Han Guo, Jiaojiao Zhao, Keying Tian, Qinghui Guo, Siruan Chen, Yuhan Ge, Wenyan Guo, Xingchen Lin, Hui Bai, Lei Yang, Lei Yang, Xia Qin, Panpan Zhang, Zhanfeng Jia, Ruifang Zheng, Zuxiao Yang, Yun Stone Shi, Dezhi Kong, Tengfei Ji, Wei Zhang
Postoperative cognitive dysfunction (POCD) is a debilitating neurological complication that occurs following surgery, for which no effective interventions are currently available. Here, we identified YZG-331, a novel adenosine analog, as a promising neuroprotective agent that rescues cognitive deficits and mitigates dendritic spine loss in a murine POCD model. Integrated proteomic profiling and bioinformatics pathway analysis revealed that YZG-331 selectively targets NMDA receptor (NMDAR) signaling. Electrophysiological recordings and living-cell calcium imaging demonstrated that YZG-331 suppressed NMDAR-mediated currents and calcium influx in a dose-dependent manner. Furthermore, Mg2+ is required for YZG-331 to inhibit NMDAR activity. YZG-331 disrupts the formation of NMDAR condensates in the presence of Mg2+, thereby attenuating NMDAR-mediated excitotoxicity. Our findings establish YZG-331 as a prospective therapeutic candidate for POCD and reveal Mg2+-dependent receptor modulation as a novel pharmacological strategy for targeting NMDAR-associated neuropathologies.