Irisin Protects Against Seawater Aspiration-Induced Acute Lung Injury via Inhibiting JAK2/STAT1 Signal Pathway
5 affiliations
- 1Science and Technology Innovation Research Institute, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, 710038, People’s Republic of China
- 2Institute of Pulmonary Diseases, Fourth Military Medical University, Xi’an, Shaanxi, 710032, People’s Republic of China
- 3The Key Laboratory of Aerospace Medicine, Ministry of Education, Fourth Military Medical University, Xi’an, Shaanxi, 710032, People’s Republic of China
- 4Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Army Medical University (Southwest Hospital), Chongqing, 400038, People’s Republic of China
- 5Department of Toxicology, Shaanxi Provincial Key Laboratory of Free Radical Biology and Medicine, Fourth Military Medical University, Xi’an, 710032, People’s Republic of China
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.
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BibTeX
@article{guo2026irisin,
title = {{Irisin Protects Against Seawater Aspiration-Induced Acute Lung Injury via Inhibiting JAK2/STAT1 Signal Pathway}},
author = {Xian Guo and Jiaying Gao and Yifeng Wang and Xinxin Wang and Qi Zhao and Yujuan Li and Yongheng Gao and Jian Chen and Ru Zhang and Zebing Hu and Weihua Yu and Faguang Jin},
journal = {Drug Design, Development and Therapy},
year = {2026},
month = oct,
doi = {10.2147/dddt.s639983},
url = {https://doi.org/10.2147/dddt.s639983},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Irisin Protects Against Seawater Aspiration-Induced Acute Lung Injury via Inhibiting JAK2/STAT1 Signal Pathway
AU - Xian Guo
AU - Jiaying Gao
AU - Yifeng Wang
AU - Xinxin Wang
AU - Qi Zhao
AU - Yujuan Li
AU - Yongheng Gao
AU - Jian Chen
AU - Ru Zhang
AU - Zebing Hu
AU - Weihua Yu
AU - Faguang Jin
PY - 2026
DA - 2026/10/30
JO - Drug Design, Development and Therapy
DO - 10.2147/dddt.s639983
UR - https://doi.org/10.2147/dddt.s639983
AB - 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.
SN - 1177-8881
ER -