YAP Regulates the Nrf2 Signaling Axis to Attenuate Oxidative Stress and Neuroinflammation in Retinal Ganglion Cell Degeneration.

PURPOSE: Oxidative stress is a key driver of retinal ganglion cell (RGC) degeneration after optic nerve injury. Yes-associated protein (YAP), a Hippo pathway effector, is known to reprogram stress responses, yet its role in regulating oxidative stress during RGC degeneration is unclear.

METHODS

This study investigated the role of YAP 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 pharmacologically and genetically. We assessed its effects on nuclear factor erythroid 2-related factor 2 (Nrf2) signaling-related outcomes; on oxidative stress markers, including superoxide dismutase-1/2 (SOD-1/2), NAD(P)H:quinone oxidoreductase 1 (Nqo-1), and reactive oxygen species (ROS); and on neuroinflammation (microglial and astrocytic activation) via quantitative reverse-transcription PCR and immunofluorescence.

RESULTS

YAP activation demonstrated robust neuroprotection in both the in vivo ONC model and in vitro oxidative-stress paradigms, significantly enhancing RGC survival, whereas YAP suppression exacerbated RGC degeneration. Mechanistically, YAP activation was associated with elevated Nrf2 signaling activity, as indicated by upregulation of antioxidant effectors (Nqo-1, SOD-2) and reduced intracellular ROS. YAP activation attenuated neuroinflammation, characterized by decreased microglial reactivity and astrocytic activation, whereas inhibition of YAP reversed these effects.

CONCLUSIONS

This study identified YAP as a neuroprotective regulator in both in vivo ONC and primary RGC models. YAP activation attenuated oxidative stress and neuroinflammation, which correlated with the activity of Nrf2-mediated antioxidant pathways, highlighting the potential relevance of YAP and Nrf2 interaction for therapeutic targeting in RGC injury.