Vitamin D–VDR Axis Regulates STAT1/STAT6 Activation and Cytokine Transcription in Cerebral Palsy

Background: The association between cerebral palsy (CP) and systemic immune changes is increasingly evident; however, the molecular mechanisms between metabolic state and T cell activation remain unclear. Vitamin D and its nuclear receptor, vitamin D receptor (VDR), are recognized adaptive immune regulators. This study aimed to investigate whether dysfunction of the vitamin D-VDR axis leads to STAT signaling pathway dysregulation and abnormal cytokine transcription in children with CP.,Methods: This study included 80 children with CP and 32 age-matched healthy controls. Serum levels of 25-hydroxyvitamin D [25(OH)D], circulating VDR protein, and cytokines were detected using enzyme-linked immunosorbent assay (ELISA). VDR and cytokine expression in peripheral blood mononuclear cells (PBMCs) were analyzed using Western blotting and quantitative PCR. Mechanistic studies were conducted in Jurkat T cells treated with 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], with and without siRNA-mediated VDR knockdown. The relevant pathways were identified by detecting the phosphorylation levels of STAT1 and STAT6.,Results: Compared with the control group, serum 25(OH)D levels and VDR expression were significantly decreased in children with cerebral palsy. These changes were accompanied by increased circulating cytokine levels. In PBMCs, decreased VDR expression was associated with increased cytokine expression. In Jurkat T cells, 1,25(OH)₂D₃ upregulated VDR expression and inhibited the phosphorylation of STAT1 and STAT6, resulting in decreased transcription and secretion of both Th1-related cytokines (IFN-γ, IL-2) and Th2-related cytokines (IL-4, IL-10). VDR knockdown enhanced STAT activation and cytokine expression and attenuated the inhibitory effect of vitamin D.,Conclusion: Dysfunction of the vitamin D-VDR axis in cerebral palsy is associated with enhanced STAT1/STAT6 activation and increased cytokine transcription. These findings suggest that the vitamin D-VDR pathway, as a negative regulator of T cell activation, may contribute to the immune dysregulation in cerebral palsy.