1,25(OH)2D3/VDR Alleviates Cuprotosis of Pancreatic β Cells by Mediating Histone Lactylation

Background: Diabetes represents a significant global health challenge and poses a serious threat to human wellbeing. 1,25(OH)2D3 (vitamin D, VD) has been recognized for its anti-diabetic effects. Nevertheless, it is still unknown how 1,25-dihydroxyvitamin D3 (1,25D) prevents Type 2 diabetes mellitus (T2DM).MethodsCuCl2 was used to induce the pancreatic β-cell lines MIN6 and EndoC-βH1. To accomplish knockdown, these β-cells were then transfected with siRNA that targeted FDX1. The amount of insulin released was measured using an enzyme-linked immunosorbent assay (ELISA). To assess the cuprotosis process, concentrations of copper (Cu), pyruvate acid (PA), and α-ketoglutarate dehydrogenase (α-KG) were evaluated. Cell viability was also evaluated using an assay called the Cell Counting Kit 8 (CCK-8). The expression of FDX1, vitamin D receptor (VDR), and histone lactylation was measured using western blotting. The enrichment of histone lactylation on FDX1 and FDX1 promoter activity was determined using chromatin immunoprecipitation (ChIP) and luciferase reporter gene assays. ResultsInduction of cuprotosis in pancreatic β-cells significantly suppressed cell viability and insulin secretion, simultaneously reduced α-KG and PA levels, and elevated RNA level of FDX1. VD3 treatment promotes viability and represses cuprotosis in pancreatic β-cells. VD3 treatment up-regulated insulin secretion in MIN6 cells, whereas VDR knockdown abolished this effect. VD3 notably upregulated VDR and downregulated FDX1, which was abolished by VDR knockout (VDR-KO). VD3 reduced histone lactylation of FDX1 and its promoter activity, consequently suppressing FDX1 expression.Conclusion The VD3/VDR axis can alleviate the cuprotosis of pancreatic β-cells by regulating the histone lactylation of FDX1.