ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Inflammation Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1609923
Degradation of IRAK4 for the Treatment of Lipopolysaccharide induced acute lung injury in mice
Provisionally accepted
- 1Department of Neurology, Tiantai People's Hospital of Zhejiang Province, Taizhou, Zhejiang Province, China
- 2Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, China
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Excessive pulmonary inflammation in acute lung injury (ALI) results in high patient mortality.Interleukin-1 receptor-associated kinase 4 (IRAK4) is a potential therapeutic target for inflammatory diseases. However, due to the dual functionality of IRAK4 as both an active kinase and a scaffolding protein, inhibiting its kinase activity yield moderate anti-inflammatory results.The present study explored the efficacy of KT-474, a prototypical IRAK4 degrader, which effectively diminished cellular IRAK4 levels, achieving half-maximal degradation at a concentration of 4.0 nM in RAW 264.7 cells. KT-474 effectively inhibited the activation of downstream nuclear factor (NF)-κB signaling, exhibiting stronger pharmacological impacts compared to conventional kinase inhibitors. Additionally, a lipopolysaccharide-induced acute inflammatory mouse model was established, and KT-474 displayed significant therapeutic benefits in vivo compared to kinase inhibitors. Therefore, these findings highlight the therapeutic potential of IRAK4 degrader for the treatment of acute lung injury.
Keywords: interleukin-1 receptor-associated kinase 4 (IRAK4), Acute Lung Injury, KT-474, inflammatory disease, anti-inflammation
Received: 11 Apr 2025; Accepted: 02 Jul 2025.
Copyright: © 2025 Ye, Chen, Huang, Qiu, Luo and Zheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Ruixiang Luo, Department of Neurology, Tiantai People's Hospital of Zhejiang Province, Taizhou, Zhejiang Province, China
Lulu Zheng, Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang Province, China
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