Inhibition of cathepsin L ameliorates inflammation through the A20/NF-κB pathway in endotoxin-induced acute lung injury

  • iScience. 2024 Oct 4;27(11):111024. doi: 10.1016/j.isci.2024.111024.
Shiyi Yang  1 ,  Kaijun Chen  1 ,  Jinkang Yu  1 ,  Zhangchu Jin  1 ,  Min Zhang  1 ,  Zhouyang Li  1 ,  Yang Yu  2 ,  Nanxia Xuan  2 ,  Baoping Tian  2 ,  Na Li  1 ,  Zhengtong Mao  3 ,  Wenbing Wang  3 ,  Tianpeng Chen  3 ,  Yinfang Wu  1 ,  Yun Zhao  1 ,  Min Zhang  1 ,  Xia Fei  1 ,  Songmin Ying  4  5 ,  Wen Li  1 ,  Fugui Yan  1 ,  Xingxian Zhang  3 ,  Gensheng Zhang  2 ,  Huahao Shen  1  6 ,  Zhihua Chen  1
Affiliations
  • 1. Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
  • 2. Department of Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
  • 3. College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China.
  • 4. International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu 322000, China.
  • 5. Department of Pharmacology & Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou 310009, China.
  • 6. State Key Lab of Respiratory Disease, Key Cite of National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China.
PMID: 39559762 DOI: 10.1016/j.isci.2024.111024
Abstract

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a severe inflammatory condition that remains refractory; however, its molecular mechanisms are largely unknown. Previous studies have shown numerous compounds containing 4-indolyl-2-aminopyrimidine that display strong anti-inflammatory properties. In our research, we identified that a 4-Indole-2-Arylaminopyrimidine derivative named "IAAP" suppressed lipopolysaccharide (LPS)-induced inflammation. Immunoprecipitation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified that IAAP interacts with a lysosomal cysteine protease, Cathepsin L (CTSL), and restrains its activity. The nuclear factor kappa B (NF-κB) family plays a central role in controlling innate immunity. Canonical NF-κB activation, such as stimulation with lipopolysaccharide (LPS), typically involves the degradation of A20. We observed that IAAP suppression of CTSL prevented the LPS-induced degradation of A20, thereby ameliorating NF-κB activation. This study identifies CTSL as a crucial regulator of A20/NF-κB signaling and suggests IAAP as a potential lead compound for developing drugs to treat ALI/ARDS.

Keywords
Biological sciences; Molecular biology; Molecular interaction.
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