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Targeting necroptosis prevents viral-induced lung damage

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Fig. 1: UH15-38 inhibits viral-triggered RIPK3-dependent cell death in alveoli.


  1. Gautam A, Boyd DF, Nikhar S, Zhang T, Siokas I, Van de Velde L-A, et al. Necroptosis blockade prevents lung injury in severe influenza. Nature. 2024.

  2. Vitale I, Pietrocola F, Guilbaud E, Aaronson SA, Abrams JM, Adam D, et al. Apoptotic cell death in disease-Current understanding of the NCCD 2023. Cell Death Differ. 2023;30:1097–154.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ye K, Chen Z, Xu Y. The double-edged functions of necroptosis. Cell Death Dis. 2023;14:163.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2000;1:489–95.

    Article  CAS  PubMed  Google Scholar 

  5. Snyder AG, Hubbard NW, Messmer MN, Kofman SB, Hagan CE, Orozco SL, et al. Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates antitumor immunity. Sci Immunol. 2019;4:eaaw2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Galluzzi L, Kepp O, Chan FK, Kroemer G. Necroptosis: Mechanisms and Relevance to Disease. Annu Rev Pathol. 2017;12:103–30.

    Article  CAS  PubMed  Google Scholar 

  7. Othumpangat S, Beezhold DH, Noti JD. Influenza virus infection modulates the death receptor pathway during early stages of infection in human bronchial epithelial cells. Physiol Genomics. 2018;50:770–9.

    Article  CAS  PubMed  Google Scholar 

  8. Thapa RJ, Ingram JP, Ragan KB, Nogusa S, Boyd DF, Benitez AA, et al. DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death. Cell Host Microbe. 2016;20:674–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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.e1113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Balachandran S, Rall GF. Benefits and Perils of Necroptosis in Influenza Virus Infection. J Virol. 2020;94:e01101–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mandal P, Berger SB, Pillay S, Moriwaki K, Huang C, Guo H, et al. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell. 2014;56:481–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lloreda CL. COVID’s toll on the brain: new clues emerge. Nature. 2024;628:20–20.

    Article  Google Scholar 

  13. Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ. 2020;27:1451–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yang S, Ling Y, Zhao F, Li W, Song Z, Wang L, et al. Hymecromone: a clinical prescription hyaluronan inhibitor for efficiently blocking COVID-19 progression. Signal Transduct Target Ther. 2022;7:91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Solon M, Ge N, Hambro S, Haller S, Jiang J, Baca M, et al. ZBP1 and TRIF trigger lethal necroptosis in mice lacking caspase-8 and TNFR1. Cell Death Differ. 2024.

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This work has been supported by the European Union NextGenerationEU via MUR-PNRR M4C2-II.3 PE6 project PE00000019 Heal Italia (CUP: E83C22004670001) to GM., the Jiangsu Province International Joint Laboratory for Regenerative Medicine Fund and Suzhou Foreign Academician Workstation Fund (SWY202202) to YS.

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GM and YS conceived and supervised the project; all authors wrote the manuscript; PL and JZ prepared Fig. 1.

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Correspondence to Yufang Shi or Gerry Melino.

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YS and GM are Editorial Board Member of Cell Death Differentiation. The authors declare no other competing interests.

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All of the authors have approved this submitted version.

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Shi, Y., Li, P., Zhou, J. et al. Targeting necroptosis prevents viral-induced lung damage. Cell Death Differ 31, 541–543 (2024).

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