SDR42E1 modulates Vitamin D absorption and cancer pathogenesis

Summary

1 IntroductionVitamin D is a vital fat-soluble nutrient crucial for calcium and phosphorus homeostasis, bone health, and immune function. Despite the availability of dietary sources and sunlight exposure (1), deficiencies can arise due to impaired absorption and metabolism. These processes are orchestrated by a network of critical proteins, like ATP-binding cassette B member 2 (ABCB2) and solute carrier family proteins, including SLC7A5 (2, 3). In circulation, vitamin D binds to vitamin D-binding protein (VDBP) and undergoes hydroxylation in the liver by cytochrome P450 enzymes such as CYP2R1, CYP11A1, and CYP27A1, which hydroxylate vitamin D, followed by activation in the kidney by CYP27B1. The vitamin D receptor (VDR) mediates its biological effects, while CYP24A1 regulates its inactivation (4). Both VDR and CYP24A1 influence these processes, although key mechanistic gaps remain incompletely understood (5).Short-chain Dehydrogenase/Reductase 42E member 1 (SDR42E1), a member of the short-chain dehydrogenase/reductase enzyme family plays a potentially significant role in lipid and steroid metabolism (6–8), potentially functioning as an oxidoreductase and steroid delta-isomerase (9, 10). The largest genome-wide association study (GWAS) on vitamin D deficiency (11), identified a nonsense variant (rs11542462) on chromosome 16q23 that replaces glutamine with a termination codon at position 30 (p.Q30*), producing a truncated, non-functional SDR42E1 enzyme (12–14). Interestingly, this variant correlates with elevated serum levels of 8-dehydrocholesterol (8-DHC) and 7-dehydrocholesterol (7-DHC), precursors in vitamin D synthesis (15). Lately, our in silico studies identified these sterols, along with vitamin D3 and 25-hydroxyvitamin D (25(OH)D), as potential substrates of the SDR42E1 (9); however, its precise role in vitamin D metabolism remains unclear.Our recent research, utilizing clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRI...