Cf-02, a novel benzamide-linked small molecule, blunts NF-κB activation and NLRP3 inflammasome assembly and improves acute onset of accelerated and severe lupus nephritis in mice

Shin Ruen Yang, Kuo Feng Hua, Chih Yu Yang, Ann Chen, Jui Chun Weng, Yu Ling Tsai, Chih Jun Wan, Chung Yao Wu, Chia Chung Lee, Jia Feng Chan, Chih Yu Hsieh, Yu Juei Hsu, Chia Chao Wu, Debabrata Mukhopadhyay, Hsu Shan Huang, Feng Cheng Liu, Shuk Man Ka

Research output: Contribution to journalArticlepeer-review

Abstract

In the present study, acute onset of severe lupus nephritis was successfully treated in mice using a new, benzamide-linked, small molecule that targets immune modulation and the NLRP3 inflammasome. Specifically, 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (Cf-02) (a) reduced serum levels of IgG anti-dsDNA, IL-1β, IL-6, and TNF-α, (b) inhibited activation of dendritic cells and differentially regulated T cell functions, and (c) suppressed the NF-κB/NLRP3 inflammasome axis, targeting priming and activating signals of the inflammasome. Moreover, treatment with Cf-02 significantly inhibited secretion of IL-1β in lipopolysaccharide-stimulated macrophages, but this effect was abolished by autophagy induction. These results recommend Cf-02 as a promising drug candidate for the serious renal conditions associated with systemic lupus erythematosus. Future investigations should examine whether Cf-02 may also be therapeutic in other types of chronic kidney disease involving NLRP3 inflammasome-driven signaling.

Original languageEnglish (US)
Article numbere21785
JournalFASEB Journal
Volume35
Issue number8
DOIs
StatePublished - Aug 2021

Keywords

  • autophagy
  • benzamide-linked small molecule
  • NF-κB/NLRP3 inflammasome axis
  • severe lupus nephritis

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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