{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:51:58Z","timestamp":1790092318399,"version":"4.0.1"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Intestinal ischemia reperfusion (I\/R) injury is a severe condition characterized by inflammation, oxidative stress, and compromised intestinal barrier function, which can lead to death. This study investigated the effects of paricalcitol, a synthetic vitamin D receptor (VDR) agonist, on intestinal I\/R injury, focusing on the activating transcription factor 4 (ATF4)-C\/EBP homologous protein (CHOP) signaling pathway and the modulation of endoplasmic reticulum stress (ERS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study consists of both <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> experiments. <jats:italic>In vivo<\/jats:italic> experiment, a mouse model of intestinal I\/R injury was established by clamping the superior mesenteric artery, and followed by 24 or 72\u00a0h of reperfusion. 6-week-old male C57BL\/6\u00a0J mice were randomly assigned to six groups: sham, I\/R 24h, I\/R 72\u00a0h, and their respective paricalcitol-treated counterparts. VDR knockout mice and wild-type mice were assigned to WT, VDR-KO, WT + I\/R and VDR-KO + I\/R groups. The paricalcitol-treated groups received oral gavage of paricalcitol (0.3\u00a0\u03bcg\/kg) once daily for 5\u00a0days before I\/R. <jats:italic>In vitro<\/jats:italic>, IEC-6 cells were incubated in a microaerophilic system (5% CO<jats:sub>2<\/jats:sub>, 1% O<jats:sub>2<\/jats:sub>, 94% N<jats:sub>2<\/jats:sub>) for 6\u00a0h to induce hypoxia. The cells were then transferred to complete medium with or without paricalcitol (200\u00a0nM) and cultured under normoxic conditions for 24\u00a0h to establish the hypoxia\/re-oxygenation (H\/R) model and investigate the protective effects of paricalcitol on H\/R-induced injury in cells. We further utilized VDR- and ATF4-silenced cells to examine how paricalcitol regulates the expression of VDR, ATF4, and CHOP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrated that protective paricalcitol treatment reduces ERS and apoptosis by activating VDR and inhibiting the ATF4-CHOP pathway, thereby alleviating intestinal I\/R injury <jats:italic>in vivo<\/jats:italic> and H\/R injury <jats:italic>in vitro<\/jats:italic>. Furthermore, experiments with VDR knockout mice demonstrated that the absence of VDR exacerbated I\/R injury, underscoring the protective role of VDR in intestinal epithelial cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings suggest that the protective effects of paricalcitol may offer a promising therapeutic strategy for managing intestinal I\/R injury.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1529343","type":"journal-article","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T05:34:36Z","timestamp":1743658476000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Paricalcitol alleviates intestinal ischemia-reperfusion injury via inhibition of the ATF4-CHOP pathway"],"prefix":"10.3389","volume":"16","author":[{"given":"Jiawei","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongqing","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongzhi","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"109130","DOI":"10.1016\/j.jnutbio.2022.109130","article-title":"Vitamin-D ameliorates sepsis-induced acute lung injury via augmenting miR-149-5p and downregulating ER stress","volume":"110","author":"Ahmad","year":"2022","journal-title":"J. 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