{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T05:07:42Z","timestamp":1788584862957,"version":"build-2803163510"},"reference-count":52,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100016047","name":"Science Fund of the Republic of Serbia","doi-asserted-by":"publisher","award":["6999"],"award-info":[{"award-number":["6999"]}],"id":[{"id":"10.13039\/501100016047","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Chronic endoplasmic reticulum (ER) stress and increased apoptosis are involved in the pathogenesis of glycogen storage disease Ib (GSD Ib), whereas small molecule phenylbutyrate (4\u2010PBA) showed the capability of reducing ER stress\u2010induced apoptosis. The objective was to generate an in\u00a0vitro system in which capability of small molecules (SMs) to influence ER stress and apoptosis could be screened at the expression level.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>G6PT\u2010deficient FlpInHEK293 cell line was created and validated using the CRISPR\/Cas9 knockout method. Molecular markers of unfolded protein response (<jats:italic>ATF4<\/jats:italic>, <jats:italic>DDIT3<\/jats:italic>, <jats:italic>HSPA5<\/jats:italic>, <jats:italic>XBP1s<\/jats:italic>), and apoptosis (<jats:italic>BCL2<\/jats:italic>\/<jats:italic>BAX<\/jats:italic>, <jats:italic>CASP3<\/jats:italic>, <jats:italic>CASP7<\/jats:italic>) in G6PT\u2010deficient cells were analyzed using RT\u2010qPCR method before and upon the treatment with 4\u2010PBA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Treatment with the most effective dose of 1\u2009mM 4\u2010PBA reduced the expression of UPR markers and executioner caspases, while increased <jats:italic>BCL2<\/jats:italic>\/<jats:italic>BAX<\/jats:italic> ratio in G6PT\u2010deficient cells. Our results proved the concept that 4\u2010PBA could alleviate markers of ER stress detected in the GSD Ib in\u00a0vitro model system and prevent cell death.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This cost\u2010effective in\u00a0vitro model screens the therapeutic potential of SMs affecting ER stress and apoptosis in G6PT\u2010deficient kidney cells, offering a first\u2010line screening assay for promising compounds. 4\u2010PBA's potential repurposing for GSD Ib patients opens new research directions.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.70054","type":"journal-article","created":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T10:59:00Z","timestamp":1736765940000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Phenylbutyric Acid Modulates Apoptosis and <scp>ER<\/scp> Stress\u2010Related Gene Expression in Glycogen Storage Disease Type Ib In\u00a0Vitro 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