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This study investigated the therapeutic potential of avanafil (AVA), a selective phosphodiesterase-5 inhibitor (PDE5I), in a lipopolysaccharide (LPS)\u2013induced rat model that mimics inflammation-driven MDD and AIH. LPS administration significantly impaired cognitive behavior, induced depressive-like symptoms, elevated pro-inflammatory cytokines, disrupted gut and blood-brain barrier (BBB) integrity, and caused hepatic dysfunction. AVA treatment markedly improved behavioral performance in the novel object recognition and forced swim test, enhanced zonula occludens-1 (ZO-1) expression, and attenuated LPS-induced elevations of matrix metalloproteinase-9 (MMP-9), interleukin-1\u03b2 (IL-1\u03b2), tumor necrosis factor alpha (TNF-\u03b1), and interleukin-6 (IL-6). Mechanistically, AVA downregulated the TLR4\/NF-\u03baB\/IDO pathway, restored serotonin levels, reduced quinolinic acid accumulation, and activated the Nrf2\/HO-1 signaling cascade in both hippocampal and liver tissues. These findings suggest that AVA exerts neuroprotective and hepatoprotective effects by modulating intestinal permeability, inflammation, and oxidative stress, making it a promising therapeutic candidate for conditions associated with systemic inflammation such as MDD and AIH.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>\n                    Created in BioRender. Elgindy, A. (2026)\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/BioRender.com\/7czd3fv\" ext-link-type=\"uri\">https:\/\/BioRender.com\/7czd3fv<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1007\/s12035-026-05854-4","type":"journal-article","created":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T21:56:34Z","timestamp":1777154194000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Therapeutic Repurposing of Avanafil Against Lipopolysaccharide-induced Depression and Autoimmune Hepatitis: Gut-brain-liver Axis Orchestration Via Regulation of TLR4\/NF-\u03baB\/IDO and Nrf2\/HO-1 Pathways"],"prefix":"10.1007","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3663-5440","authenticated-orcid":false,"given":"Kawther Magdy","family":"Ibrahim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hebatalla I.","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laila A.","family":"Ramadan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amany","family":"Balah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"5854_CR1","doi-asserted-by":"publisher","first-page":"665","DOI":"10.5498\/wjp.v13.i9.665","volume":"13","author":"YH Yang","year":"2023","unstructured":"Yang YH, Cui DJ, Yang ZL, Yuan WQ, Huang B (2023) Immune function, gastrointestinal hormone levels, and their clinical significance in patients with gastric ulcers complicated with depression. 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