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Aprepitant (Ap), a neurokinin-1 receptor (NK-1R) antagonists, is an antiemetic commonly used in preventing chemotherapy-induced nausea and vomiting. This study aimed to evaluate the potential protective effect of Ap against acute lung injury (ALI) associated with HIR, utilizing the Pringle maneuver to induce 30\u00a0min of hepatic ischemia followed by 1\u00a0h of reperfusion, while targeting the NLRP3\/IL-1\u03b2 signaling pathway. Serum alanine transaminase (ALT), aspartate transaminase (AST), Lung malondialdehyde (MDA), total antioxidant capacity (TAC), reduced glutathione (GSH), tumor necrosis factor-alpha (TNF-\u03b1), caspase-3 levels, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)\u00a0inflammasome, cleaved caspase-3 expressions were evaluated. Hepatic and lung specimens were evaluated histopathologically and an immunohistochemical study of lung interlukin 1beta (IL-1\u03b2) was also performed. HIR caused hepatic and lung damage as shown histopathologically and by an increase in serum ALT, AST and lung IL-1\u03b2. A significant increase in lung MDA, TNF-\u03b1, caspase-3 levels, NLRP3 and cleaved caspase-3 expressions and decrease in TAC and GSH parameters were detected. Ap significantly ameliorated the oxidative stress, inflammatory, and apoptotic parameters, and this was accompanied by a significant improvement in the histopathological findings with reduction in lung IL-1\u03b2. Targeting the NLRP3\/IL-1\u03b2 signaling pathway, as shown by Ap in our murine model, could reveal a promising therapeutic approach to protect against ALI during major liver surgeries.<\/jats:p>","DOI":"10.1038\/s41598-025-25930-4","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T10:18:49Z","timestamp":1763461129000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Aprepitant alleviates acute lung injury in a rat model of hepatic ischemia\u2013reperfusion via NLRP3\/IL-1\u03b2 signaling pathway"],"prefix":"10.1038","volume":"15","author":[{"given":"Walaa Yehia","family":"Abdelzaher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina T.","family":"Kelleni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0292-419X","authenticated-orcid":false,"given":"Marly Nady","family":"Adly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina Ezzat","family":"Attya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Atef","family":"Fawzy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed A.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"issue":"5","key":"25930_CR1","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1111\/liv.14091","volume":"39","author":"WA Dar","year":"2019","unstructured":"Dar, W. 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A Permission was received from the Study Ethics Committee of the Faculty of Medicine, Minia University (Approval number:\n                      585\/2022\n                      ) to the protocol of our experiment, and all methods were done in accordance with the relevant scientific guidelines and regulations. The current study also complies with ARRIVE guidelines.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"All authors have seen and approved the content and fulfil the journal\u2019s requirements for authorship.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"40358"}}