Elucidating Forsythin’s Anti-Inflammatory Action Through Modulation of the P38 MAPK Pathway in SARS-CoV-2 Infection

Qinhai Ma , Peifang Xie , Yangqing Zhan , Ruihan Chen , Bin Liu , Yongjie Su , Wanli Qiu , Xuanxuan Li , Tingting Zhao , Nanshan Zhong , Zifeng Yang

Engineering ›› 2025, Vol. 54 ›› Issue (11) : 187 -201.

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Engineering ›› 2025, Vol. 54 ›› Issue (11) :187 -201. DOI: 10.1016/j.eng.2025.01.020
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Elucidating Forsythin’s Anti-Inflammatory Action Through Modulation of the P38 MAPK Pathway in SARS-CoV-2 Infection
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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection disrupts immune function by activating inflammatory pathways related to disease severity. Understanding virus-induced inflammation is crucial for developing anti-coronavirus disease 2019 (COVID-19) therapies. This study used principal component analysis, heatmaps, and other tools to examine mitogen-activated protein kinase (MAPK) pathway gene expression, and found that alterations in MAPK pathway genes were correlated with immune response changes. Further analysis linked P38-related gene expression to clinical symptoms, with transcriptomic data showing a strong association between MAPK gene expression changes and SARS-CoV-2 infection. In infected cell models, P-P38 protein and inflammatory factors were significantly upregulated. Analysis of the GSE217948 dataset showed a significant correlation between plasma markers (interferon inducible protein 10 (IP-10) and interleukin (IL)-6) and symptoms (fever and fatigue). Activation of P38 appears to release inflammatory factors tied to these symptoms making P38 as a key pathway in virus-induced inflammation. Forsythin (KD-1), an anti-inflammatory compound from forsythia showed efficacy against SARS-CoV-2, inhibiting replication, reducing P38 levels, and lowering inflammatory markers (IL-6, IL-8, IP-10, tumor necrosis factor-α (TNF-α), and monocyte chemotactic protein-1 (MCP-1)) in both cell and animal models. In specific cell models, KD-1 blocked P38 activation, thereby reducing inflammation. In a P38 overexpression model, KD-1 decreased P38 phosphorylation and downstream inflammatory proteins. This study identifies the P38 pathway as a therapeutic target for COVID-19, supporting KD-1’s potential in mitigating virus-induced inflammation and guiding further research into anti- inflammatory treatments for respiratory viruses.

Keywords

SARS-CoV-2 / P38 MAPK pathway / Anti-inflammatory / Forsythin (KD-1) / Clinical symptoms

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Qinhai Ma, Peifang Xie, Yangqing Zhan, Ruihan Chen, Bin Liu, Yongjie Su, Wanli Qiu, Xuanxuan Li, Tingting Zhao, Nanshan Zhong, Zifeng Yang. Elucidating Forsythin’s Anti-Inflammatory Action Through Modulation of the P38 MAPK Pathway in SARS-CoV-2 Infection. Engineering, 2025, 54(11): 187-201 DOI:10.1016/j.eng.2025.01.020

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CRediT authorship contribution statement

Qinhai Ma: Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Peifang Xie: Writing – original draft, Supervision, Software, Resources, Methodology, Formal analysis, Data curation. Yangqing Zhan: Writing – original draft, Visualization, Validation, Supervision, Software, Methodology, Investigation, Data curation. Ruihan Chen: Writing – original draft, Validation, Software, Investigation, Formal analysis, Data curation, Conceptualization. Bin Liu: Supervision, Software, Resources, Methodology, Investigation, Formal analysis, Data curation. Yongjie Su: Visualization, Methodology, Formal analysis, Data curation. Wanli Qiu: Supervision, Software, Methodology, Investigation. Xuanxuan Li: Validation, Methodology, Investigation. Tingting Zhao: Methodology, Data curation. Nanshan Zhong: Writing – review & editing, Visualization, Validation, Supervision, Software, Project administration, Funding acquisition, Conceptualization. Zifeng Yang: Writing – review & editing, Validation, Supervision, Project administration, Investigation, Funding acquisition, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was supported by the National Administration of Traditional Chinese Medicine (ZYYCXTU-D-202201 and ZYYCXTU-D-202206), the National Natural Science Foundation of China (82474155, 82174053, 82141201, and 82341099), the Guangdong Basic and Applied Basic Research Foundation (2022A1515010301), the Macao Science and Technology Development Fund (0022/2021/A1), the Young Top Talent of Science and Technology Innovation Department of Guangdong Province (2021TQ060189), and the Youth Lift Project of China Association for Science and Technology (2020-2022QNRC001).

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