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Methotrexate (MTX) is prescribed for cancer and inflammation-related disorders; nevertheless, it is exceptionally highly toxic and has multiple kinds of adverse reactions, including pulmonary injury. Our work was designed to demonstrate the ability of etoricoxib (ETO) to mitigate MTX-induced lung injury in experimental animals. Adult male Wistar rats were separated into four groups. The first group consisted of healthy controls that received carboxymethyl cellulose (1 ml\/day, p.o.), the second group received a single dose of MTX (20 mg\/kg\/day, <jats:italic>i.p.<\/jats:italic>), the third group received ETO (10 mg\/kg\/day, p.o.) for three weeks, and the fourth group first received a single MTX (20 mg\/kg, i.p.) and then was treated with ETO for three weeks. Concomitant treatment with ETO and MTX improved the histological structure of the lung tissue. It significantly altered the levels of oxidant\/antioxidant markers, such as malondialdehyde (MDA), heme oxygenase-1 (HO-1), reduced glutathione (GSH), and nuclear factor erythroid 2-related factor 2 (Nrf-2), in favor of antioxidants. Moreover, ETO can normalize the proinflammatory cascade, which includes tumor necrosis factor-alpha (TNF-\u03b1) and interleukin-1 beta (IL-1\u03b2). At the molecular level, ETO downregulated the protein expression of toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-\u03baB), and p38 mitogen-activated protein kinase\u00a0(p38 MAPK) in inflamed rat lungs. In conclusion, our findings indicate that oral administration of ETO ameliorates MTX-induced lung injury by inhibiting oxidative stress and suppressing the TLR4\/NF-\u03baB and TLR4\/p38-MAPK inflammatory signaling pathways.<\/jats:p>","DOI":"10.1007\/s10753-024-02198-w","type":"journal-article","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T23:53:40Z","timestamp":1732665220000},"page":"2407-2416","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Potential Effect of Etoricoxib in Reducing Inflammation in Methotrexate-Induced Pulmonary Injury in Rats: Role of Oxidative Stress and the TLR4\/p38-MAPK\/NF-\u03baB Signaling Pathway"],"prefix":"10.1007","volume":"48","author":[{"given":"Ali M. 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