Abstract

Background Perioperative neurocognitive disorders (PND) are common postoperative complications, particularly in elderly patients, marked by learning and memory deficits with limited treatment options. Human umbilical cord mesenchymal stem cells (hUC-MSCs) hold promise due to their neuroprotective and immunomodulatory effects, but their underlying mechanisms remain unclear. Methods This study established a PND model in aged mice using tibial fracture intramedullary fixation surgery, followed by intravenous hUC-MSCs administration. Subsequently, behavioral tests, pathological examination, proteomic analysis, and other experiments were performed to verify the therapeutic effect and underlying mechanism of hUC-MSCs on PND in mice. Results hUC-MSCs significantly improved cognitive function in PND mice, reduced hippocampal neuronal apoptosis and neuroinflammation, and restored dendritic spine density. Mechanistically, hUC-MSCs secreted β-NGF to activate the TrkA signaling pathway, upregulate STMN2 and NMNAT2 expression, and inhibit the SARM1/NF-κB pathway, thereby alleviating neuroinflammation and dendritic degeneration. Overexpression of SARM1 in the hippocampal CA1 region and β-NGF knockdown in hUC-MSCs both reversed the therapeutic effects of hUC-MSCs, confirming their critical roles. Conclusions hUC-MSCs ameliorate PND pathology through the β-NGF-mediated STMN2/NMNAT2-SARM1-NF-κB pathway, offering a novel cell-based therapeutic strategy for PND. Future research may focus on optimizing the secretory function of hUC-MSCs or developing small-molecule drugs targeting β-NGF to enhance therapeutic efficacy.