Abstract: | Received: 21 July 2020 | Revised: 31 August 2020 Accepted: 7 September 2020 DOI: 10.1002/jcp.30055 ORIGINAL RESEARCH ARTICLE Quantitative proteomics reveals a broad‐spectrum antiviral property of ivermectin, benefiting for COVID‐19 treatment Na Li1,2,3 | Lingfeng Zhao4 1 University Creative Research Initiatives Center, Shandong First Medical University, Jinan, Shandong, China | Xianquan Zhan1,2,3,5,6 Abstract Viruses such as human cytomegalovirus (HCMV), human papillomavirus (HPV), 2 Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China 3 State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan, China 4 Epstein–Barr virus (EBV), human immunodeficiency virus (HIV), and coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2]) represent a great burden to human health worldwide. FDA‐approved anti‐parasite drug ivermectin is also an antibacterial, antiviral, and anticancer agent, which offers more potentiality to improve global public health, and it can effectively inhibit the replication of Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sothern Medical University, Tianhe, Guangzhou, Guangdong, China SARS‐CoV‐2 in vitro. This study sought to identify ivermectin‐related virus infection 5 ovarian cancer cells TOV‐21G treated with and without ivermectin (20 μmol/L) for Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China 6 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China pathway alterations in human ovarian cancer cells. Stable isotope labeling by amino acids in cell culture (SILAC) quantitative proteomics was used to analyze human 24 h, which identified 4447 ivermectin‐related proteins in ovarian cancer cells. Pathway network analysis revealed four statistically significant antiviral pathways, including HCMV, HPV, EBV, and HIV1 infection pathways. Interestingly, compared with the reported 284 SARS‐CoV‐2/COVID‐19‐related genes from GencLip3, we Correspondence Xianquan Zhan, University Creative Research Initiatives Center, Shandong First Medical University, 6699 Qingdao Rd, Jinan, 250117 Shandong, China. Email:yjzhan2011@gmail.com identified 52 SARS‐CoV‐2/COVID‐19‐related protein alterations when treated with and without ivermectin. Protein–protein network (PPI) was constructed based on the interactions between 284 SARS‐CoV‐2/COVID‐19‐related genes and between 52 SARS‐CoV‐2/COVID‐19‐related proteins regulated by ivermectin. Molecular complex detection analysis of PPI network identified three hub modules, including Funding information Hunan Provincial Hundred Talent Plan (to X.Z.); Shandong First Medical University Talent Introduction Funds (to X.Z.) cytokines and growth factor family, MAP kinase and G‐protein family, and HLA class proteins. Gene Ontology analysis revealed 10 statistically significant cellular components, 13 molecular functions, and 11 biological processes. These findings demonstrate the broad‐spectrum antiviral property of ivermectin benefiting for COVID‐19 treatment in the context of predictive, preventive, and personalized medicine in virus‐related diseases. KEYWORDS ivermectin, quantitative proteomics, SARS‐CoV‐2/COVID‐19, stable isotope labeling by amino acids in cell culture, virus‐related..