The bromodomain protein BRD4 positively regulates necroptosis via modulating MLKL expression

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Necroptosis is a programmed form of necrotic cell death, which is tightly regulated by the necroptotic signaling pathway containing receptor-interacting protein (RIP)1, RIP3, and mixed-lineage kinase domain-like (MLKL) protein. In addition to the RIP1-RIP3-MLKL axis, other factors regulating necroptosis are still largely unknown. Here a cell-based small-molecule screening led to the finding that BET inhibitors protected cells from necroptosis in the TNFα/Smac-mimetic/Z-VAD-FMK (TSZ)-induced cell necroptosis model. Mechanistic studies revealed that BET inhibitors acted by downregulating MLKL expression. Further research demonstrated that BRD4, IRF1, P-TEFb, and RNA polymerase II formed a transcription complex to regulate the expression of MLKL, and BET inhibitors interfered with the transcription complex formation. In necroptosis-related disease model, the BET inhibitor JQ-1 showed promising therapeutic effects. Collectively, our studies establish, for the first time, BRD4 as a new epigenetic factor regulating necroptosis, and highlight the potential of BET inhibitors in the treatment of necroptosis-related diseases.

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We are thankful to Dr. Jiahuan Han (Xiamen University, China) for generously providing MLKL-/- mice for this research. This work was supported by the National Natural Science Foundation of China (81473140, 81573349, 81773633, and 21772130), National Science and Technology Major Project (2018ZX09711002-014-002, 2018ZX09711002-011-019, and 2018ZX09711003-003-006), and 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University.

Author contributions

S.Y. and Y.W. conceived the project and designed the research. Y.X., L.L., L. Z., Y.C., and C.W. performed the experiments and analyzed the data. Q.Y., K.C., H.L., R.X., and Y.H. analyzed the data. S.Y., S.H., and Y.W. wrote the manuscript.

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Correspondence to Shengyong Yang.

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