Angelica Sinensis Polysaccharide Suppresses Epithelial-Mesenchymal Transition and Pulmonary Fibrosis via a DANCR/AUF-1/FOXO3 Regulatory Axis

Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of lung fibroblasts and extracellular matrix deposition. Angelica sinensis polysaccharide (ASP), the major bioactive component that can extracted from roots of angelica, plays functional roles in immunomodulation, anti-tumor activity, and hematopoiesis. Emerging evidence has suggested that long noncoding RNAs (lncRNAs) play important roles in pathophysiological processes in various diseases. However, the roles of lncRNAs and ASP in IPF remain poorly understood. In the present study, we investigated the effects of ASP in IPF, as well as their functional interactions with lncRNA DANCR (differentiation antagonizing non-protein coding RNA). IPF models were established by treating Sprague-Dawley rats with BLM and treating alveolar type Ⅱ epithelial (RLE-6TN) cells with TGF-β1. Our results showed that ASP treatment suppressed pulmonary fibrosis in rats and fibrogenesis in RLE-6TN cells. The lncRNA DANCR is downregulated after ASP treatment in both rat lung tissues and RLE-6TN cells, and DANCR overexpression dramatically reversed the suppressive effects of ASP in IPF. Mechanistically, DANCR directly binds with AUF1 (AU-binding factor 1), thereby upregulating FOXO3 mRNA and protein levels. Moreover, overexpression of AUF1 or FOXO3 reversed the functional effects induced by ASP treatment. In conclusion, our findings showed that DANCR mediates ASP-induced suppression of IPF via upregulation of FOXO3 protein levels in an AUF1-dependent manner. Therefore, DANCR could serve as a promising therapeutic target in IPF treatment with ASP.