Qingqi Guxue Decoction induces S cell cycle arrest to inhibit replication of severe fever with thrombocytopenia syndrome virus

Xixi Shi; Zining Wang; Zixiang Liu; Qinting Lin; Mengqian Huang; Tze Yean Lim; Xiaoyan Li; Tao Wang

doi:10.1016/j.virs.2025.03.011

April 2025

Citation: Xixi Shi, Zining Wang, Zixiang Liu, Qinting Lin, Mengqian Huang, Tze Yean Lim, Xiaoyan Li, Tao Wang. Qingqi Guxue Decoction induces S cell cycle arrest to inhibit replication of severe fever with thrombocytopenia syndrome virus .VIROLOGICA SINICA, 2025, 40(2) : 260-274. http://dx.doi.org/10.1016/j.virs.2025.03.011

Qingqi Guxue Decoction induces S cell cycle arrest to inhibit replication of severe fever with thrombocytopenia syndrome virus

Xixi Shi ^a ,
Zining Wang ^a ,
Zixiang Liu ^a ,
Qinting Lin ^a ,
Mengqian Huang ^a ,
Tze Yean Lim ^a ,
Xiaoyan Li ^b,c ,
Tao Wang ^{a,c
,,}

a. School of Life Sciences, Tianjin University, Tianjin 300110, China;
b. Tianjin Centers for Disease Control and Prevention, Tianjin 300022, China;
c. Tianjin Key Laboratory of Pathogenic Microbiology of Infectious Disease, Tianjin 300011, China

Corresponding author: Tao Wang, wangtaobio@tju.edu.cn
Received Date: 25 September 2024
Accepted Date: 25 March 2025
Available online: 27 March 2025

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) is a novel emerging acute infectious disease caused by severe fever with thrombocytopenia syndrome virus (SFTSV), characterized by high fever and thrombocytopenia. It has been proved that traditional Chinese medicine (TCM) has displayed definite therapeutic effects on viral hemorrhagic fever, indicating its potential to treat SFTS. In this study, SFTS-relative key targets were predicted via gene ontology (GO) analysis and kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. Molecular docking was then used to select stable binders. Molecules matched TCMs were identified, and a new prescription, Qingqi Guxue decoction (QQGX), was formulated to clear heat and nourish blood, with a resulting drug composition network. We explored the optimal drug proportion for QQGX. Through an in-depth study of molecular mechanisms, we found that QQGX induces S phase arrest by promoting the degradation of cyclin A2 (CCNA2) and cyclin-dependent kinase 2 (CDK2), thereby inhibiting SFTSV replication. Finally, we verified the effectiveness and safety of QQGX based on the mouse liver bile duct organoid model infected with SFTSV. In summary, our study prepared a TCM decoction using the method of network pharmacology. This decoction has a significant inhibitory effect on the replication of SFTSV and provides a new treatment strategy for hemorrhagic fever with TCM.
- Qingqi Guxue decoction (QQGX)
- , Severe fever with thrombocytopenia syndrome virus (SFTSV)
- , Traditional Chinese medicine (TCM)
- , Cell cycle
- , S arrest

Electronic Supplementary Material

10.1016j.virs.2025.03.011-ESM6.xlsx
10.1016j.virs.2025.03.011-ESM2.xls
10.1016j.virs.2025.03.011-ESM1.docx
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10.1016j.virs.2025.03.011-ESM3.xlsx
10.1016j.virs.2025.03.011-ESM5.xls

