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Targeting necroptosis prevents viral-induced lung damage

Cell Death & Differentiation (2024)Cite this article

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A recent study featured in Nature reveals a promising drug candidate, UH15-38, that significantly reduces lung damage and increases survival rates in mice with influenza A virus (IAV) infection by inhibiting necroptosis, a type of inflammatory cell death [1]. The research team led by Gregory Cuny, Paul Thomas, Alexei Degterev and Siddharth Balachandran showed that UH15-38 specifically targets and deactivates RIPK3, an essential kinase in the necroptosis pathway. This discovery not only unveils new pathways involved in inflammatory diseases, such as severe influenza A infection, but also highlights the potential of this drug to treat a wide array of inflammatory viral or non-viral conditions.

Apoptosis was considered the only form of cell death, but novel mechanisms, such as necroptosis, has broadened our comprehension of cell death [2]. Necroptosis plays a role in several pathophysiological scenarios, such as development, immune responses, and inflammatory conditions [3]. Necroptosis involves a cascade of signaling events that culminate in necrotic-like death. At the heart of this process is the activation of receptor-interacting protein kinase-1 (RIPK1) [4] and RIPK3 [5], forming the necrosome complex, that, in turn, activates the Mixed-Lineage-Kinase-Domain-Like protein (MLKL), causing it to oligomerize on the plasma membrane, where it leads to cell lysis [6]. The initiation of necroptosis is carefully regulated by various elements, including death receptors like tumor necrosis factor receptor 1 (TNFR1) and the level of caspase-8, which normally prevents necroptosis by deactivating RIPK1 and RIPK3. However, necroptosis can occur without restraint under specific conditions, e.g. low caspase-8 activity or when certain triggers are present. This is in fact the case in IAV-infected lung epithelial cells, in which caspase-8 is dramatically reduced [7].

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

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Funding

Funding

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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Authors and Affiliations

  1. The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Soochow University, Suzhou, 215000, China

    Yufang Shi, Peishan Li & Jun Zhou

  2. Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy

    Yufang Shi & Gerry Melino

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  1. Yufang Shi
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  2. Peishan Li
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Contributions

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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Shi, Y., Li, P., Zhou, J. et al. Targeting necroptosis prevents viral-induced lung damage. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01299-1

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