Necroptosis-blocking compound NBC1 targets heat shock protein 70 to inhibit MLKL polymerization and necroptosis

Significance Necroptosis is a regulated form of necrotic cell death implicated in many human diseases, including infection, inflammation, neurodegeneration, and cancer. TNF-induced necroptosis results in the formation of MLKL tetramers, which further polymerize to form disulfide bond-dependent amyloid-like fibers to promote cell death. Here we report the identification of a necroptosis-blocking compound, NBC1, which covalently conjugates two cysteines of chaperone Hsp70. Importantly, Hsp70 requires these two cysteines to promote polymerization of MLKL tetramers in an ATP-independent manner. NBC1 blocks MLKL polymerization and subsequent cell death. This work reinforces the importance of MLKL polymer formation and identifies chaperone Hsp70 as an obligatory facilitator for MLKL polymerization, providing further insights for intervention of necroptosis-associated diseases.