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However, the mechanisms by which PLpro\u2010mediated immune evasion leads to inflammatory responses are not well understood. In this study, we demonstrate for the first time that PLpro induces inflammation in colonic epithelial cells and colonic inflammation in a mouse model, acting through the ISG15 signaling pathway. Using high\u2010throughput screening, we identified two natural product\u2010derived compounds, coptisine sulfate and (+)\u2010shikonin, that inhibit the interaction between PLpro and ISG15 at the PLpro\/ISG15 interface. We further investigated the mechanism of action of these two inhibitors using surface plasmon resonance, thermal shift assays, molecular docking, and molecular simulation studies. Importantly, both coptisine sulfate and (+)\u2010shikonin were able to reduce intestinal inflammation in the PLpro\u2010induced mouse model. These findings provide novel insights into how the SARS\u2010CoV\u20102 PLpro can drive inflammatory responses and introduce two natural compound\u2010based inhibitors that may offer a new approach to alleviate gastrointestinal complications associated with COVID\u201019 infection. Our results highlight the potential of targeting the PLpro\/ISG15 interaction as a therapeutic strategy against SARS\u2010CoV\u20102.<\/jats:p>","DOI":"10.1002\/jmv.70448","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T10:28:07Z","timestamp":1750069687000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Papain\u2010Like Protease of SARS\u2010CoV\u20102 Induces Intestinal Inflammation via the ISG15 Pathway: Identification of Natural Compound Inhibitors"],"prefix":"10.1002","volume":"97","author":[{"given":"Fang","family":"Wu","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Screening &amp; NMPA Key Laboratory for Research and Evaluation of Drug Metabolism &amp; Guangdong\u2010Hong Kong\u2010Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyong","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qili","family":"Lun","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Screening &amp; 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