A new study published in Genes & Diseases by researchers from The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University at Xiu Shan, The First Affiliated Hospital of Chongqing Medical University and Affiliated Hospital of North Sichuan Medical College reveals that the loss of the vitamin D receptor (VDR) plays a pivotal role in driving endometrial fibrosis through autophagy-mediated epithelial–mesenchymal transition (EMT).
Through transcriptomic analysis, immunohistochemistry, and western blot assays, the researchers found that VDR expression was markedly reduced in endometrial tissues from IUA patients compared with healthy controls. Functional experiments demonstrated that silencing VDR in endometrial epithelial cells inhibited autophagy and enhanced EMT, as indicated by reduced expression of the epithelial marker CDH1 and increased expression of mesenchymal markers CDH2, COL1, and α-SMA.
Further mechanistic studies identified ATG7 as a direct transcriptional target of VDR. Loss of VDR activated the MAPK/ERK and PI3K/AKT/mTOR signaling pathways, both known to suppress autophagy and promote fibrosis. Conversely, overexpression of VDR restored autophagy and reversed EMT, while treatment with calcitriol (active vitamin D3) produced similar effects, reinforcing the therapeutic potential of vitamin D signaling in IUA.
Animal experiments provided additional confirmation: uterine-specific VDR knockout mice exhibited extensive endometrial fibrosis, decreased autophagy markers (LC3-II, ATG7, LAMP1), and elevated fibrosis markers (p62, CDH2). Notably, treatment with rapamycin, an autophagy activator, mitigated fibrosis, confirming the role of VDR-mediated autophagy in maintaining endometrial homeostasis.
Collectively, these findings demonstrate that VDR deficiency disrupts autophagy and promotes EMT, leading to endometrial fibrosis, and that vitamin D or VDR-targeted therapy may serve as a promising approach for preventing or treating intrauterine adhesion.
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