NEDD4 promotes reactive astrogliosis by enhancing K63-linked ubiquitination and inhibiting chaperone-mediated autophagy degradation of YAP1

deficiency. Mechanistically, NEDD4 interacts with YAP1 and mediates K63-linked ubiquitination at lysine 254, thereby preventing its degradation via the chaperone-mediated autophagy (CMA) pathway involving HSC70. Furthermore, we demonstrate that the ROS-FOXM1 signaling cascade drives NEDD4 expression, thereby stabilizing YAP1 and promoting astrocyte proliferation. In summary, our findings underscore the pivotal role of the ROS-FOXM1-NEDD4-YAP1 signaling cascade in controlling astrocytic activation and tissue regeneration post-SCI, positioning NEDD4 as a viable target to regulate astrogliosis and facilitate neurological restoration after SCI.