ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Molecular and Structural Endocrinology
Volume 16 - 2025 | doi: 10.3389/fendo.2025.1585859
This article is part of the Research TopicImpact of New Vitamin D Guidelines on Pediatric and Adult Health: Insights, Evidence, and ImplicationsView all articles
SDR42E1 modulates vitamin D absorption and cancer pathogenesis: insights from an in vitro model
Provisionally accepted
- 1Middle East University, Amman, Jordan
- 2Hamad bin Khalifa University, Doha, Qatar
- 3American University of Beirut, Beirut, Beirut, Lebanon
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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. This study investigates the role of SDR42E1, a gene encoding a short-chain dehydrogenase/reductase enzyme, in vitamin D regulation and sterol metabolism. Using CRISPR/Cas9 gene-editing, we generated an SDR42E1 knock-in model in HCT116 colorectal cells, which exhibit high endogenous SDR42E1 expression, harboring a nonsense variant associated with vitamin D deficiency. Integrated transcriptomic and proteomic analyses revealed significant dysregulation of sterol absorption and metabolism (fold change (FC) = 1.8, P = 0.007) and cancer-related signaling pathways (FC = −1.7, P = 0.02). Notably, key differentially expressed genes included upregulated LRP1B and ABCC2, alongside downregulated WNT16 and SLC7A5. Proteomic profiling confirmed alterations in cell proliferation-related proteins, including reduced ALDOA expression (FC = −0.37, P = 0.0005). Functionally, SDR42E1 deficiency reduced cell viability by 53% (P = 0.0001), an effect reversed by transient SDR42E1 overexpression with restoring ABCC2 expression. These findings establish SDR42E1 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.
Keywords: Vitamin D regulation, SDR42E1, Endocrine disorders, Genetics in Endocrinology, precision medicine
Received: 01 Mar 2025; Accepted: 27 May 2025.
Copyright: © 2025 Hendi and Nemer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Georges Michel Nemer, Hamad bin Khalifa University, Doha, Qatar
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