{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T05:02:01Z","timestamp":1784869321624,"version":"3.55.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Restraint stress is known to induce damage to vital organs. Previous work indicates that acute restraint stress (ARS) causes significant hepatic injury in mice. Interestingly, while the liver gradually recovered following removal of the stressor, stress-induced behavioral abnormalities persisted for up to 7 days after stress cessation. Soluble epoxide hydrolase (sEH) plays a key regulatory role in neuroinflammation and mood disorders. However, whether and how hepatic sEH upregulation contributes to ARS-induced neurological damage remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In a mouse model of ARS, behavioral tests were used to assess neurological impairment. Hepatic function was evaluated by blood flow measurement, metabolomics, and serum ALT\/AST levels. Hepatic sEH expression was examined by IHC and western blot, and EETs and IL\u20116 were quantified with biochemical kits. Microglial activation and neuronal injury in the hypothalamus were assessed by IHC, and IL\u20116 expression in hypothalamic neurons was visualized by immunofluorescence double staining.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Restraint stress-induced behavioral abnormalities in mice. These abnormalities persisted for at least 7 days and were accompanied by reduced hepatic blood flow, liver injury, and perturbation of arachidonic acid metabolism. Stress markedly upregulated hepatic sEH expression, decreased epoxyeicosatrienoic acids (EETs), and increased interleukin-6 (IL-6). In the hypothalamus, sEH expression was elevated, microglia exhibited M1-type activation (CD86+), and neuronal loss occurred, while IL-6 levels within hypothalamic neurons was increased. Treatment with the sEH inhibitor TPPU significantly ameliorated stress-induced behavioral abnormalities, liver injury, hypothalamic neuroinflammation, and the abnormal intraneuronal increase of IL-6.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings reveal that ARS elicits behavioral abnormalities via the liver\u2013brain axis mediated by hepatic sEH upregulation, which reduces EETs and promotes IL-6 release, leading to hypothalamic microglial activation and subsequent neuronal injury. These results identify hepatic sEH as a potential therapeutic target and highlight the liver\u2013brain axis as a critical mediator in ARS-induced behavioral abnormalities and neurological damage.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1895669","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T04:22:53Z","timestamp":1784866973000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatic sEH drives stress-induced neuroinflammation via IL-6 and liver-brain axis"],"prefix":"10.3389","volume":"17","author":[{"given":"Shuoqi","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Forensic Medicine, Hebei North University","place":["Zhangjiakou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine, Hebei North 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