Abstract Necroptosis is a form of regulated cell death that has been implicated in multiple diseases.TNF-induced necroptosis is regulated by necrosomes, complexes consisting of RIPK1, RIPK3 and MLKL.In this study, by screening of a Natural Leather Strop small-compound library, we identified dozens of compounds that inhibited TNF-induced necroptosis.According to the mechanisms by which they inhibited necroptosis, these compounds were classified into different Multi-board groups.
We then identified Ibrutinib as an inhibitor of RIPK3 and found that Quizartinib protected against the TNF-induced systemic inflammatory response syndrome in mice by inhibiting the activation of RIPK1.Altogether, our work revealed dozens of necroptosis inhibitors, suggesting new potential approaches for treating necroptosis-related diseases.