YAP activation protects retinal ganglion cells from degeneration by boosting Nrf2 antioxidant signaling

Retinal ganglion cell (RGC) degeneration, particularly following optic nerve injury, is a leading cause of irreversible vision loss. A primary driver of this degeneration is oxidative stress, exacerbated by the retina's high metabolic demands and continuous light exposure. Current therapeutic strategies often fall short in effectively mitigating this damage. Yes-associated protein (YAP), a key effector in the Hippo signaling pathway, is known for its role in regulating cellular stress responses and tissue regeneration, yet its specific involvement in modulating oxidative stress and neuroinflammation during RGC degeneration remained largely unexplored, representing a critical gap this study addresses.

Researchers investigated YAP's role in RGC injury using an in vivo optic nerve crush (ONC) model and an in vitro oxidative-stress model with primary RGCs. YAP expression was modulated both pharmacologically and genetically to observe its effects. The study assessed outcomes related to nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, oxidative stress markers like superoxide dismutase-1/2 (SOD-1/2), NAD(P)H:quinone oxidoreductase 1 (Nqo-1), and reactive oxygen species (ROS). Neuroinflammation, characterized by microglial and astrocytic activation, was also evaluated using quantitative reverse-transcription PCR and immunofluorescence techniques.

YAP activation demonstrated robust neuroprotection across both experimental paradigms, significantly enhancing RGC survival in the in vivo ONC model and in vitro oxidative-stress conditions. Conversely, YAP suppression consistently exacerbated RGC degeneration. Mechanistically, YAP activation was strongly associated with elevated Nrf2 signaling activity. This was evidenced by the upregulation of crucial antioxidant effectors, specifically Nqo-1 and SOD-2, which correlated with a marked reduction in intracellular ROS levels. Furthermore, YAP activation effectively attenuated neuroinflammation, characterized by a notable decrease in microglial reactivity and astrocytic activation. These protective effects were reversed when YAP was inhibited, underscoring its critical role in these pathways. The findings highlight a direct link between YAP activation and the modulation of key antioxidant and anti-inflammatory responses.

YAP activation significantly enhanced RGC survival and elevated Nrf2 signaling, reducing oxidative stress and neuroinflammation.