xCT regulates redox homeostasis and promotes photoreceptor survival after retinal detachment.

Backgrounds: Photoreceptor degeneration underlies various retinal disorders that lead to vision impairment. Currently, no effective medication is available to rescue photoreceptors under disease conditions. Elucidation of the molecular pathways involved in photoreceptor degeneration is a prerequisite for the rational design of therapeutic interventions. Photoreceptors are among the most energy-demanding tissues that require highly active oxidative phosphorylation. Therefore, disruption of metabolic support to photoreceptors results in a redox imbalance and subsequent cell death. We hypothesize that the redox regulatory pathway could be a potential therapeutic target to rescue photoreceptors under disease conditions.

Methods: Experimental retinal detachment was induced in mice. A murine photoreceptor-derived 661w cell line treated with HO was employed as an in vitro model to study the cellular response to oxidative stress. The expression and functional role of xCT, an upstream regulator of redox homeostasis, was assessed in vivo and in vitro. An xCT expression vector was constructed for an in vivo study to evaluate the therapeutic potential of this molecule.

Results: xCT expression was upregulated in detached retina and HO-stimulated 661w cells compared to the control cells. Pharmacological inhibition of xCT by sulfasalazine (SAS) promoted photoreceptor degeneration after retinal detachment and 661w cell death upon HO treatment. Additionally, SAS treatment induced reactive oxidative species (ROS) accumulation, glutathione (GSH) depletion, and glutamate release in 661w cells. In contrast, xCT overexpression via viral infection protected photoreceptors from degeneration after retinal detachment.

Conclusion: We conclude that xCT expression is upregulated in photoreceptors after retinal detachment and plays a neuroprotective role in preserving photoreceptors. Mechanistically, xCT promotes cellular homeostasis by regulating intracellular ROS and GSH levels, which are critical to photoreceptor survival after retinal detachment. Collectively, our findings identify xCT as a potential therapeutic target for protection of photoreceptors under disease conditions.