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.