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However, the rapid mutation of viruses often leads to vaccine failure and drug resistance, highlighting the limitations of these conventional methods. Consequently, the development of novel broad-spectrum, host-targeting antiviral strategies has become a major research focus. Itaconate, an endogenous immunomodulatory metabolite, inhibits viral replication via post-translational modifications; however, its mechanism in suppressing viral endocytosis remains unclear. This study demonstrates that itaconate inhibits viral endocytosis by covalently modifying the Cys128 site of the adaptor-related protein complex 1 gamma 1 subunit (AP1G1), thereby providing a new target for host-directed antiviral drug development. It was found that itaconate binds to AP1G1 at Cys128, impairing its interaction with clathrin, which inhibits clathrin-mediated viral particle uptake and reduces cellular susceptibility to infection (i.e., the likelihood of cells being infected by viruses and undergoing infection). Furthermore, the natural product Licochalcone B was identified as targeting the same site as itaconate. In both BEAS-2B cell models and mouse infection models, Licochalcone B reduced pulmonary viral loads by over 95%. This study is the first to propose and validate the feasibility of inhibiting broad-spectrum viral infection by targeting AP1G1, elucidating a novel molecular mechanism of itaconate-mediated regulation, offering a new target for broad-spectrum antiviral drug development, and identifying Licochalcone B as a promising broad-spectrum antiviral agent.<\/jats:p>","DOI":"10.1186\/s43556-025-00348-6","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T09:28:20Z","timestamp":1762766900000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Itaconate reduces viral endocytosis by targeting Cys128 of the adaptor-related protein complex 1 gamma 1 subunit in the host, providing a novel target for antiviral drug development"],"prefix":"10.1186","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7518-4439","authenticated-orcid":false,"given":"Xinqi","family":"Deng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongge","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinling","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luni","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijian","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naixuan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeqing","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muxuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolan","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunguo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"issue":"7830","key":"348_CR1","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1038\/s41586-020-2608-y","volume":"586","author":"N van Doremalen","year":"2020","unstructured":"van Doremalen N, Lambe T, Spencer A, Belij-Rammerstorfer S, Purushotham JN, Port JR, et al. 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