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Irisin Protects Against Seawater Aspiration-Induced Acute Lung Injury via Inhibiting JAK2/STAT1 Signal Pathway

Year: 2026

Type: article

Abstract: Purpose: Seawater aspiration-induced acute lung injury (SW-ALI) is a life-threatening inflammatory disorder with no specific pharmacological treatment. Irisin, an exercise-induced peptide, modulates inflammation, but its role in SW-ALI remains undefined. This study aims to investigate the protective effects and mechanisms of irisin against SW-ALI. Methods: A murine model of SW-ALI was established in C57BL/6 mice via intratracheal seawater, followed by intraperitoneal administration of irisin. Pulmonary function was assessed using whole-body plethysmography (WBP). Lung injury severity was evaluated by histology, lung index and bronchoalveolar lavage fluid (BALF) protein concentration and cell counts. Immune infiltration and p-STAT1 nuclear translocation were detected by immunofluorescence. RNA sequencing (RNA-seq) identified transcriptomic alterations and signaling pathways in lung tissues, validated by RT-qPCR and ELISA. In vitro, seawater-stimulated RAW264.7 macrophages were used to evaluate inflammatory responses and JAK2/STAT1 signaling. A JAK2 activator coumermycin A1(CA) was employed to verify the necessity of the pathway. Results: Irisin improved respiratory function, reduced lung index, BALF protein levels and cell counts, and alleviated lung pathology in SW-ALI mice. RNA-seq revealed that irisin reprogrammed pulmonary gene expression, suppressing inflammatory and immune pathways, specifically downregulating the expression and secretion of inflammation-related molecules, including chemokines (CXCL9, CXCL10), interferons (IFN-β), and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) both in vivo and in vitro. Concurrently, irisin attenuated seawater-induced infiltration of neutrophils and M1-like macrophages in lung tissues, and suppressed M1-like polarization of seawater-stimulated RAW264.7 cells. Mechanistically, irisin inhibited JAK2/STAT1 phosphorylation and p-STAT1 nuclear translocation. Furthermore, CA-mediated JAK2 activation partially abrogated irisin's suppression of M1-like polarization, inflammation-related molecules release, and p-STAT1 nuclear translocation. Conclusion: Irisin alleviates SW-ALI, involving the inhibition of the JAK2/STAT1 pathway, which suppresses M1-like macrophage polarization and the subsequent release of pro-inflammatory cytokines, chemokines, and type I interferons, suggesting a potential therapeutic strategy for SW-ALI.

Source: Drug Design Development and Therapy

DOI: 10.2147/dddt.s639983