Functional characterization of the SDR42E1 reveals its role in vitamin D biosynthesis

Vitamin D deficiency poses a widespread health challenge, shaped by environmental and genetic determinants. A recent discovery identified a genetic regulator, rs11542462, in the SDR42E1 gene, though its biological implications remain largely unexplored. Our bioinformatic assessments revealed pronounced SDR42E1 expression in skin keratinocytes and the analogous HaCaT human keratinocyte cell lines, prompting us to select the latter as an experimental model. Employing CRISPR/Cas9 gene-editing technology and multi-omics approach, we discovered that depleting SDR42E1 showed a 1.6-fold disruption in steroid biosynthesis pathway (P-value = 0.03), considerably affecting crucial vitamin D biosynthesis regulators. Notably, SERPINB2 (P-value = 2.17 × 10⁻¹⁰³), EBP (P-value = 2.46 × 10⁻¹³), and DHCR7 (P-value = 8.03 × 10⁻⁰⁹) elevated by ∼2–3 fold, while ALPP (P-value <2.2 × 10⁻³⁰⁸), SLC7A5 (P-value = 1.96 × 10⁻²¹⁵), and CYP26A1 (P-value = 1.06 × 10⁻⁰⁸) downregulated by ∼1.5–3 fold. These alterations resulted in accumulation of 7-dehydrocholesterol precursor and reduction of vitamin D₃ production, as evidenced by the drug enrichment (P-value = 4.39 × 10⁻⁰⁶) and total vitamin D quantification (R² = 0.935, P-value = 0.0016) analyses. Our investigation unveils SDR42E1's significance in vitamin D homeostasis, emphasizing the potential of precision medicine in addressing vitamin D deficiency through understanding its genetic basis.