Abstract

Oxidative stress plays a critical role in lens fibrosis, and nuclear factor erthroid 2-related factor 2 (Nrf2) is a key antioxidant transcription factor. This study investigates the specific role and underlying mechanism of Nrf2 in fibrotic cataract using in vitro and in vivo models. An in vitro model of fibrotic cataract was established by treating lens epithelial cells (LECs) with TGF-β2 (10 ng/mL). We found that oxidative stress participated in epithelial-mesenchymal transition (EMT) in LECs, concomitant with reduced Nrf2 expression. Moreover, Nrf2 overexpression alleviated oxidative stress, suppressed cell migration, and inhibited EMT. The anterior capsule injury method was utilized to establish a murine model of anterior subcapsular cataract (ASC). In the ASC model, LECs displayed increased oxidative stress and reduced Nrf2 expression. Consistently, Nfe2l2-knockout mice exhibited exacerbated lens fibrosis and higher oxidative stress levels compared to wild-type controls. The mechanism of Nrf2 in lens fibrosis was then investigated by RNA sequencing and validated in LECs in vitro. Our data revealed that Nrf2 promoted PINK1-mediated mitophagy, through which it attenuated oxidative stress and suppressed EMT in LECs. To elucidate how Nrf2 regulates PINK1, the Nrf2 binding sites in the promoter region of PINK1 were predicted using the JASPAR database and subsequently confirmed by both chromatin immunoprecipitation and electrophoretic mobility shift assay. We found that Nrf2 directly binds to the PINK1 promoter to drive its transcription. Collectively, our study suggests that Nrf2 activation mitigates lens fibrosis by promoting PINK1-dependent mitophagy, identifying the Nrf2-PINK1 axis as a potential therapeutic target.