The TAK1-YAP Axis synergistically suppresses oxidative stress and apoptosis via a non-canonical signaling pathway: A neuroprotective mechanism in ischemic stroke.

Ischemic stroke (IS) is one of the leading causes of global disability and mortality, yet effective treatments targeting oxidative stress (OS) and neuronal apoptosis remain lacking. This study investigates the neuroprotective role of Yes-associated protein (YAP) in IS and its regulatory mechanisms. Using clinical IS patient serum samples, a mouse middle cerebral artery occlusion (MCAO) model, and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model, we found that YAP protein levels were significantly downregulated post-ischemia, correlating with aggravated OS and neuronal apoptosis. Overexpression of Yap1 via adeno-associated virus (AAV) vectors reduced infarct volume, restored cerebral blood flow, and improved neurological and cognitive functions in MCAO mice. Mechanistically, YAP alleviated oxidative damage by enhancing the activity of antioxidant enzymes (e.g., GSH-Px, SOD) and inhibited apoptosis, as validated by TUNEL and Annexin V/PI assays. Intriguingly, under ischemic conditions, YAP phosphorylation was regulated by TAK1 rather than the canonical Hippo signaling pathway. Knockdown of TAK1 synergized with YAP activation to mitigate oxidative damage and neuronal apoptosis. These findings reveal the critical neuroprotective role of YAP in IS and identify the TAK1-YAP interaction as a therapeutic target. This study provides a mechanistic foundation for developing YAP-based interventions for IS.