Abstract
Signal transducer and activator of transcription (STAT) 3 contributes to the development of cardiovascular diseases by modulating macrophages inflammation. However, the underlying implication of STAT3 pathway in Kawasaki disease (KD) has not been fully elucidated. Our reserach endeavors to investigate the potential role of STAT3 in macrophages inflammatory response and cardiovascular injury in the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis model. In vitro experiments, we found that STAT3 was highly phosphorylated in LCWE-treated RAW264.7 macrophages and STAT3 blockade by AG490 significantly inhibited LCWE-mediated inflammatory response in RAW264.7 macrophages and mouse primary peritoneal macrophages. Furthermore, inhibition of macrophages STAT3 signaling attenuated mouse coronary endothelial cells damage induced by RAW264.7 cells-conditioned medium. In vivo experiments, our results showed that the protein level of phospho (p)-STAT3 was upregulated in the heart tissue of LCWE-injected mice and pharmacological inhibition of STAT3 with AG490 mitigated cardiac inflammation and vascular injury in the LCWE-induced KD mouse model. Collectively, our study reveals that targeting STAT3 pathway alleviates KD-associated macrophages inflammation and cardiovascular lesions and STAT3 may be a promising therapeutic target for KD.
Similar content being viewed by others
Data availability
All data generated or analysed during this study are included in this published article (and its Supplementary Information files).
References
McCrindle, B. W. et al. Diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the American heart association. Circulation 135 (17), e927–e999 (2017).
Kato, H. et al. Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. Circulation 94 (6), 1379–1385 (1996).
Jone, P. N. et al. Update on Diagnosis and Management of Kawasaki Disease: A Scientific Statement From the American Heart Association. Circulation 150 (23), 481–500 (2024).
Ohashi, R. et al. M1 macrophage is the predominant phenotype in coronary artery lesions following Kawasaki disease. Vasc Med. 24 (6), 484–492 (2019).
Stock, A. T. et al. Intimal macrophages develop from circulating monocytes during vasculitis. Clin. Transl Immunol. 11 (8), e1412 (2022).
Guo, M. M., Chang, L. S., Huang, Y. H., Wang, F. S. & Kuo, H. C. Epigenetic Regulation of Macrophage Marker Expression Profiles in Kawasaki Disease. Front. Pediatr. 8, 129 (2020).
Lehman, T. J., Walker, S. M., Mahnovski, V. & McCurdy, D. Coronary arteritis in mice following the systemic injection of group B Lactobacillus casei cell walls in aqueous suspension. Arthritis Rheum. 28 (6), 652–659 (1985).
Wakita, D. et al. Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease-Associated Abdominal Aortic Aneurysm. Arterioscler. Thromb. Vasc Biol. 36 (5), 886–897 (2016).
Zheng, F. et al. KCa3.1 Inhibition of Macrophages Suppresses Inflammatory Response Leading to Endothelial Damage in a Cell Model of Kawasaki Disease. J. Inflamm. Res. 14, 719–735 (2021).
Yang, S. et al. A novel STAT3 CCD inhibitor for suppressing macrophage activation and lipopolysaccharide-induced acute lung injury. Int. Immunopharmacol. 143 (Pt 2), 113523 (2024).
Cao, L. et al. The STAT3 inhibitor B9 alleviates lipopolysaccharide-induced acute lung injury through its anti-inflammatory effects. Int. Immunopharmacol. 135, 112221 (2024).
Qin, Z. et al. Angiotensin II-induced TLR4 mediated abdominal aortic aneurysm in apolipoprotein E knockout mice is dependent on STAT3. J. Mol. Cell. Cardiol. 87, 160–170 (2015).
Wu, Q. Y. et al. A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy. Cell. Death Dis. 11 (2), 131 (2020).
Yang, Y. et al. Equisetin protects from atherosclerosis in vivo by binding to STAT3 and inhibiting its activity. Pharmacol. Res. 206, 107289 (2024).
Qi, X. L. et al. 1,25-Dihydroxyvitamin D3 regulates T lymphocyte proliferation through activation of P53 and inhibition of ERK1/2 signaling pathway in children with Kawasaki disease. Eur. Rev. Med. Pharmacol. Sci. 21 (16), 3714–3722 (2017).
