2. Academic Validation
  3. Euchrenone A10 attenuates septic lung injury though S100A8/A9-dependent TLR4/MyD88/NF-κB signaling

Euchrenone A10 attenuates septic lung injury though S100A8/A9-dependent TLR4/MyD88/NF-κB signaling

  • Phytomedicine. 2025 Sep 27:148:157336. doi: 10.1016/j.phymed.2025.157336.
Lvzhou Zhou 1,  Yao Xiao 1,  Jinlian He 2,  Hong Ren 1,  Caiping Zhao 1,  Chuanhai Zhang 3,  Xiao Shu 1,  Ying Chen 1,  Danli Chen 1,  Yulian Chen 1,  Xizi He 1,  Lirong Lian 1,  Jie Shao 1,  Juan Wang 1,  Yi Wang 4,  Canzhe Li 5,  Jianjie OuYang 6,  Runze Li 7,  Zhongde Zhang 8,  Liang Liu 9,  Hudan Pan 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510000, China; The Second School of Clinical Medicine, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China.
  • 2 Guangzhou National Laboratory, Guangzhou, Guangdong, 510000, China.
  • 3 State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, 999078, China.
  • 4 Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, 519031, China.
  • 5 Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
  • 6 Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou City, 510120, China.
  • 7 State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510000, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, 519031, China; The Second School of Clinical Medicine, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China; Guangzhou National Laboratory, Guangzhou, Guangdong, 510000, China.
  • 8 State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510000, China. Electronic address: Doctorzzd99@163.com.
  • 9 State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510000, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, 519031, China; The Second School of Clinical Medicine, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China; Guangzhou National Laboratory, Guangzhou, Guangdong, 510000, China. Electronic address: lliu@must.edu.mo.
  • 10 State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510000, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, 519031, China; The Second School of Clinical Medicine, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China. Electronic address: hdpan@gzucm.edu.cn.
PMID: 41038141 DOI: 10.1016/j.phymed.2025.157336
Abstract

Background: Euchrenone A10 (A10), an isoprenylated flavanone isolated from Glycyrrhiza (licorice), exhibits significant bioactivities, including anti-inflammatory and antioxidant effects. However, the effects and mechanisms underlying A10's protective role in sepsis-associated acute lung injury (SALI) remain incompletely understood.

Objective: This study aims to elucidate the pharmacological effects of A10 and the underlying mechanisms by which it protects against SALI, using both in vitro and in vivo experiments.

Methods: To evaluate the effects of A10 against SALI, mice were pretreated with A10 (12.5, 25, or 50 mg/kg) or dexamethasone (Dex, 50 μg/kg) prior to sepsis induction via intraperitoneal administration of lipopolysaccharide (LPS, 10 mg/kg) or cecal ligation and puncture (CLP). Survival rates, pulmwasy function, bronchoalveolar lavage fluid inflammatory cell infiltration, protein exudation, and lung histopathology were systematically assessed. Molecular docking and biolayer interferometry (BLI) were employed to characterize the interactions between S100A8/A9 and A10 or paquinimod (paq). Complementary in vitro studies using LPS (150 ng/ml)-stimulated Raw264.7 macrophages were conducted to examine A10's effects on inflammatory gene expression.

Results: To evaluate the therapeutic effects of A10, we employed LPS-induced SALI and CLP-induced ALI models. A10 dose-dependently alleviated pulmonary injury and improved survival rates in septic mice. Notably, A10 inhibited the expression of S100A8/A9 and suppressed the TLR4/MyD88/NF-κB signaling pathway in both in vivo and in vitro models. Mechanistic studies using molecular docking and BLI indicated that A10 directly binds to S100A8/A9, thereby blocking its interaction with the TLR4 receptor. Furthermore, in vivo and in vitro experiments confirmed that A10 shares the same binding site on S100A8/A9 as the S100A9-specific inhibitor paq, competitively displacing paq and inhibiting downstream TLR4/MyD88/NF-κB signaling.

Conclusion: A10 exerts its anti-inflammatory effects by binding to the S100A8/A9 protein, thereby inhibiting the TLR4-NF-κB inflammatory cascade. These properties highlight its therapeutic potential as monotherapy for SALI.

Keywords

Acute respiratory distress syndrome; Euchrenone A10; S100A8/A9; Sepsis-related acute lung injury.

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