Involvement of STAT3 activation in ameliorating all-trans-retinal-induced ferroptosis in photoreceptor-derived 661W cells in vitro.

Ferroptosis, a form of iron-dependent programmed cell death, has emerged as a critical player in various diseases, including retinal degenerative disorders. Previous studies have highlighted that ferroptosis, triggered by all-trans-retinal (atRAL) accumulation in photoreceptor cells, contributes significantly to the pathogenesis of dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1). However, the underlying molecular mechanisms regulating this process remain poorly understood. In this study, we explore the involvement of signal transducer and activator of transcription 3 (STAT3) in the regulation of atRAL-induced 661W photoreceptor cells (mouse-derived photoreceptor cells) ferroptosis. We found that atRAL treatment induces phosphorylation of STAT3 in 661W photoreceptor cells. Meanwhile, we also discovered that the accumulation of Reactive oxygen species (ROS) induced by atRAL partly contributes to the activation of STAT3 in 661W photoreceptor cells. Importantly, our data suggest that inhibition of STAT3 phosphorylation, resulting in increased lipid peroxidation through upregulation of the acyl-CoA synthetase long-chain family member 4 (ACSL4) and prostaglandin-endoperoxide synthase 2 (PTGS2) gene, exacerbates ferroptosis in atRAL-loaded 661W photoreceptor cells. Additionally, our findings further confirm that STAT3 activator Colivelin may significantly reduce ferroptosis in 661W photoreceptor cells exposed to atRAL by regulating the ACSL4 and PTGS2 gene. Overall, these results revealed that activated STAT3 mitigates atRAL-induced ferroptosis in photoreceptor cells, possibly by reducing ACSL4 and PTGS2 gene expression. This pathway highlights the therapeutic potential of STAT3 as a novel target for treating dry AMD and STGD1.