References
1. Baba, M., Okamoto, M., Toyama, M., Sakakibara, N., Shimojima, M., Saijo, M., Niwa, T.,Yagi, Y., 2023. Amodiaquine derivatives as inhibitors of severe fever with thrombocytopenia syndrome virus (SFTSV) replication. Antiviral Res, 210, 105479.
2. Boezio, B., Audouze, K., Ducrot, P.,Taboureau, O., 2017. Network-based Approaches in Pharmacology. Mol Inform, 36.
3. Chen, C.C., Qin, X.M., Du, G.H.,Zhou, Y.Z., 2019. The "compatible art" of effective components from traditional Chinese medicine: research on the compatibility and proportion of effective components. Acta Pharmaceutica Sinica, 54(5), 808-817.
4. Clevers, H., 2016. Modeling Development and Disease with Organoids. Cell, 165, 1586-1597.
5. Corro, C., Novellasdemunt, L.,Li, V.S.W., 2020. A brief history of organoids. Am J Physiol Cell Physiol, 319, C151-c165.
6. Davy, C.,Doorbar, J., 2007. G2/M cell cycle arrest in the life cycle of viruses. Virology, 368, 219-226.
7. Ding, J., Li, J., Zhang, Z., Du, Y., Liu, Y., Wang, P.,Du, H., 2023. Network pharmacology combined with metabolomics to explore the mechanism for Lonicerae Japonicae flos against respiratory syncytial virus. BMC Complement Med Ther, 23, 449.
8. Dutta, D., Heo, I.,Clevers, H., 2017. Disease Modeling in Stem Cell-Derived 3D Organoid Systems. Trends Mol Med, 23, 393-410.
9. Efferth, T., Li, P.C., Konkimalla, V.S.,Kaina, B., 2007. From traditional Chinese medicine to rational cancer therapy. Trends Mol Med, 13, 353-361.
10. Feuer, R., Mena, I., Pagarigan, R., Slifka, M.K.,Whitton, J.L., 2002. Cell cycle status affects coxsackievirus replication, persistence, and reactivation in vitro. J Virol, 76, 4430-4440.
11. Frazzi, R., 2021. BIRC3 and BIRC5: multi-faceted inhibitors in cancer. Cell Biosci, 11, 8.
12. Gearhart, T.L.,Bouchard, M.J., 2010. Replication of the hepatitis B virus requires a calcium-dependent HBx-induced G1 phase arrest of hepatocytes. Virology, 407, 14-25.
13. Gu, X.L., Su, W.Q., Zhou, C.M., Fang, L.Z., Zhu, K., Ma, D.Q., Jiang, F.C., Li, Z.M., Li, D., Duan, S.H., Peng, Q.M., Wang, R., Jiang, Y., Han, H.J.,Yu, X.J., 2022. SFTSV infection in rodents and their ectoparasitic chiggers. PLoS Negl Trop Dis, 16, e0010698.
14. Guo, X., Zhang, L., Zhang, W., Chi, Y., Zeng, X., Li, X., Qi, X., Jin, Q., Zhang, X., Huang, M., Wang, H., Chen, Y., Bao, C., Hu, J., Liang, S., Bao, L., Wu, T., Zhou, M.,Jiao, Y., 2013. Human antibody neutralizes severe Fever with thrombocytopenia syndrome virus, an emerging hemorrhagic Fever virus. Clin Vaccine Immunol, 20, 1426-1432.
15. Ji, M., Hu, J., Zhang, D., Huang, B., Xu, S., Jiang, N., Chen, Y., Wang, Y., Wu, X.,Wu, Z., 2024. Inhibition of SFTSV replication in humanized mice by a subcutaneously administered anti-PD1 nanobody. EMBO Mol Med, 16, 575-595.
16. Jung, S.I., Kim, Y.E., Yun, N.R., Kim, C.M., Kim, D.M., Han, M.A., Kim, U.J., Kim, S.E., Kim, J., Ryu, S.Y., et al., 2021. Effects of steroid therapy in patients with severe fever with Thrombocytopenia syndrome: A multicenter clinical cohort study. PLoS Negl Trop Dis, 15, e0009128.
17. Kang, S.Y., Yoo, J.R., Park, Y., Kim, S.H., Heo, S.T., Park, S.H., Kim, M., Kim, T.J., Oh, S., Lee, M.S., Kim, J.M., Cho, N.H., Lee, K.M.,Lee, K.H., 2023. Fatal outcome of severe fever with thrombocytopenia syndrome (SFTS) and severe and critical COVID-19 is associated with the hyperproduction of IL-10 and IL-6 and the low production of TGF-β. J Med Virol, 95, e28894.
