modulates vitamin D absorption and cancer pathogenesis: insights from an model.

INTRODUCTION

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.

METHODS

This study investigates the role of , a gene encoding a short-chain dehydrogenase/reductase enzyme, in vitamin D regulation and sterol metabolism. Using CRISPR/Cas9 gene-editing, we generated an knock-in model in HCT116 colorectal cells, which exhibit high endogenous expression, harboring a nonsense variant associated with vitamin D deficiency.

RESULTS

Integrated transcriptomic and proteomic analyses revealed significant dysregulation of sterol absorption and metabolism (fold change (FC) = 1.8, = 0.007) and cancer-related signaling pathways (FC = -1.7, = 0.02). Notably, key differentially expressed genes included upregulated and , alongside downregulated and . Proteomic profiling confirmed alterations in cell proliferation-related proteins, including reduced ALDOA expression (FC = -0.37, P = 0.0005). Functionally, deficiency reduced cell viability by 53% (P = 0.0001), an effect reversed by transient overexpression with restoring ABCC2 expression.

CONCLUSION

These findings establish 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.