK3 C-lobe phosphorylation is essential for necroptotic signaling. Cell Death Dis. 13, 565 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Garcia, L. R. et al. Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance. Nat. Commun. 12, 3364 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Pradhan, A. J. et al. Acylation of MLKL impacts its function in necroptosis. ACS Chem. Biol. 19, 407–418 (2024).

    CAS  PubMed  Google Scholar 

  76. Tanzer, M. C. et al. Necroptosis signalling is tuned by phosphorylation of MLKL residues outside the pseudokinase domain activation loop. Biochem. J. 471, 255–265 (2015).

    CAS  PubMed  Google Scholar 

  77. Frank, D. et al. Ubiquitylation of RIPK3 beyond-the-RHIM can limit RIPK3 activity and cell death. iScience 25, 104632 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Liu, L. et al. Tankyrase-mediated ADP-ribosylation is a regulator of TNF-induced death. Sci. Adv. 8, eabh2332 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Tanzer, M. C. et al. Quantitative and dynamic catalogs of proteins released during apoptotic and necroptotic cell death. Cell Rep. 30, 1260–1270 (2020). This study provides a comprehensive overview of proteins released by apoptotic and necroptotic cells, highlighting both shared and unique components of their secretomes. The careful analysis of the factors released during distinct cell death modalities and the identification of which have important extracellular functions is critical for defining the role of cell death in health and disease.

  80. Phulphagar, K. et al. Proteomics reveals distinct mechanisms regulating the release of cytokines and alarmins during pyroptosis. Cell Rep. 34, 108826 (2021).

    CAS  PubMed  Google Scholar 

  81. Ravichandran, K. S. Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity 35, 445–455 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang, Q., Ju, X., Zhou, Y. & Chen, K. Necroptotic cells release find-me signal and are engulfed without proinflammatory cytokine production. In Vitro Cell Dev. Biol. Anim. 51, 1033–1039 (2015).

    CAS  PubMed  Google Scholar 

  83. Hogquist, K. A., Nett, M. A., Unanue, E. R. & Chaplin, D. D. Interleukin 1 is processed and released during apoptosis. Proc. Natl Acad. Sci. USA 88, 8485–8489 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhu, M. et al. Mitochondria released by apoptotic cell death initiate innate immune responses. Immunohorizons 3, 26–27 (2019).

    PubMed  Google Scholar 

  85. Qin, S. et al. Role of HMGB1 in apoptosis-mediated sepsis lethality. J. Exp. Med. 203, 1637–1642 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Frank, D. & Vince, J. E. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 26, 99–114 (2019).

    PubMed  Google Scholar 

  87. Conos, S. A. et al. Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner. Proc. Natl Acad. Sci. USA 114, E961–E969 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Kang, T. B., Yang, S. H., Toth, B., Kovalenko, A. & Wallach, D. Caspase-8 blocks kinase RIPK3-mediated activation of the NLRP3 inflammasome. Immunity 38, 27–40 (2013). This study shows how MLKL can trigger lethal in vivo inflammation via inflammasome-mediated activation of a single cytokine, IL-1β. Together with Conos et al. (2017) and Polykratis et al. (2019), this raises the interesting prospect that MLKL-mediated membrane rupture/DAMP release may not always be the fundamental driver of necroptotic-associated diseases.

  89. Polykratis, A. et al. A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain. Nat. Cell Biol. 21, 731–742 (2019).

    CAS  PubMed  Google Scholar 

  90. Höckendorf, U. et al. RIPK3 restricts myeloid leukemogenesis by promoting cell death and differentiation of leukemia initiating cells. Cancer Cell 30, 75–91 (2016).

    PubMed  Google Scholar 

  91. Lei, Y. X. et al. The pseudokinase MLKL contributes to host defense against Streptococcus pluranimalium infection by mediating NLRP3 inflammasome activation and extracellular trap formation. Virulence 14, 2258057 (2023).

    PubMed  PubMed Central  Google Scholar 

  92. Lei, X., Chen, Y., Lien, E. & Fitzgerald, K. A. MLKL-driven inflammasome activation and caspase-8 mediate inflammatory cell death in influenza A virus infection. mBio 14, e0011023 (2023).

    PubMed  Google Scholar 

  93. Huang, H. R. et al. RIPK3 activates MLKL-mediated necroptosis and inflammasome signaling during Streptococcus infection. Am. J. Respir. Cell Mol. Biol. 64, 579–591 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Liu, Y. et al. Mixed lineage kinase-like protein protects against Clostridium perfringens infection by enhancing NLRP3 inflammasome–extracellular traps axis. iScience 25, 105121 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Shlomovitz, I. et al. Necroptosis directly induces the release of full-length biologically active IL-33 in vitro and in an inflammatory disease model. FEBS J. 286, 507–522 (2019).

    CAS  PubMed  Google Scholar 

  96. Pinci, F. et al. Tumor necrosis factor is a necroptosis-associated alarmin. Front. Immunol. 13, 1074440 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Rickard, J. A. et al. RIPK1 regulates RIPK3–MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 157, 1175–1188 (2014).

    CAS  PubMed  Google Scholar 

  98. Zhao, J. et al. MLKL is involved in the regulation of skin wound healing and interplay between macrophages and myofibroblasts in mice. Sci. Rep. 15, 13612 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhou, S. et al. Myofiber necroptosis promotes muscle stem cell proliferation via releasing tenascin-C during regeneration. Cell Res. 30, 1063–1077 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Mehrotra, P. et al. Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair. Nature 631, 207–215 (2024). This powerful study is the first to demonstrate the potential of pyroptotic supernatants to promote wound healing through the release of prostaglandins.

    CAS  PubMed  Google Scholar 

  101. Holley, C. L. et al. Pyroptotic cell corpses are crowned with F-actin-rich filopodia that engage CLEC9A signaling in incoming dendritic cells. Nat. Immunol. 26, 42–52 (2025).

    CAS  PubMed  Google Scholar 

  102. Zargarian, S. et al. Phosphatidylserine externalization, ‘necroptotic bodies’ release, and phagocytosis during necroptosis. PLoS Biol. 15, e2002711 (2017).

    PubMed  PubMed Central  Google Scholar 

  103. Lu, J. et al. Efficient engulfment of necroptotic and pyroptotic cells by nonprofessional and professional phagocytes. Cell Discov. 5, 39 (2019).

    PubMed  PubMed Central  Google Scholar 

  104. Barker, R. N. et al. Antigen presentation by macrophages is enhanced by the uptake of necrotic, but not apoptotic, cells. Clin. Exp. Immunol. 127, 220–225 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Liebold, I. et al. Apoptotic cell identity induces distinct functional responses to IL-4 in efferocytic macrophages. Science 384, eabo7027 (2024). This study elegantly defines the distinct immunological outcomes following the engulfment of different forms of dying cells, uncovering how the mode of cell death and the type of dying cell can shape the subsequent immune response.

    CAS  PubMed  Google Scholar 

  106. Miao, L. et al. Extracellular vesicles containing GAS6 protect the liver from ischemia-reperfusion injury by enhancing macrophage efferocytosis via MerTK–ERK–COX2 signaling. Cell Death Discov. 10, 401 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Nozaki, K., Li, L. & Miao, E. A. Innate sensors trigger regulated cell death to combat intracellular infection. Annu. Rev. Immunol. 40, 469–498 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Petrie, E. J. et al. Viral MLKL homologs subvert necroptotic cell death by sequestering cellular RIPK3. Cell Rep. 28, 3309–3319 (2019).

    CAS  PubMed  Google Scholar 

  109. Palmer, S. N., Chappidi, S., Pinkham, C. & Hancks, D. C. Evolutionary profile for (host and viral) MLKL indicates its activities as a battlefront for extensive counteradaptation. Mol. Biol. Evol. 38, 5405–5422 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Fletcher-Etherington, A. et al. Human cytomegalovirus protein pUL36: a dual cell death pathway inhibitor. Proc. Natl Acad. Sci. USA 117, 18771–18779 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Li, S. et al. A viral necrosome mediates direct RIPK3 activation to promote inflammatory necroptosis. Proc. Natl Acad. Sci. USA 122, e2420245122 (2025).

    CAS  PubMed  Google Scholar 

  112. Wang, G., Zhang, D., Orchard, R. C., Hancks, D. C. & Reese, T. A. Norovirus MLKL-like protein initiates cell death to induce viral egress. Nature 616, 152–158 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Guo, R. et al. Loss of MLKL ameliorates liver fibrosis by inhibiting hepatocyte necroptosis and hepatic stellate cell activation. Theranostics 12, 5220–5236 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Duan, X. et al. Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation. Cell Death Dis. 11, 134 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Wang, R. et al. Gut stem cell necroptosis by genome instability triggers bowel inflammation. Nature 580, 386–390 (2020). This study identifies an important means by which necroptosis can be triggered in the intestine even when caspase-8 is not directly pharmacologically or genetically targeted. Examining in more detail the means by which necroptosis can occur in the presence of caspase-8 will be important to understand.