18. Kim, K.H., Kim, J., Ko, M., Chun, J.Y., Kim, H., Kim, S., Min, J.Y., Park, W.B., Oh, M.D.,Chung, J., 2019. An anti-Gn glycoprotein antibody from a convalescent patient potently inhibits the infection of severe fever with thrombocytopenia syndrome virus. PLoS Pathog, 15, e1007375.
19. Kuchta, K., Cameron, S., Lee, M., Cai, S.Q.,Shoyama, Y., 2022. Which East Asian herbal medicines can decrease viral infections? Phytochem Rev, 21, 219-237.
20. Li, D.,Saldanha, F.J.D., 2008. Clinical Analysis of Acupuncture Combined with Chinese Patent Medicine in the Treatment of Dengue Fever. Practical Traditional Chinese Medicine, 24(09), 553-554.
21. Li, H., Zhang, L.K., Li, S.F., Zhang, S.F., Wan, W.W., Zhang, Y.L., Xin, Q.L., Dai, K., Hu, Y.Y., Wang, Z.B., et al., 2019. Calcium channel blockers reduce severe fever with thrombocytopenia syndrome virus (SFTSV) related fatality. Cell Res, 29, 739-753.
22. Li, Q., Jia, C., Wu, H., Liao, Y., Yang, K., Li, S., Zhang, J., Wang, J., Li, G., Guan, F., Leung, E., Yuan, Z., Hua, Q.,Pan, R.Y., 2022. Nao Tan Qing ameliorates Alzheimer's disease-like pathology by regulating glycolipid metabolism and neuroinflammation: A network pharmacology analysis and biological validation. Pharmacol Res, 185, 106489.
23. Lim, S.,Kaldis, P., 2013. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development, 140, 3079-3093.
24. Liu, S., Liu, H., Kang, J., Xu, L., Zhang, K., Li, X., Hou, W., Wang, Z.,Wang, T., 2020. The Severe Fever with Thrombocytopenia Syndrome Virus NSs Protein Interacts with CDK1 To Induce G(2) Cell Cycle Arrest and Positively Regulate Viral Replication. J Virol, 94, e01575-19. .
25. Lu, Q.B., Zhang, S.Y., Cui, N., Hu, J.G., Fan, Y.D., Guo, C.T., Qin, S.L., Yang, Z.D., Wang, L.Y., Wang, H.Y., Zhang, X.A., Liu, W.,Cao, W.C., 2015. Common adverse events associated with ribavirin therapy for Severe Fever with Thrombocytopenia Syndrome. Antiviral Res, 119, 19-22.
26. Luo, N., Li, M., Xu, M., Shi, C., Shi, X., Ni, R., Chen, Y., Zheng, L., Tu, Y., Hu, D., Yu, C., Li, Q.,Lu, Y., 2023. Research Progress of Fever with Thrombocytopenia Syndrome. Intensive Care Res, 10.1007/s44231-023-00035-6, 1-10.
27. Muhammad, J., Khan, A., Ali, A., Fang, L., Yanjing, W., Xu, Q.,Wei, D.Q., 2018. Network Pharmacology: Exploring the Resources and Methodologies. Curr Top Med Chem, 18, 949-964.
28. Sakaguchi, K., Koga, Y., Yagi, T., Nakahara, T., Todani, M., Fujita, M.,Tsuruta, R., 2019. Severe Fever with Thrombocytopenia Syndrome Complicated with Pseudomembranous Aspergillus Tracheobronchitis in a Patient without Apparent Risk Factors for Invasive Aspergillosis. Intern Med, 58, 3589-3592.
29. Sehgal, A., Mehta, S., Sahay, K., Martynova, E., Rizvanov, A., Baranwal, M., Chandy, S., Khaiboullina, S., Kabwe, E.,Davidyuk, Y., 2023. Hemorrhagic Fever with Renal Syndrome in Asia: History, Pathogenesis, Diagnosis, Treatment, and Prevention. Viruses, 15, 561.
30. Seo, J.W., Kim, D., Yun, N.,Kim, D.M., 2021. Clinical Update of Severe Fever with Thrombocytopenia Syndrome. Viruses, 13, 1213.
