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Although neuronal phospholipid homeostasis is critical for membrane integrity and synaptic function, how ZIKV infection reprograms lipid metabolism to drive neuropathogenesis remains unclear. Here, we identify calcium-independent phospholipase A2\u03b2 (iPLA2\u03b2) as a key mediator of ZIKV-induced neuronal lipid remodeling. iPLA2\u03b2 is rapidly upregulated in neurons and in the neonatal brain following infection, and its expression is promoted by the viral envelope protein, which interacts with iPLA2\u03b2 in neurons. Genetic ablation of iPLA2\u03b2 reduces viral burden in the developing brain and in primary neurons and disrupts ZIKV-induced phospholipid remodeling, characterized by altered arachidonic acid\u2013containing phospholipids and depletion of docosahexaenoic acid-enriched species. Importantly, sustained iPLA2\u03b2 activity promotes phospholipid remodeling that supports efficient ZIKV replication, thereby increasing viral burden and contributing to a pro-inflammatory lipid environment. This is associated with increased prostaglandin E\u2082 production, glial activation, and neuronal loss. Both genetic and pharmacological inhibition of iPLA2\u03b2 partially restores phospholipid homeostasis and reduces viral burden, accompanied by attenuation of neuroinflammatory responses. Functionally, targeting iPLA2\u03b2 improves survival and neurobehavioral outcomes and mitigates long-term cognitive deficits following neonatal ZIKV infection. Collectively, these findings support iPLA2\u03b2-dependent phospholipid remodeling as a host process that facilitates ZIKV replication and links infection to neuroinflammation and neurological injury, highlighting iPLA2\u03b2 as a potential therapeutic target in ZIKV-associated neuropathogenesis.<\/jats:p>","DOI":"10.1186\/s12974-026-03973-2","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T12:37:17Z","timestamp":1784551037000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["iPLA2\u03b2-dependent phospholipid remodeling drives ZIKV-induced neuroinflammation and neurological injury"],"prefix":"10.1186","volume":"23","author":[{"given":"Li","family":"Jiao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sirong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahong","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianyu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dehong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1376-3827","authenticated-orcid":false,"given":"Qiangming","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"3973_CR1","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1038\/s41564-020-0714-0","volume":"5","author":"TC Pierson","year":"2020","unstructured":"Pierson TC, Diamond MS. 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