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

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

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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