02657nas a2200577   4500000000100000000000100001008004100002260001200043653003500055653002000090100002000110700001800130700001800148700001500166700001900181700002500200700002000225700002500245700001700270700002300287700001700310700001600327700001900343700001600362700002000378700002200398700001800420700002200438700002000460700002000480700001800500700002100518700002500539700002600564700001600590700001900606700002100625700002200646700002600668700002100694700002000715700001900735700002000754700002700774245006600801856005500867300001200922490000800934520112300942022001402065       2024                            d  c2024-0410aCell death and immune response10aInfluenza virus1 aAvishekh Gautam1 aDavid F. Boyd1 aSameer Nikhar1 aTing Zhang1 aIoannis Siokas1 aLee-Ann Van de Velde1 aJessica Gaevert1 aVictoria Meliopoulos1 aBikash Thapa1 aDiego A. Rodriguez1 aKathy Q. Cai1 aChaoran Yin1 aDaniel Schnepf1 aJulius Beer1 aCarly DeAntoneo1 aRiley M. Williams1 aMaria Shubina1 aBrandi Livingston1 aDingqiang Zhang1 aMark D. Andrake1 aSeungheon Lee1 aRaghavender Boda1 aAnantha L. Duddupudi1 aJeremy Chase Crawford1 aPeter Vogel1 aChristian Loch1 aMartin Schwemmle1 aLawrence C. Fritz1 aStacey Schultz-Cherry1 aDouglas R. Green1 aGregory D. Cuny1 aPaul G. Thomas1 aAlexei Degterev1 aSiddharth Balachandran00aNecroptosis blockade prevents lung injury in severe influenza  uhttps://www.nature.com/articles/s41586-024-07265-8  a835-8430 v6283 aSevere influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome1–5 (ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection6–8 and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.  a1476-4687