PNSC928, a plant-derived compound, specifically disrupts CtBP2-p300 interaction and reduces inflammation in mice with acute respiratory distress syndrome

  • Biol Direct. 2024 Jun 21;19(1):48. doi: 10.1186/s13062-024-00491-0.
Fan Li  #  1 ,  Wenqing Yan  #  2  3  4 ,  Weihua Dong  3  4 ,  Zhiping Chen  5  6 ,  Zhi Chen  7  8  9
Affiliations
  • 1. Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
  • 2. Department of Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Shanghai, Shanghai, 200065, China.
  • 3. Department of Emergency, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, China.
  • 4. Department of Emergency, Jiangxi Provincial People's Hospital, No. 92, Aiguo Road, Donghu District, Nanchang, Jiangxi, 330006, China.
  • 5. Department of Emergency, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, China. [email protected].
  • 6. Department of Emergency, Jiangxi Provincial People's Hospital, No. 92, Aiguo Road, Donghu District, Nanchang, Jiangxi, 330006, China. [email protected].
  • 7. Department of Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Shanghai, Shanghai, 200065, China. [email protected].
  • 8. Department of Emergency, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, China. [email protected].
  • 9. Department of Emergency, Jiangxi Provincial People's Hospital, No. 92, Aiguo Road, Donghu District, Nanchang, Jiangxi, 330006, China. [email protected].
  • # Contributed equally.
PMID: 38902802 DOI: 10.1186/s13062-024-00491-0
Abstract

Background: Prior research has highlighted the involvement of a transcriptional complex comprising C-terminal binding protein 2 (CtBP2), Histone Acetyltransferase p300, and nuclear factor kappa B (NF-κB) in the transactivation of proinflammatory cytokine genes, contributing to inflammation in mice with acute respiratory distress syndrome (ARDS). Nonetheless, it remains uncertain whether the therapeutic targeting of the CtBP2-p300-NF-κB complex holds potential for ARDS suppression.

Methods: An ARDS mouse model was established using lipopolysaccharide (LPS) exposure. RNA-Sequencing (RNA-Seq) was performed on ARDS mice and LPS-treated cells with CtBP2, p300, and p65 knockdown. Small molecules inhibiting the CtBP2-p300 interaction were identified through AlphaScreen. Gene and protein expression levels were quantified using RT-qPCR and immunoblots. Tissue damage was assessed via histological staining.

Key findings: We elucidated the specific role of the CtBP2-p300-NF-κB complex in proinflammatory gene regulation. RNA-seq analysis in LPS-challenged ARDS mice and LPS-treated CtBP2-knockdown (CtBP2KD), p300KD, and p65KD cells revealed its significant impact on proinflammatory genes with minimal effects on other NF-κB targets. Commercial inhibitors for CtBP2, p300, or NF-κB exhibited moderate cytotoxicity in vitro and in vivo, affecting both proinflammatory genes and Other targets. We identified a potent inhibitor, PNSC928, for the CtBP2-p300 interaction using AlphaScreen. PNSC928 treatment hindered the assembly of the CtBP2-p300-NF-κB complex, substantially downregulating proinflammatory cytokine gene expression without observable cytotoxicity in normal cells. In vivo administration of PNSC928 significantly reduced CtBP2-driven proinflammatory gene expression in ARDS mice, alleviating inflammation and lung injury, ultimately improving ARDS prognosis.

Conclusion: Our results position PNSC928 as a promising therapeutic candidate to specifically target the CtBP2-p300 interaction and mitigate inflammation in ARDS management.

Keywords
ARDS; CtBP2; PNSC928; Proinflammatory cytokine genes; p300.
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