  116. Miyata T. et al. Differential role of MLKL in alcohol-associated and non-alcohol-associated fatty liver diseases in mice and humans. JCI Insight 6, e140180 (2021).

  117. Garnish, S. E. et al. A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation. Nat. Commun. 14, 6046 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Tao, P. et al. A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1. Nature 577, 109–114 (2020).

    CAS  PubMed  Google Scholar 

  119. Chun, H. J. et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419, 395–399 (2002). First came mutations in TP53 (1990), then FAS (1995) and, with this study, CASP8, showing how dysregulated cell death drives cancer, immunodeficiencies and, together with several other studies, inflammatory conditions and infections. These findings underscore the importance of delineating the fundamental signaling machinery of cell death pathways and their cross-talk.

  120. Lehle, A. S. et al. Intestinal inflammation and dysregulated immunity in patients with inherited caspase-8 deficiency. Gastroenterology 156, 275–278 (2019).

    PubMed  Google Scholar 

  121. Cuchet-Lourenco, D. et al. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science 361, 810–813 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Li, Y. et al. Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 116, 970–975 (2019).

    CAS  PubMed  Google Scholar 

  123. Uchiyama, Y. et al. Primary immunodeficiency with chronic enteropathy and developmental delay in a boy arising from a novel homozygous RIPK1 variant. J. Hum. Genet. 64, 955–960 (2019).

    PubMed  Google Scholar 

  124. Liu, Z. et al. Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency. Sci. Immunol. 8, eade2860 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Faergeman, S. L. et al. A novel neurodegenerative spectrum disorder in patients with MLKL deficiency. Cell Death Dis. 11, 303 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Wang, B. et al. A rare variant in MLKL confers susceptibility to ApoE ε4-negative Alzheimer’s disease in Hong Kong Chinese population. Neurobiol. Aging 68, 160.e1–160.e7 (2018).

    CAS  PubMed  Google Scholar 

  127. Hildebrand, J. M. et al. A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes. Cell Death Dis. 12, 345 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Ying, Z. et al. Mixed lineage kinase domain-like protein MLKL breaks down myelin following nerve injury. Mol. Cell. 72, 457–468 (2018).

    CAS  PubMed  Google Scholar 

  129. Hildebrand, J. M. et al. A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction. Nat. Commun. 11, 3150 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Yang, Y. et al. Defective prelamin A processing promotes unconventional necroptosis driven by nuclear RIPK1. Nat. Cell Biol. 26, 567–580 (2024).

    CAS  PubMed  Google Scholar 

  131. Tovey Crutchfield, E. C. et al. MLKL deficiency protects against low-grade, sterile inflammation in aged mice. Cell Death Differ. 30, 1059–1071 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Juznic, L. et al. SETDB1 is required for intestinal epithelial differentiation and the prevention of intestinal inflammation. Gut 70, 485–498 (2021).

    CAS  PubMed  Google Scholar 

  133. Pefanis, A. et al. Dynamics of necroptosis in kidney ischemia-reperfusion injury. Front. Immunol. 14, 1251452 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Newton, K. et al. RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury. Cell Death Differ. 23, 1565–1576 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Ni, H. M. et al. Receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis contributes to ischemia-reperfusion injury of steatotic livers. Am. J. Pathol. 189, 1363–1374 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Xu, J. et al. MLKL deficiency attenuated hepatocyte oxidative DNA damage by activating mitophagy to suppress macrophage cGAS–STING signaling during liver ischemia and reperfusion injury. Cell Death Discov. 9, 58 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Wu, M. C. L. et al. Ischaemic endothelial necroptosis induces haemolysis and COVID-19 angiopathy. Nature 643, 182–191 (2025). A tour de force study that identified necroptotic endothelial cell death in humans and mice as a major driver of red blood cell lysis and ischemia-driven microvascular damage.

    CAS  PubMed  Google Scholar 

  138. Zhang, Y. et al. Catalytically inactive RIP1 and RIP3 deficiency protect against acute ischemic stroke by inhibiting necroptosis and neuroinflammation. Cell Death Dis. 11, 565 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Feng, Y. et al. GSK840 alleviates retinal neuronal injury by inhibiting RIPK3/MLKL-mediated RGC necroptosis after ischemia/reperfusion. Invest. Ophthalmol. Vis. Sci. 64, 42 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Mei, F. et al. Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic stroke. EMBO Mol. Med. 17, 679–695 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Degterev, A. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112–119 (2005).

