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Shuqing Granule (SG) is a traditional Chinese medicine containing ingredients such as indirubin, shinpterocarpin, naringenin, and quercetin. It exhibits anti-inflammatory and antiviral activities as well as broad-spectrum antiviral effects, yet its potential role in the treatment of COVID-19 remains unclear. This study thus aimed to explore the therapeutic effects of SG on COVID-19, with a focus on its potential anti-SARS-CoV-2 activity linked to these bioactive ingredients. Methods: The potential therapeutic ability of SG was investigated by combining network pharmacology, molecular docking, and experimental verification. First, key ingredients in SG and their corresponding targets, as well as COVID-19-related targets, were identified. Then, enrichment analyses were performed to highlight potential key pathways. Additionally, molecular docking was conducted to assess the binding capacity of the key ingredients to ACE2. Finally, experiments such as Western blot and ELISA were conducted to verify the effect of SG. Results: The results showed that 15 key ingredients such as quercetin in SG could affect overlapping targets such as RELA. Molecular docking results showed that key ingredients in SG, such as isoliquiritigenin, formononetin, shinpterocarpin, indirubin, naringenin, kaempferol, and 7-Methoxy-2-methylisoflavone, might bind to angiotensin-converting enzyme II (ACE2)\u2014a critical receptor in the process of COVID-19 infection\u2014thereby exerting antiviral effects. Experiments such as Western blot and ELISA further demonstrated that SG could reduce inflammation induced by the SARS-CoV-2 S1 protein by 50%. This effect might be achieved by downregulating ACE2 expression by 1.5 times and inhibiting the NF-\u03baB signaling pathway. Conclusions: This study confirmed that SG has potential as a candidate for COVID-19 treatment. It also provided a new approach for the application of traditional Chinese medicine in combating the virus.<\/jats:p>","DOI":"10.3390\/ph18081216","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T13:28:22Z","timestamp":1755523702000},"page":"1216","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Network Pharmacology and Experiment Verification-Based Strategy for Exploring the Mechanisms of Shuqing Granule in the Treatment of COVID-19"],"prefix":"10.3390","volume":"18","author":[{"given":"Xiaoping","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"An","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuemeng","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianqi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengjie","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuangui","family":"Liu","sequence":"additional","affiliation":[{"name":"National and Local United Engineering R&D Center of Ginseng Innovative Drugs, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0871-3454","authenticated-orcid":false,"given":"Fang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1146\/annurev-micro-020518-115759","article-title":"Human Coronavirus: Host-Pathogen Interaction","volume":"73","author":"Fung","year":"2019","journal-title":"Annu. 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