NR2F1 and STAT3: Unraveling the Mechanisms of Fibrotic Cataract Formation

Cataracts, a leading cause of vision impairment worldwide, can often necessitate surgical intervention to restore eyesight. Despite these measures, many patients experience the development of anterior subcapsular cataracts (ASC), which are marked by the growth of fibrotic tissue beneath the lens capsule. This complication is primarily attributed to epithelial-mesenchymal transition (EMT), a biological process whereby lens epithelial cells acquire migratory and fibrotic characteristics. Recent research has shed light on the molecular mechanisms involved, particularly the role of the transcription factor NR2F1 in promoting fibrotic cataract formation via the activation of the STAT3 signaling pathway.

The study, conducted by researchers at Chongqing Medical University and Chongqing General Hospital, was published on January 28, 2025, in *Genes & Diseases*. The findings reveal that NR2F1 facilitates fibrosis by directly activating the STAT3 pathway, a crucial driver of cellular processes linked to fibrosis and apoptosis. These insights stem from investigations into the effects of transforming growth factor-beta (TGF-β), which has long been recognized as a contributor to EMT in various tissues. However, the downstream molecular mechanisms had remained poorly understood until now.

According to Professor Wenjuan Wan, the senior author of the study, "Our research uncovers a critical link between autophagy dysfunction and fibrotic cataract formation. By identifying NR2F1 as a direct activator of the STAT3 pathway, we have revealed a powerful mechanism that fuels lens fibrosis and cell death. The translational potential of these findings is significant, as targeting this pathway could lead to non-surgical therapies addressing the root molecular causes of lens opacification."

The researchers confirmed elevated NR2F1 protein levels in cataract-affected lens tissues and TGF-β1-stimulated human lens epithelial cells. Interestingly, while mRNA levels of NR2F1 decreased, protein levels increased, indicating post-transcriptional dysregulation. This phenomenon was attributed to impaired autophagy, a cellular cleanup process essential for maintaining cellular health. When autophagy was inhibited, NR2F1 protein levels rose significantly, mimicking the effects of TGF-β1.

Functional experiments demonstrated that silencing NR2F1 led to a marked suppression of the EMT process, with reduced expression of fibrotic markers such as FN1, VIM, and α-SMA, alongside decreased cell migration and apoptosis. In mouse models of ASC, injecting NR2F1-silencing adeno-associated virus (AAV) resulted in visibly clearer lenses and a reduction in fibrotic plaques.

Mechanistically, the study provided evidence that NR2F1 binds directly to the promoter of STAT3, instigating its phosphorylation and subsequent activation. The significance of this interaction was further validated using a p-STAT3 inhibitor, which successfully reduced markers associated with fibrosis and apoptosis.

The implications of these findings are substantial, as they indicate that the NR2F1-STAT3 axis plays a pivotal role in fibrotic cataract formation. Current therapeutic strategies predominantly focus on surgical intervention, yet the recurrence of fibrotic complications poses a significant challenge to long-term patient outcomes. By targeting NR2F1, researchers suggest it may be possible to develop pharmaceutical agents that prevent fibrosis at a molecular level, providing a new avenue for treatment that could complement existing surgical methods.

Beyond the realm of ophthalmology, the NR2F1-STAT3 axis might have relevance in other fibrotic diseases, suggesting broader implications in fields such as oncology and tissue regeneration. Continued research is essential to translate these findings from bench to bedside, validating their effectiveness in clinical settings and exploring their potential to inform patient-centered approaches.

In summary, the investigation into the NR2F1-STAT3 signaling pathway not only enhances the understanding of cataract-associated fibrosis but also opens new therapeutic possibilities that could significantly improve patient care and outcomes. The identification of this molecular mechanism represents a critical step towards developing effective treatments that address the underlying causes of cataract formation, highlighting the importance of ongoing research in this vital area of medical science.