    CAS  PubMed  Google Scholar 

  142. Linkermann, A. et al. RIP1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury. Kidney Int. 81, 751–761 (2012).

    CAS  PubMed  Google Scholar 

  143. Chen, Y. et al. Red blood cells undergo lytic programmed cell death involving NLRP3. Cell 188, 3013–3029 (2025).

    CAS  PubMed  Google Scholar 

  144. Zhang, T. et al. Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation. Nat. Cell Biol. 25, 950–962 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Zhang, Y. et al. RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome. Nat. Commun. 8, 14329 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Muller, T. et al. Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure. Cell. Mol. Life Sci. 74, 3631–3645 (2017).

    PubMed  PubMed Central  Google Scholar 

  147. Chen, H. et al. RIPK3 collaborates with GSDMD to drive tissue injury in lethal polymicrobial sepsis. Cell Death Differ. 27, 2568–2585 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Linkermann, A. et al. Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury. Proc. Natl Acad. Sci. USA 110, 12024–12029 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Bader, S. M. et al. Endothelial caspase-8 prevents fatal necroptotic hemorrhage caused by commensal bacteria. Cell Death Differ. 30, 27–36 (2023).

    CAS  PubMed  Google Scholar 

  150. Tisch, N. et al. Caspase-8 in endothelial cells maintains gut homeostasis and prevents small bowel inflammation in mice. EMBO Mol. Med. 14, e14121 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Wu, X. et al. MLKL-mediated endothelial necroptosis drives vascular damage and mortality in systemic inflammatory response syndrome. Cell Mol. Immunol. 21, 1309–1321 (2024).

    CAS  PubMed  Google Scholar 

  152. Zou, C. et al. Reduction of mNAT1/hNAT2 contributes to cerebral endothelial necroptosis and Aβ accumulation in Alzheimer’s disease. Cell Rep. 33, 108447 (2020).

    CAS  PubMed  Google Scholar 

  153. Bader, S. M. et al. Necroptosis does not drive disease pathogenesis in a mouse infective model of SARS-CoV-2 in vivo. Cell Death Dis. 15, 100 (2024).

    Google Scholar 

  154. Oltean, T., Maelfait, J., Saelens, X. & Vandenabeele, P. Need for standardization of influenza A virus-induced cell death in vivo to improve consistency of inter-laboratory research findings. Cell Death Discov. 10, 247 (2024). This study summed up conflicting high-profile reports in the literature and proposed steps to resolve contradictory findings.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Salvadores, N. et al. Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer’s disease. Acta Neuropathol. Commun. 10, 31 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Tye H. et al. Divergent roles of RIPK3 and MLKL in high-fat diet-induced obesity and MAFLD in mice. Life Sci. Alliance 8, e202302446 (2024). This is scientific rigor. Here, carefully controlled experiments define how necroptosis signaling influences metabolism.

  157. Vucur, M. et al. Sublethal necroptosis signaling promotes inflammation and liver cancer. Immunity 56, 1578–1595 (2023). Although several studies point toward necroptosis as a powerful driver of anticancer immune responses, this important paper highlights a dark protumorigenic side to necroptosis signaling not previously appreciated.

    CAS  PubMed  Google Scholar 

  158. Yao, K. et al. RIPK1 in necroptosis and recent progress in related pharmaceutics. Front. Immunol. 16, 1480027 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Weisel, K. et al. A randomised, placebo-controlled study of RIPK1 inhibitor GSK2982772 in patients with active ulcerative colitis. BMJ Open Gastroenterol. 8, e000680 (2021).

    PubMed  PubMed Central  Google Scholar 

  160. Weisel, K. et al. A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis. Arthritis Res. Ther. 23, 85 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Vissers, M. et al. Safety, pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders: randomized, placebo-controlled, double-blind phase I/Ib studies in healthy subjects and patients. Clin. Transl. Sci. 15, 2010–2023 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Su, H. et al. Structure-based design of potent and selective inhibitors targeting RIPK3 for eliminating on-target toxicity in vitro. Nat. Commun. 16, 4288 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Xu L. & Zhuang C. Mixed lineage kinase domain-like protein (MLKL): from mechanisms to therapeutic opportunities. Adv. Sci. https://doi.org/10.1002/advs.202509277 (2025).

