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Here, we demonstrate that\n                    <jats:italic>lyssavirus<\/jats:italic>\n                    N proteins induce LD biogenesis by upregulating glycerol\u20103\u2010phosphate acyltransferase 4 (GPAT4) expression and promoting its translocation to the LD surface, a conserved mechanism across the\n                    <jats:italic>lyssavirus<\/jats:italic>\n                    genus. Mechanistically, GPAT4\u2010mediated LD formation sequesters free fatty acids, leading to acyl\u2010protein thioesterase 1 (APT1)\u2010dependent depalmitoylation of NADH\u2010cytochrome B5 reductase 1 (CYB5R1) at Cys208 and Cys278. This post\u2010translational modification triggers autophagic degradation of CYB5R1, thereby impairing its ability to induce ferroptosis via two complementary pathways: nuclear receptor co\u2010activator 4 (NCOA4)\u2010mediated ferritinophagy and H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    production. Conversely, diacylglycerol O\u2010acyltransferase (DGAT) inhibitors or GPAT4 knockdown restores CYB5R1 palmitoylation and stability, reinstates ferroptosis, and suppresses RABV infection. Our findings reveal a novel \u201c\n                    <jats:italic>lyssavirus<\/jats:italic>\n                    N\u2010GPAT4\u2010LD\u2010CYB5R1 palmitoylation\u201d axis that modulates ferroptosis susceptibility, highlighting protein palmitoylation as a critical regulatory node in virus\u2010host interactions and identifying GPAT4 as a potential antiviral target.\n                  <\/jats:p>","DOI":"10.1002\/advs.77672","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:35:56Z","timestamp":1789018556000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lyssavirus Nucleoprotein Induces GPAT4\u2010Mediated CYB5R1 Depalmitoylation to Suppress Ferroptosis and Promote Viral Replication"],"prefix":"10.1002","author":[{"given":"Jianqing","family":"Zhao","sequence":"first","affiliation":[{"name":"National Key Laboratory of Agricultural Microbiology Huazhong Agricultural 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Laboratory of Preventive Veterinary Medicine of Hubei Province College of Veterinary Medicine Huazhong Agricultural University  Wuhan China"},{"name":"Frontiers Science Center for Animal Breeding and Sustainable Production  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0569-8105","authenticated-orcid":false,"given":"Ling","family":"Zhao","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Agricultural Microbiology Huazhong Agricultural University  Wuhan China"},{"name":"Key Laboratory of Preventive Veterinary Medicine of Hubei Province College of Veterinary Medicine Huazhong Agricultural University  Wuhan China"},{"name":"Frontiers Science Center for Animal Breeding and Sustainable Production  Wuhan China"},{"name":"Hubei Hongshan Laboratory  Wuhan 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