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Here we show GPR35\u2019s critical role in ion flux that in turn controls cellular osmotic pressure and Na<jats:sup>+<\/jats:sup>-dependent transport in HepG2 and SW480 cells. GPR35 deficiency results in increased levels of intracellular Na<jats:sup>+<\/jats:sup>, osmotic stress and changes in osmolytes leading to increased cells size and decreased glutamine import in vitro and in vivo. The GPR35-T108M risk variant, which increases risk for primary sclerosing cholangitis and inflammatory bowel disease, leads to lower intracellular Na<jats:sup>+<\/jats:sup> levels, and enhanced glutamine uptake. High salt diet (HSD) in wildtype mice resembles the intestinal epithelial phenotype of their <jats:italic>Gpr35<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup> littermates with decreased Goblet cell size and numbers. This indicates that GPR35\u2019s regulation of the Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>-ATPase controls ion homeostasis, osmosis and Na<jats:sup>+<\/jats:sup>-dependent transporters.<\/jats:p>","DOI":"10.1038\/s42003-025-07848-9","type":"journal-article","created":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T07:24:19Z","timestamp":1742628259000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["GPR35 prevents osmotic stress induced cell damage"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2137-117X","authenticated-orcid":false,"given":"Joshua E.","family":"Elias","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6659-2106","authenticated-orcid":false,"given":"Mekdes","family":"Debela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin W.","family":"Sewell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0054-7503","authenticated-orcid":false,"given":"Richard J.","family":"Stopforth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Partl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5288-5221","authenticated-orcid":false,"given":"Sophie","family":"Heissbauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6123-9574","authenticated-orcid":false,"given":"Lorraine M.","family":"Holland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8289-9931","authenticated-orcid":false,"given":"Tom H.","family":"Karlsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1419-3344","authenticated-orcid":false,"given":"Arthur","family":"Kaser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6079-4389","authenticated-orcid":false,"given":"Nicole C.","family":"Kaneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,22]]},"reference":[{"key":"7848_CR1","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1159\/000168759","volume":"14","author":"M Cirillo","year":"1994","unstructured":"Cirillo, M., Capasso, G., Di Leo, V. 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