| Summary: | The integrity of lens epithelial cells (LECs) lays the foundation for lens function and transparency. By contrast, epithelial-mesenchymal transition (EMT) of LECs leads to lens fibrosis, such as anterior subcapsular cataracts (ASC) and fibrotic forms of posterior capsule opacification (PCO). However, the underlying mechanisms remain unclear. Here, we aimed to explore the role of long non-coding RNA (lncRNA) <i>H19</i> in regulating TGF-β2-induced EMT during lens fibrosis, revealing a novel lncRNA-based regulatory mechanism. In this work, we identified that lncRNA H19 was highly expressed in LECs, but downregulated by exposure to TGF-β2. In both human lens epithelial explants and SRA01/04 cells, knockdown of <i>H19</i> aggravated TGF-β2-induced EMT, while overexpressing <i>H19</i> partially reversed EMT and restored lens epithelial phenotypes. Semi-in vivo whole lens culture and <i>H19</i> knockout mice demonstrated the indispensable role of <i>H19</i> in sustaining lens clarity through maintaining LEC features. Bioinformatic analyses further implied a potential <i>H19</i>-centered regulatory mechanism via Smad-dependent pathways, confirmed by in vitro experiments. In conclusion, we uncovered a novel role of <i>H19</i> in inhibiting TGF-β2-induced EMT of the lens by suppressing Smad-dependent signaling, providing potential therapeutic targets for treating lens fibrosis.
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