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Antiviral strategies that target both viral infection and host pathological responses are urgently needed. Here, we evaluated the antiviral efficacy and underlying mechanisms of sodium copper chlorophyllin (SCC) against PRRSV infection. In vitro analyses demonstrated that SCC exhibited potent and dose\u2010dependent inhibitory activity against both classical and highly pathogenic PRRSV\u20102 strains in Marc\u2010145 cells and immortalized porcine alveolar macrophages (iPAMs). Cotreatment produced the strongest antiviral effect, indicating that SCC primarily targets early stages of viral infection. Mechanistically, SCC directly disrupted viral particle integrity, resulting in viral RNA release and loss of infectivity. In addition, SCC significantly inhibited viral adsorption, internalization, and intracellular genome replication, while exerting no detectable effect on progeny virion release. SCC also reduced the expression of the key PRRSV entry receptor CD163 in porcine macrophages, thereby impairing virus\u2010host interactions. Furthermore, SCC markedly alleviated PRRSV\u2010induced oxidative stress and inflammatory responses by reducing intracellular reactive oxygen species (ROS) and enhancing antioxidant gene expression (heme oxygenase\u20101 [\n                    <jats:italic>HO-1<\/jats:italic>\n                    ], NAD(P)H quinone oxidoreductase 1 [\n                    <jats:italic>NQO1<\/jats:italic>\n                    ], and glutamate\u2013cysteine ligase modifier subunit [\n                    <jats:italic>GCLM<\/jats:italic>\n                    ]), while suppressing proinflammatory cytokines (TNF\u2010\u03b1, IL\u20106, and IL\u20108). Network pharmacology analysis supported the involvement of oxidative stress\u2010 and metabolism\u2010related pathways. Importantly, in a PRRSV challenge model, oral administration of SCC significantly reduced viral loads, alleviated fever, and attenuated lung pathology. Collectively, SCC displays broad antiviral activity through direct virucidal effects, inhibition of early viral entry, and modulation of host responses, highlighting its potential as a therapeutic candidate for PRRSV control.\n                  <\/jats:p>","DOI":"10.1155\/tbed\/6975628","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T09:54:11Z","timestamp":1780394051000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sodium Copper Chlorophyllin Inhibits Porcine Reproductive and Respiratory Syndrome Virus Infection Through Multiple Antiviral Mechanisms"],"prefix":"10.1155","volume":"2026","author":[{"given":"Xinrong","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Rui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0346-0198","authenticated-orcid":false,"given":"Junhai","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5177-3893","authenticated-orcid":false,"given":"Nan","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiyu","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9612-7931","authenticated-orcid":false,"given":"Longxiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3329-8152","authenticated-orcid":false,"given":"Lizhi","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1575-3569","authenticated-orcid":false,"given":"Yue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"e_1_2_10_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2024.110252"},{"key":"e_1_2_10_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.prevetmed.2025.106627"},{"key":"e_1_2_10_3_2","doi-asserted-by":"publisher","DOI":"10.3389\/fvets.2022.1024720"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40813-023-00342-w"},{"key":"e_1_2_10_5_2","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines12121387"},{"key":"e_1_2_10_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines12060606"},{"key":"e_1_2_10_7_2","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines12080942"},{"key":"e_1_2_10_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2025.110745"},{"key":"e_1_2_10_9_2","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2025.2548625"},{"key":"e_1_2_10_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2024.110298"},{"key":"e_1_2_10_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2025.146756"},{"key":"e_1_2_10_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1012915"},{"key":"e_1_2_10_13_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1670488"},{"key":"e_1_2_10_14_2","doi-asserted-by":"publisher","DOI":"10.3389\/fvets.2025.1663508"},{"key":"e_1_2_10_15_2","doi-asserted-by":"publisher","DOI":"10.1080\/10408398.2025.2524471"},{"key":"e_1_2_10_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.0c00096"},{"key":"e_1_2_10_17_2","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms13061189"},{"key":"e_1_2_10_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2025.157689"},{"key":"e_1_2_10_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-025-04112-z"},{"key":"e_1_2_10_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2023.109673"},{"key":"e_1_2_10_21_2","doi-asserted-by":"publisher","DOI":"10.1177\/030098589503200218"},{"key":"e_1_2_10_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01689-22"},{"key":"e_1_2_10_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00513-07"},{"key":"e_1_2_10_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2018.01.004"},{"key":"e_1_2_10_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2021.12.011"},{"key":"e_1_2_10_26_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-animal-022114-111025"},{"key":"e_1_2_10_27_2","first-page":"61","article-title":"In 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