ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Inflammation Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1590096
Rutin ameliorates LPS-induced acute lung injury in mice by inhibiting the cGAS-STING-NLRP3 signaling pathway
Provisionally accepted
- 1Southwest Medical University, Luzhou, Sichuan, China
- 2The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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AbstractAcute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), represent critical respiratory failures with high mortality rates and limited treatment options. While the flavonoid rutin exhibits documented anti-inflammatory and antioxidant properties, its therapeutic mechanisms in ALI/ARDS remain unclear. This study investigated rutin's efficacy against lipopolysaccharide (LPS)-induced ALI in mice, with a mechanistic focus on the cGAS-STING pathway and NLRP3 inflammasome activation. The proteomic profiling of lung tissues from LPS-challenged mice identified significant dysregulation of proteins integral to the cGAS-STING cascade and pyroptotic processes. Gene ontology and KEGG pathway analyses underscored the pivotal role of immune and inflammatory responses in ALI, particularly in cytosolic DNA-sensing and NOD-like receptor signaling pathways. Rutin administration significantly alleviated LPS-induced lung injury, reducing oxidative stress, apoptosis, and proinflammatory cytokine levels (IL-6, IL-1β, TNF-α). Mechanistically, rutin demonstrated dual suppression: 1) inhibiting cGAS-STING activation through decreased expression of cGAS, STING, and phosphorylation of TBK1/IRF3 (P<0.05), and 2) attenuating NLRP3-mediated pyroptosis via downregulation of NLRP3-ASC-caspase1-GSDMD signaling (P<0.05). Pharmacological STING inhibition (C-176) validated the cGAS-STING-NLRP3 regulatory hierarchy in ALI pathogenesis. These findings elucidate rutin's novel therapeutic mechanism through coordinated suppression of the cGAS-STING-NLRP3 axis, positioning it as a promising candidate for ALI/ARDS intervention.
Keywords: Acute Lung Injury, cGAS-STING pathway, NLRP3 inflammasome, pyroptosis, Rutin, Oxidative Stress
Received: 08 Mar 2025; Accepted: 22 Apr 2025.
Copyright: © 2025 Zhou, Wang, Wang, Xu, Luo, Zhang 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: Yuying Li, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
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