Vitamin D receptor regulates macrophage polarization and cuproptosis via transcriptional activation of ATP7B to mitigate intrauterine adhesion fibrosis.

BACKGROUND: Intrauterine adhesion (IUA) significantly contributes to female infertility, primarily characterized by abnormal fibrotic remodeling of the endometrium. The intricate interplay among various cellular components within the endometrial microenvironment plays a pivotal role in IUA pathophysiology. Among these implicated factors, the vitamin D receptor (VDR) has emerged as a potential regulator of fibrotic processes; however, its specific role and underlying mechanisms in IUA remain inadequately understood. This study aimed to investigate the role of VDR in IUA pathogenesis and its impact on endometrial macrophage behavior. METHODS: To investigate VDR's role in IUA, we conducted a comprehensive analysis of clinical endometrial samples from patients diagnosed with IUA. Complementary to this, we performed in vitro experiments using bone marrow-derived macrophages (BMDMs) obtained from both wild-type (WT) and VDR conditionnal knockout (VDR-cKO) mice. Furthermore, in vivo studies were carried out using an IUA mouse model alongside VDR-cKO mice to assess the physiological relevance of our findings. RESULTS: Our investigation revealed a marked reduction in VDR expression within endometrial macrophages from IUA patients. In vitro assessments indicated that VDR deficiency led to enhanced pro-inflammatory M1 polarization, evidenced by increased level of iNOS and decreased CD206 in BMDMs. Mechanistically, VDR conditional knockout was found to induce cuproptosis, characterized by downregulation of ATP7B and upregulation of DLAT. Additionally, we demonstrated that VDR transcriptionally activates ATP7B expression, with luciferase reporter assays confirming VDR's direct binding to the ATP7B promoter. In vivo experiments further established that macrophage-specific VDR knockout intensified endometrial fibrosis, heightened M1 polarization, and increased cuproptosis in the IUA mouse model, while administration of a VDR agonist effectively reversed these phenotypic alterations. CONCLUSION: Our findings reveal a novel mechanistic pathway by which macrophage-specific VDR deficiency exacerbates IUA pathogenesis through dysregulation of the ATP7B-cuproptosis axis and promotion of profibrotic M1-like macrophage polarization. These insights suggest that VDR agonism may represent a promising therapeutic approach for the prevention and treatment of IUA, warranting further investigation into its clinical applicability.