  164. Rashidi, M. et al. The pyroptotic cell death effector gasdermin D is activated by gout-associated uric acid crystals but is dispensable for cell death and IL-1β release. J. Immunol. 203, 736–748 (2019).

    CAS  PubMed  Google Scholar 

  165. Deepagan, V. G. et al. Lipid nanoparticle-delivered intrabodies for inhibiting necroptosis and pyroptosis. Biochem. J. 482, BCJ20253191 (2025).

    CAS  PubMed  Google Scholar 

  166. Mannion, J. et al. A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death. Immunity 57, 1514–1532 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Van Hoecke, L. et al. Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes. Nat. Commun. 9, 3417 (2018).

    PubMed  PubMed Central  Google Scholar 

  168. Niemela, J. et al. Caspase-8 deficiency presenting as late-onset multi-organ lymphocytic infiltration with granulomas in two adult siblings. J. Clin. Immunol. 35, 348–355 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Dillon, C. P. et al. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell 157, 1189–1202 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Kaiser, W. J. et al. RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proc. Natl Acad. Sci. USA 111, 7753–7758 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Consonni, F. et al. Study of the potential role of caspase-10 mutations in the development of autoimmune lymphoproliferative syndrome. Cell Death Dis. 15, 315 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Petrie, E. J. et al. Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis. Nat. Commun. 9, 2422 (2018).

    PubMed  PubMed Central  Google Scholar 

  173. Rodriguez, D. A. et al. Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis. Cell Death Differ. 23, 76–88 (2016).

    CAS  PubMed  Google Scholar 

  174. Xie, T. et al. Structural insights into RIP3-mediated necroptotic signaling. Cell Rep. 5, 70–78 (2013).

    CAS  PubMed  Google Scholar 

  175. Murphy, J. M. et al. Insights into the evolution of divergent nucleotide-binding mechanisms among pseudokinases revealed by crystal structures of human and mouse MLKL. Biochem. J. 457, 369–377 (2014).

    CAS  PubMed  Google Scholar 

  176. Meng, Y. et al. Human RIPK3 maintains MLKL in an inactive conformation prior to cell death by necroptosis. Nat. Commun. 12, 6783 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Chen, W. et al. Diverse sequence determinants control human and mouse receptor interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in necroptotic signaling. J. Biol. Chem. 288, 16247–16261 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Tanzer, M. C. et al. Evolutionary divergence of the necroptosis effector MLKL. Cell Death Differ. 23, 1185–1197 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Nagata, M., Carvalho Schafer, Y., Wachsmuth, L. & Pasparakis, M. A shorter splicing isoform antagonizes ZBP1 to modulate cell death and inflammatory responses. EMBO J. 43, 5037–5056 (2024).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We wish to thank the insights and advice from members of the WEHI Inflammation Division, particularly J. Murphy and A. Samson, and apologize to authors whose work could not be cited owing to space constraints. This work was supported by National Health and Medical Research Council of Australia Investigator Grants 2008692 to J.E.V. and 2016547 to N.M.D. and a Suzanne Cory Fellowship to M.C.T.

Author information

Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    James E. Vince, Nadia M. Davidson & Maria C. Tanzer

  2. The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia

    James E. Vince, Nadia M. Davidson & Maria C. Tanzer

Authors
  1. James E. Vince
    View author publications

    Search author on:PubMed Google Scholar

  2. Nadia M. Davidson
    View author publications

    Search author on:PubMed Google Scholar

  3. Maria C. Tanzer
    View author publications

    Search author on:PubMed Google Scholar

Contributions

J.E.V. and M.C.T. conceived and wrote specific sections of the original manuscript draft. N.M.D. performed the human CELLxGENE analysis of necroptotic pathway expression and contributed to the writing of the relevant text. All authors reviewed and edited the final manuscript. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to James E. Vince or Maria C. Tanzer.

Ethics declarations

Competing interests

The authors have no competing interests to declare.

Peer review

Peer review information

Nature Immunology thanks Junying Yuan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Jamie D. K. Wilson, in collaboration with the Nature Immunology team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vince, J.E., Davidson, N.M. & Tanzer, M.C. Necroptotic cell death consequences and disease relevance. Nat Immunol 26, 1863–1876 (2025). https://doi.org/10.1038/s41590-025-02298-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41590-025-02298-1

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing