2. Academic Validation
  3. Dimethyl fumarate inhibits necroptosis and alleviates systemic inflammatory response syndrome by blocking the RIPK1-RIPK3-MLKL axis

Dimethyl fumarate inhibits necroptosis and alleviates systemic inflammatory response syndrome by blocking the RIPK1-RIPK3-MLKL axis

  • Pharmacol Res. 2023 Feb 14;106697. doi: 10.1016/j.phrs.2023.106697.
Fu-Li Shi 1,  Li-Sha Yuan 1,  Tak-Sui Wong 2,  Qing Li 1,  Ya-Ping Li 1,  Rong Xu 1,  Yi-Ping You 1,  Tao Yuan 1,  Hong-Rui Zhang 1,  Zi-Jian Shi 3,  Qing-Bing Zha 4,  Bo Hu 5,  Xian-Hui He 6,  Dong-Yun Ouyang 7
Affiliations

Affiliations

  • 1 Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
  • 2 Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
  • 3 Department of Fetal Medicine, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
  • 4 Department of Fetal Medicine, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China; Department of Clinical Laboratory, the Fifth Affiliated Hospital of Jinan University, Heyuan 517000, China.
  • 5 Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China. Electronic address: [email protected].
  • 6 Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China; Department of Clinical Laboratory, the Fifth Affiliated Hospital of Jinan University, Heyuan 517000, China. Electronic address: [email protected].
  • 7 Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China. Electronic address: [email protected].
PMID: 36796462 DOI: 10.1016/j.phrs.2023.106697
Abstract

Necroptosis has been implicated in various inflammatory diseases including tumor-necrosis factor-α (TNF-α)-induced systemic inflammatory response syndrome (SIRS). Dimethyl fumarate (DMF), a first-line drug for treating relapsing-remitting multiple sclerosis (RRMS), has been shown to be effective against various inflammatory diseases. However, it is still unclear whether DMF can inhibit Necroptosis and confer protection against SIRS. In this study, we found that DMF significantly inhibited necroptotic cell death in macrophages induced by different necroptotic stimulations. Both the autophosphorylation of receptor-interacting serine/threonine kinase 1 (RIPK1) and RIPK3 and the downstream phosphorylation and oligomerization of MLKL were robustly suppressed by DMF. Accompanying the suppression of necroptotic signaling, DMF blocked the mitochondrial reverse electron transport (RET) induced by necroptotic stimulation, which was associated with its electrophilic property. Several well-known anti-RET reagents also markedly inhibited the activation of the RIPK1-RIPK3-MLKL axis accompanied by decreased necrotic cell death, indicating a critical role of RET in necroptotic signaling. DMF and other anti-RET reagents suppressed the ubiquitination of RIPK1 and RIPK3, and they attenuated the formation of necrosome. Moreover, oral administration of DMF significantly alleviated the severity of TNF-α-induced SIRS in mice. Consistent with this, DMF mitigated TNF-α-induced cecal, uterine, and lung damages accompanied by diminished RIPK3-MLKL signaling. Collectively, DMF represents a new Necroptosis Inhibitor that suppresses the RIPK1-RIPK3-MLKL axis through blocking mitochondrial RET. Our study highlights DMF's potential therapeutic applications for treating SIRS-associated diseases.

Keywords

Antimycin A (PubChem CID: 14957); Dimethyl fumarate; Dimethyl fumarate (PubChem CID: 637568); Dimethyl malonate (PubChem CID: 7943); Dimethyl succinate (PubChem CID: 7820); GSK′872 (PubChem CID: 54674134); MLKL; Monomethyl fumarate (PubChem CID: 5369209); N-acetyl-L-cysteine (PubChem CID: 12035); Necrostatin-1 (PubChem CID: 2828334); RIPK3; Rotenone (PubChem CID: 6758); necroptosis; reverse electron transport; systemic inflammatory response syndrome.

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