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Natural products offer promising antiviral candidates, but animal-derived peptides remain underexplored. Here, we identified PI-8, a Periplaneta americana (P. americana)-derived peptide with validated binding to ISG15, and evaluated its anti-FIPV effect and mechanism. PI-8 showed low cytotoxicity (CC50 &gt; 40 \u03bcM) and inhibited FIPV replication with an IC50 of 12.9 \u03bcM, acting primarily at the post-entry stage. PI-8 significantly upregulated IFNA1, IFNB, ISG15, and MX1 in infected CRFK cells. In FIPV-infected cats, PI-8 reduced RNA levels in blood, saliva, and anal swabs, and lowered tissue viral burden in liver, spleen, lung, kidney, and intestine. It also alleviated gross and histopathological lesions and decreased inflammatory cytokine expression. These findings suggest that PI-8 is an P. americana-derived peptide with dual anti-FIPV and immunomodulatory activity associated with an IFN-ISG15-related antiviral response. PI-8 represents a potential host-directed therapeutic candidate for FIPV infection.<\/jats:p>","DOI":"10.3390\/biology15151324","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T09:46:38Z","timestamp":1786009598000},"page":"1324","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Natural Peptide from the American Cockroach Suppresses Feline Infectious Peritonitis Virus"],"prefix":"10.3390","volume":"15","author":[{"given":"Tengyu","family":"Zhu","sequence":"first","affiliation":[{"name":"Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taiyuan 030031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Hou","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taiyuan 030031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Jing","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taiyuan 030031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibo","family":"Wu","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taiyuan 030031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Meng","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taiyuan 030031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruobing","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taiyuan 030031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Yuan","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taiyuan 030031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunchengai","family":"Cao","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taiyuan 030031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyan","family":"Yang","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taiyuan 030031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taiyuan 030031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyin","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taiyuan 030031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taiyuan 030031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaogui","family":"Sun","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taiyuan 030031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6273-9140","authenticated-orcid":false,"given":"Lin","family":"Jin","sequence":"additional","affiliation":[{"name":"Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taiyuan 030031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Vasinioti, V.I., Lucente, M.S., Catella, C., Buonavoglia, C., Decaro, N., Pratelli, A., and Capozza, P. 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