{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T09:51:14Z","timestamp":1780480274335,"version":"3.54.1"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019779","name":"Qatar National Library","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019779","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Vitamin D is a pleiotropic hormone essential for bone health and overall physiological function. Despite its significance, vitamin D deficiency remains widespread and is often influenced by genetic factors. <\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study investigates the role of <jats:italic>SDR42E1<\/jats:italic>, a gene encoding a short-chain dehydrogenase\/reductase enzyme, in vitamin D regulation and sterol metabolism. Using CRISPR\/Cas9 gene-editing, we generated an <jats:italic>SDR42E1<\/jats:italic> knock-in model in HCT116 colorectal cells, which exhibit high endogenous <jats:italic>SDR42E1<\/jats:italic> expression, harboring a nonsense variant associated with vitamin D deficiency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Integrated transcriptomic and proteomic analyses revealed significant dysregulation of sterol absorption and metabolism (fold change (FC) = 1.8, <jats:italic>P<\/jats:italic> = 0.007) and cancer-related signaling pathways (FC = \u22121.7, <jats:italic>P<\/jats:italic> = 0.02). Notably, key differentially expressed genes included upregulated <jats:italic>LRP1B<\/jats:italic> and <jats:italic>ABCC2<\/jats:italic>, alongside downregulated <jats:italic>WNT16<\/jats:italic> and <jats:italic>SLC7A5<\/jats:italic>. Proteomic profiling confirmed alterations in cell proliferation-related proteins, including reduced ALDOA expression (FC = \u22120.37, P = 0.0005). Functionally, <jats:italic>SDR42E1<\/jats:italic> deficiency reduced cell viability by 53% (P = 0.0001), an effect reversed by transient <jats:italic>SDR42E1<\/jats:italic> overexpression with restoring ABCC2 expression. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings establish <jats:italic>SDR42E1<\/jats:italic> as a key modulator of vitamin D-related pathways and highlight its potential as a therapeutic target for addressing vitamin D deficiency and associated pathologies, including cancer.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1585859","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T04:10:43Z","timestamp":1752811843000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["SDR42E1 modulates vitamin D absorption and cancer pathogenesis: insights from an in vitro 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