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This study aimed to elucidate the mechanisms underlying TRM-induced lung injury and to investigate the potential protective role of rutin (RUT), a bioactive flavonoid with potent antioxidant and anti-inflammatory properties. In a rat model, lung tissues were analyzed using histopathological examination, biochemical assays for oxidative stress parameters, RT-qPCR for gene expression analysis [nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), nuclear factor kappa B (NF-\u03baB), tumor necrosis factor alpha (TNF-\u03b1), inducible nitric oxide synthase (iNOS), Bax, Bcl-2, and Caspase-3], and immunohistochemical (IHC) evaluation of Beclin-1 and 3-nitrotyrosine (3-NT) expression. TRM administration caused severe pulmonary structural alterations, including alveolar collapse, interalveolar septal thickening, inflammatory infiltration, edema, and hemorrhage. These histopathological changes were associated with pronounced oxidative stress, as evidenced by suppressed superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, depletion of glutathione (GSH), increased lipid peroxidation, and disruption of the Nrf2\/HO-1\/NQO1 antioxidant signaling axis. Furthermore, TRM markedly activated endoplasmic reticulum (ER) stress responses (PERK and ATF-6), upregulated apoptotic markers (Bax and Caspase-3), downregulated Bcl-2 expression, and enhanced autophagy-related Beclin-1 immunoreactivity. In parallel, significant activation of inflammatory and nitrosative pathways was observed, characterized by elevated NF-\u03baB, TNF-\u03b1, and iNOS expression and increased nitrotyrosine accumulation. In contrast, RUT treatment substantially ameliorated TRM-induced lung injury by restoring antioxidant capacity, suppressing ER stress-mediated apoptosis and autophagy, and attenuating inflammatory and nitrosative responses. Overall, these findings demonstrate that RUT confers significant protection against TRM-induced pulmonary toxicity through coordinated modulation of oxidative stress, ER stress, apoptosis, autophagy, and inflammation.<\/jats:p>","DOI":"10.1007\/s00210-026-05314-9","type":"journal-article","created":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T04:13:59Z","timestamp":1776485639000},"page":"15013-15025","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Rutin attenuates Tramadol-induced lung injury in rats by modulating oxidative stress, inflammation, endoplasmic reticulum stress, and apoptosis"],"prefix":"10.1007","volume":"399","author":[{"given":"Mustafa \u00d6nder","family":"G\u00f6nen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nurhan","family":"Akaras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasan","family":"\u015eim\u015fek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6zge","family":"Kandemir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuneyt","family":"Caglayan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00fcseyin","family":"Mutlu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatih Mehmet","family":"Kandemir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,18]]},"reference":[{"key":"5314_CR1","doi-asserted-by":"crossref","unstructured":"Aebi H 1984 [13] Catalase in vitro. 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