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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Inflammation Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1461931
This article is part of the Research Topic Filling the Void in Lung and Metabolic Inflammation Research: Novel Drug Targets and Addressing Knowledge Gaps View all 4 articles

KAE ameliorates LPS-mediated acute lung injury by inhibiting PANoptosis through the intracellular DNA-cGAS-STING axis

Provisionally accepted
Yonghu Chen Yonghu Chen Xilin Wu Xilin Wu Zhe Jiang Zhe Jiang Xuezheng Li Xuezheng Li *
  • Yanbian University, Yanji, China

The final, formatted version of the article will be published soon.

    Background: Acute lung injury (ALI) is a severe condition characterized by inflammation , tissue damage, and persistent activation of the cyclic GMP-AMP (cGAS)-stimulator of interferon genes (STING) pathway, which exacerbates the production of pro-inflammatory mediators and promotes the progression of ALI. Specific inhibition of this pathway has been shown to alleviate ALI symptoms. Kaempferol-3-O-α-L-(4″-E-p-coumaroyl)-rhamnoside (KAE), an active compound found in the flowers of Angelica acutiloba Kitagawa, exhibits antiinflammatory and antioxidant properties. This study aimed to investigate the molecular mechanisms through which KAE regulates the cGAS-STING pathway in the context of ALI.Methods: ALI was induced using LPS. Lung damage and anti-inflammatory/antioxidant effects were assessed by H&E staining, lung edema index, and SOD, MDA, and ELISA assays.NO release and mitochondrial membrane potential (MMP) were measured by JC -1 and Griess methods. The impact of KAE on the cGAS-STING pathway and PANoptosis was analyzed using flow cytometry, Western blot, and immunofluorescence.: KAE significantly alleviated lipopolysaccharide-induced pulmonary injury by reducing inflammatory cell infiltration, alleviating pulmonary edema, enhancing antioxidant capacity, and decreasing levels of inflammatory cytokines in mouse lung tissues. In both in vitro and in vivo analyses, KAE downregulated the expression of key components of the cGAS-STING pathway, including cGAS, STING, p-TBK1, and nuclear factor-κB. KAE also reduced the assembly and activation of the PANoptosome, thereby attenuating apoptosis, necroptosis, and pyroptosis. Additionally, KAE inhibited cGAS activation by restoring the MMP, which reduced the release of cytosolic DNA. Conclusion: KAE improve ALI by inhibiting the release of cytosolic DNA and suppressing cGAS-STING pathway activation, thereby protecting cells from PANoptosis. Our findings provide valuable insights for the development and application of novel therapeutic strategies for ALI.

    Keywords: KAE, cGAS-STING, PANoptosis, Acute Lung Injury, Intracellular DNA

    Received: 09 Jul 2024; Accepted: 19 Dec 2024.

    Copyright: © 2024 Chen, Wu, Jiang and Li. 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: Xuezheng Li, Yanbian University, Yanji, China

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