Suganuma, E., Sato, S., Honda, S. & Nakazawa, A. A novel mouse model of coronary stenosis mimicking Kawasaki disease induced by Lactobacillus casei cell wall extract. Exp. Anim. 69 (2), 233–241 (2020).
Noval Rivas, M. & Arditi, M. Kawasaki disease: pathophysiology and insights from mouse models. Nat. Rev. Rheumatol. 16 (7), 391–405 (2020).
Yang, J. et al. Anakinra Treatment in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysms: A Phase I/IIa Trial. J. Pediatr. 243, 173–180 (2022).
Ling, J. et al. Case Series on the Efficacy and Safety of Tocilizumab in IVIG-Resistant Kawasaki Disease: A Retrospective Analysis of Five Patients. J. Inflamm. Res. 17, 10991–10998 (2024).
Nagatomo, Y. et al. Effective infliximab therapy for the early regression of coronary artery aneurysm in Kawasaki disease. Int. J. Cardiol. 271, 317–321 (2018).
Lee, S. H. et al. STAT3 blockade ameliorates LPS-induced kidney injury through macrophage-driven inflammation. Cell. Commun. Signal. 22 (1), 476 (2024).
Jia, C. et al. IL-37b alleviates endothelial cell apoptosis and inflammation in Kawasaki disease through IL-1R8 pathway. Cell. Death Dis. 12 (6), 575 (2021).
Zheng, Y. et al. Melatonin alleviates vascular endothelial cell damage by regulating an autophagy-apoptosis axis in Kawasaki disease. Cell. Prolif. 55 (6), e13251 (2022).
Chen, Q. et al. Targeted inhibition of STAT3 as a potential treatment strategy for atherosclerosis. Theranostics 9 (22), 6424–6442 (2019).
Guo, B. et al. Targeting the JAK2/STAT3 signaling pathway with natural plants and phytochemical ingredients: A novel therapeutic method for combatting cardiovascular diseases. Biomed. Pharmacother. 172, 116313 (2024).
Zhai, M. et al. Ursolic acid prevents angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E-knockout mice. Atherosclerosis 271, 128–135 (2018).
Patel, R. et al. Signaling through the IL-6-STAT3 Pathway Promotes Proteolytically-Active Macrophage Accumulation Necessary for Development of Small AAA. Vasc Endovascular Surg. 57 (5), 433–444 (2023).
Porritt, R. A. et al. Interleukin-1 Beta-Mediated Sex Differences in Kawasaki Disease Vasculitis Development and Response to Treatment. Arterioscler. Thromb. Vasc Biol. 40 (3), 802–818 (2020).
Porritt, R. A. et al. Inhibition of IL-6 in the LCWE Mouse Model of Kawasaki Disease Inhibits Acute Phase Reactant Serum Amyloid A but Fails to Attenuate Vasculitis. Front. Immunol. 12, 630196 (2021).
Samad, M. A. et al. STAT3 Signaling Pathway in Health and Disease. MedComm 6 (4), e70152 (2025).
Funding
This work is supported by grants from the Key R&D Program of Zhejiang (2024C03179) and Zhejiang Provincial Natural Science Foundation of China under Grant (No. LGD21H020002).
Author information
Authors and Affiliations
Contributions
Fenglei Zheng, Wang Hua and Fangqi Gong designed the study; Fenglei Zheng, Jiawen Xu, Tong Tong and Yihua Jin performed the experiments; data analysis was performed by Fenglei Zheng and Yahua Bi; data discussion was contributed by Fenglei Zheng, Yujia Wang and Fangqi Gong; and manuscript was written by Fenglei Zheng, Jiawen Xu and Yahua Bi. All authors agreed to submit to the current journal and be accountable for all aspects of this research.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Zheng, F., Xu, J., Bi, Y. et al. Targeting STAT3 pathway attenuates macrophages inflammation and cardiovascular injury in a model of Kawasaki disease. Sci Rep (2026). https://doi.org/10.1038/s41598-026-45051-w
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41598-026-45051-w
