Autophagy-induced NR2F1 activation promotes the apoptosis of lens epithelial cells and facilitates cataract-associated fibrosis through targeting STAT3.

Cataracts, a widely prevalent ocular pathology, engender visual impairment and emerge as a primary etiological factor contributing to ocular blindness. Substantial evidence substantiates that epithelial-mesenchymal transition stands prominently among the pivotal causative factors associated with this debilitating condition. However, the underlying mechanism remains unclear. In the present study, we analyzed the single-cell data and found that the mRNA expression of nuclear receptor subfamily 2 group F member 1 (NR2F1/COUP-TFI) was notably decreased in fibrocytes compared with epithelium. Interestingly, we observed a significant up-regulation of NR2F1 protein in the anterior subcapsular cataract mice model and transforming growth factor-β1 (TGF-β1)-treated SRA01/04 cells. Furthermore, we found that TGF-β1 stimulation disrupted the balance of autophagy, leading to impaired degradation and increased protein levels of NR2F1 in SRA01/04 cells. Subsequently, after anterior chamber injection of NR2F1 adeno-associated virus in anterior subcapsular cataract mice, the development of fibrosis was alleviated. In vitro, the knockdown of NR2F1 in SRA01/04 also mitigated the TGF-β1-induced epithelial-mesenchymal transition. Mechanically, NR2F1 proteins directly interacted with the promoter region of STAT3 and orchestrated the up-regulation of phosphorylated STAT3 (p-STAT3), thereby facilitating the apoptosis and migration of SRA01/04 cells via the JAK1/STAT3 pathway, resulting in epithelium fibrosis and cataracts. Furthermore, inhibition of p-STAT3 obviously attenuated apoptosis and fibrosis of SRA01/04 cells. Collectively, our study provides a novel therapeutic target for cataracts and offers insight into the underlying mechanism of the epithelial-mesenchymal transition of cataracts.