2. Academic Validation
  3. A natural chalcone cardamonin inhibits necroptosis and ameliorates dextran sulfate sodium (DSS)-induced colitis by targeting RIPK1/3 kinases

A natural chalcone cardamonin inhibits necroptosis and ameliorates dextran sulfate sodium (DSS)-induced colitis by targeting RIPK1/3 kinases

  • Eur J Pharmacol. 2023 Jun 9;175840. doi: 10.1016/j.ejphar.2023.175840.
Xiaofei Shen 1,  Hongqing Chen 2,  Tian Wen 2,  Lu Liu 3,  Qiongying Hu 2,  Fan Xie 4,  Lun Wang 5
Affiliations

Affiliations

  • 1 TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
  • 2 TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China; College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
  • 3 TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China; College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
  • 4 TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China. Electronic address: xiefan959@icloud.com.
  • 5 Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China. Electronic address: wanglun@cib.ac.cn.
PMID: 37302524 DOI: 10.1016/j.ejphar.2023.175840
Abstract

Necroptosis, a new form of programmed cell death, is involved in the pathogenesis of ulcerative colitis (UC). Inhibition of Necroptosis represents an attractive strategy for UC therapy. Herein, cardamonin, a natural chalcone isolated from Zingiberaceae family, was firstly identified as a potent Necroptosis Inhibitor. In vitro, cardamonin significantly inhibited Necroptosis in TNF-α plus Smac mimetic and z-VAD-FMK (TSZ)-, cycloheximide plus TZ (TCZ)-, or lipopolysaccharide plus SZ (LSZ)-stimulated HT29, L929, or RAW264.7 cell lines. Furthermore, TSZ-induced elevated population of necrotic cells, release of LDH and HMGB1 also could be inhibited by cardamonin in HT29 cells. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assay combined with molecular docking demonstrated that cardamonin interacted with RIPK1/3. Furthermore, cardamonin blocked the phosphorylation of RIPK1/3, thereby disrupting RIPK1-RIPK3 necrosome formation and MLKL phosphorylation. In vivo, orally administration of cardamonin attenuated dextran sulfate sodium (DSS)-induced colitis, which mainly manifested as mitigated intestinal barrier damage, suppressed necroinflammation, and reduced phosphorylation of MLKL. Taken together, our findings revealed that dietary cardamonin is a novel Necroptosis Inhibitor and has great potential for UC therapy by targeting RIPK1/3 kinases.

Keywords

Cardamonin; Epithelial barrier injury; Necroinflammation; Necroptosis; RIPK1/3; Ulcerative colitis.

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