Cyp27b1 Deficiency Impairs Ovarian Development Through Disrupted 1,25(OH)2D3 Regulation of Lipid Metabolism and Redox Homeostasis.

Female reproductive disorders are closely associated with ovarian oxidative stress and lipid dysregulation, but the upstream triggers remain poorly defined. In this study, we found that Cyp27b1, a key mitochondrial enzyme that catalyzes the conversion of 25-hydroxyvitamin D3 (25(OH)D3) to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is an important regulator of ovarian lipid homeostasis and redox balance. In the cyp27b1-/- zebrafish model, cyp27b1 deletion impaired ovarian development and caused mitochondrial dysfunction and oxidative stress, all of which were alleviated by exogenous 1,25(OH)2D3 treatment. Lipidomic analysis revealed an abnormal accumulation of triglycerides (TG) and diglycerides (DG) in the knockout group, while phosphatidylcholine (PC) and phosphatidylethanolamine (PE), key membrane lipid components, were significantly reduced, disrupting membrane integrity and energy homeostasis. Dual-luciferase reporter assays showed that 1,25(OH)2D3 increased pnpla2 promoter activity through a predicted vitamin D response element, thereby promoting TG hydrolysis in cyp27b1-/- ovaries. In contrast, insufficient 1,25(OH)2D3 production increased Pparγ expression and promoted abnormal lipid deposition. Exogenous 1,25(OH)2D3 treatment reduced lipid deposition and restored Pparγ and Pnpla2 expression toward normal levels. In conclusion, our findings suggested that Cyp27b1 deficiency impaired ovarian development through lipid overload associated oxidative damage. These results linked impaired Cyp27b1 mediated 1,25(OH)2D3 production to ovarian lipid metabolic disturbance and redox imbalance. Lipid metabolic changes involving pnpla2 and pparγ may represent potential regulatory targets for 1,25(OH)2D3 deficiency associated ovarian pathologies.