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Here we identify EphA2 as a critical mediator of pseudorabies virus (PRV)-induced inflammatory response. Genetic or pharmacological inhibition of EphA2 reduced TNF-\u03b1 production in PRV-infected cells and mice, alleviated liver and lung damage, and improved mice survival. Mechanistically, PRV infection promoted EphA2 phosphorylation at Ser-897, which activated NF-\u03baB and MAPK pathways to drive TNF-\u03b1 production. The PRV tegument protein UL40 directly bound the EphA2 kinase domain (residues 697\u2013901), a region that also interacts with Akt. Unexpectedly, Akt acted as a negative regulator of inflammation, as its knockdown exacerbated cytokine production. UL40 competitively disrupted the constitutive EphA2\u2013Akt complex in a time-dependent manner, relieving Akt-mediated restraint on EphA2 S897 phosphorylation. Accordingly, a UL40-deficient PRV mutant failed to enhance S897 phosphorylation, elicited lower inflammatory responses, and showed attenuated virulence in mice. Collectively, our findings reveal a proviral strategy whereby PRV UL40 hijacks EphA2 to counteract an intrinsic Akt-dependent inhibitory pathway. This UL40\u2013EphA2\u2013Akt cascade is a critical determinant of virus-induced inflammation, and EphA2 S897 represents a potential therapeutic target for mitigating alphaherpesvirus immunopathology.<\/jats:p>","DOI":"10.1186\/s13567-026-01829-4","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T14:39:33Z","timestamp":1787668773000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pseudorabies virus pUL40 drives inflammatory signaling through competitive hijacking of EphA2 from the Akt\u2013EphA2 interaction"],"prefix":"10.1186","volume":"57","author":[{"given":"Yutong","family":"Tian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxiang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3094-5059","authenticated-orcid":false,"given":"Rendong","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"1829_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.102022","volume":"44","author":"E Bang","year":"2021","unstructured":"Bang E, Kim DH, Chung HY (2021) Protease-activated receptor 2 induces ROS-mediated inflammation through Akt-mediated NF-\u03baB and FoxO6 modulation during skin photoaging. 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