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Immunol."],"abstract":"<jats:p>Nuclear receptor subfamily 1 group I member 2 (NR1I2; mouse ortholog Nr1i2), also known as the pregnane X receptor (PXR) or steroid and xenobiotic receptor (SXR), is a ligand-activated transcription factor classically known for its role in xenobiotic metabolism and detoxification. Beyond these canonical functions, accumulating evidence identifies NR1I2 as a key regulator of inflammation and intestinal homeostasis, particularly in inflammatory bowel disease (IBD), where dysregulated inflammatory responses are central to disease pathogenesis and NR1I2 expression is often reduced. In this review, we integrate data from whole-body and tissue-specific Nr1i2-deficient mouse models, as well as knockdown and ligand-based approaches, to define the role of Nr1i2 in intestinal inflammation under basal and pathological conditions. These studies collectively show that whole-body Nr1i2 deficiency disrupts intestinal homeostasis, impairs barrier integrity, and enhances innate immune activation, whereas tissue-restricted deletion, especially within the epithelium, frequently fails to reproduce these phenotypes, underscoring the importance of coordinated Nr1i2 activity across multiple cellular compartments. Across experimental models, most often Nr1i2 deficiency commonly exacerbates intestinal injury, particularly in response to microbial toxins or chemical damage, however attenuated inflammatory responses have been reported in selected metabolic or injury contexts. Conversely, pharmacological activation of Nr1i2 confers protective and restorative effects in a ligand-, tissue-, and context-dependent manner. Together, these findings establish NR1I2 not as a simple anti-inflammatory switch, but as an immune\u2013metabolic integrator that coordinates xenobiotic detoxification, microbial-derived signal sensing, and restraint of innate inflammatory pathways. This review provides a conceptual framework for future studies aimed at elucidating the cell- and context-specific functions of NR1I2 and for guiding the development of targeted therapeutic strategies for intestinal inflammatory disorders.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1761552","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T04:30:30Z","timestamp":1778560230000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Pregnane X receptor (NR1I2) deficiency in mice reveals context-dependent regulation of inflammatory homeostasis"],"prefix":"10.3389","volume":"17","author":[{"given":"Salah Edden","family":"Amini","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo","place":["Oslo, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/s0092-8674(00)80900-9","article-title":"An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway","volume":"92","author":"Kliewer","year":"1998","journal-title":"Cell"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.117.110155","article-title":"PXR: More than just a master xenobiotic receptor","volume":"93","author":"Oladimeji","year":"2018","journal-title":"Mol Pharmacol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.apsb.2019.06.012","article-title":"PXR: a center of transcriptional regulation in cancer","volume":"10","author":"Xing","year":"2020","journal-title":"Acta Pharm Sin B"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-200110000-00003","article-title":"The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants","volume":"11","author":"Zhang","year":"2001","journal-title":"Pharmacogenetics"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2217\/14622416.9.11.1695","article-title":"PXR: a xenobiotic receptor of diverse function implicated in pharmacogenetics","volume":"9","author":"Zhang","year":"2008","journal-title":"Pharmacogenomics"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2016.00456","article-title":"Pregnane X receptor (PXR)-mediated gene repression and cross-talk of PXR with other nuclear receptors via coactivator interactions","volume":"7","author":"Pavek","year":"2016","journal-title":"Front Pharmacol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2174\/138920008783571774","article-title":"Xenobiotic-induced transcriptional regulation of xenobiotic metabolizing enzymes of the cytochrome P450 superfamily in human extrahepatic tissues","volume":"9","author":"Pavek","year":"2008","journal-title":"Curr Drug Metab"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.2174\/1389200054633844","article-title":"Structure and function of the human nuclear xenobiotic receptor PXR","volume":"6","author":"Carnahan","year":"2005","journal-title":"Curr Drug Metab"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.4.6","article-title":"International Union of Pharmacology. 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