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Vitamin D receptor (VDR) is extensively expressed in the lung, and the disrupted vitamin D\/VDR axis may underlie various lung disorders. Therefore, the current study intended to explore the beneficial impact of paricalcitol, a VDR activator, on amiodarone-provoked lung injury and elucidate its possible involved molecular mechanisms. Male Wistar rats were intraperitoneally injected with paricalcitol (0.2 \u00b5g\/kg) and orally administered amiodarone (40 mg\/kg) once daily for four\u00a0weeks. Our findings revealed that paricalcitol diminished BALF leucocyte count and total protein, serum LDH activity, and pulmonary histopathological changes and counteracted pulmonary oxidative stress. Moreover, paricalcitol decreased pulmonary toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-\u03baB) p65, tumor necrosis factor alpha (TNF-\u03b1), transforming growth factor-beta 1 (TGF-\u03b21), and phosphorylated small mothers against decapentaplegic 3 (pSmad 3) levels in line with less lung fibrosis percentage. Interestingly, these results were accompanied by suppressed hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) lung expression. Taken together, paricalcitol protected against amiodarone-induced lung damage in rats through antioxidant, anti-inflammatory, and antifibrotic activities.<\/jats:p>","DOI":"10.1007\/s00210-025-04568-z","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T08:37:09Z","timestamp":1760431029000},"page":"4067-4081","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Attenuating amiodarone-induced lung toxicity by the vitamin D receptor activator paricalcitol in rats: targeting TLR4\/NF-\u03baB\/HIF-1\u03b1 and TGF-\u03b2\/Smad signaling pathways"],"prefix":"10.1007","volume":"399","author":[{"given":"Aamal G.","family":"El-Waseif","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Elshal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalia H.","family":"El-Kashef","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nashwa M.","family":"Abu-Elsaad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"4568_CR1","doi-asserted-by":"publisher","first-page":"251","DOI":"10.21608\/asmj.2021.192511","volume":"72","author":"AM Abood","year":"2021","unstructured":"Abood AM, Awad HEA, Hassan SM (2021) Potential role of vitamin D receptor agonist in acetaminophen-induced hepatic injury: role of caspase-1. 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