31. Singh, S., Numan, A., Sharma, D., Shukla, R., Alexander, A., Jain, G.K., Ahmad, F.J.,Kesharwani, P., 2022. Epidemiology, virology and clinical aspects of hantavirus infections: an overview. Int J Environ Health Res, 32, 1815-1826.
32. Su, W.Y., Lo, H.H., Wen, Y.L., Lu, J.W., Yen, I.C., Ho, Y.J.,Kao, L.T., 2025. Assessing Traditional Chinese Medicines for Anti-Dengue Using a National Health Insurance Research Database and Bioassays. Food Sci Nutr, 13, e70009.
33. Sun, Y., Jin, C., Zhan, F., Wang, X., Liang, M., Zhang, Q., Ding, S., Guan, X., Huo, X., Li, C., Qu, J., Wang, Q., Zhang, S., Zhang, Y., Wang, S., Xu, A., Bi, Z.,Li, D., 2012. Host cytokine storm is associated with disease severity of severe fever with thrombocytopenia syndrome. J Infect Dis, 206, 1085-1094.
34. Suo, T., Wang, H.,Li, Z., 2016. Application of proteomics in research on traditional Chinese medicine. Expert Rev Proteomics, 13, 873-881.
35. Tani, H., Fukuma, A., Fukushi, S., Taniguchi, S., Yoshikawa, T., Iwata-Yoshikawa, N., Sato, Y., Suzuki, T., Nagata, N., Hasegawa, H., Kawai, Y., Uda, A., Morikawa, S., Shimojima, M., Watanabe, H.,Saijo, M., 2016. Efficacy of T-705 (Favipiravir) in the Treatment of Infections with Lethal Severe Fever with Thrombocytopenia Syndrome Virus. mSphere, 1, e00061.-15.
36. Tani, H., Komeno, T., Fukuma, A., Fukushi, S., Taniguchi, S., Shimojima, M., Uda, A., Morikawa, S., Nakajima, N., Furuta, Y.,Saijo, M., 2018. Therapeutic effects of favipiravir against severe fever with thrombocytopenia syndrome virus infection in a lethal mouse model: Dose-efficacy studies upon oral administration. PLoS One, 13, e0206416.
37. Verbeeck, R.K., 2008. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol, 64, 1147-1161.
38. Wang, X., Wang, Z.Y., Zheng, J.H.,Li, S., 2021. TCM network pharmacology: A new trend towards combining computational, experimental and clinical approaches. Chin J Nat Med, 19, 1-11.
39. Wu, Y., Xiong, J., Zhao, X., Mei, Y.,Jiang, H., 2024. Conducted a clinical study on the treatment of acute stage bronchial asthma in children with damp heat syndrome using Ganlu Disinfectant Pill combined with acupoint application. 45(05), 51-53.
40. Yan, C., Niu, Y.,Wang, X., 2022. Blood transcriptome analysis revealed the crosstalk between COVID-19 and HIV. Front Immunol, 13, 1008653.
41. Yang, M., Sheng, Q., Ge, S., Song, X., Dong, J., Guo, C.,Liao, L., 2023. Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients. Front Pediatr, 11, 1077120.
42. Yoo, J.R., Kim, T.J., Heo, S.T., Hwang, K.A., Oh, H., Ha, T., Ko, H.K., Baek, S., Kim, J.E., Kim, J.H., Lee, J., Kang, M.J., Yoo, M.S., Kim, J.M., Lee, K.M.,Lee, K.H., 2021. IL-6 and IL-10 Levels, Rather Than Viral Load and Neutralizing Antibody Titers, Determine the Fate of Patients With Severe Fever With Thrombocytopenia Syndrome Virus Infection in South Korea. Front Immunol, 12, 711847.
43. Zhang, C., Quan, Y., Yang, L., Bai, Y.,Yang, Y., 2022. 6-Methoxyflavone induces S-phase arrest through the CCNA2/CDK2/p21CIP1 signaling pathway in HeLa cells. Bioengineered, 13, 7277-7292.
44. Zhao, L., Zhang, H., Li, N., Chen, J., Xu, H., Wang, Y.,Liang, Q., 2023. Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula. J Ethnopharmacol, 309, 116306.
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