IL‐12p70 Induces Neuroprotection via the PI3K‐AKT‐BCL2 Axis to Mediate the Therapeutic Effect of Electroacupuncture on Postoperative Cognitive Dysfunction

Abstract Postoperative cognitive dysfunction (POCD), a postsurgical decline in cognitive function, primarily affects older adults and worsens their prognosis. Although elevated interleukin‐12p70 (IL‐12p70) is closely correlated with slower cognitive decline in older adults, its role in POCD remains unclear. Here, IL‐12p70 is identified as a significant mediator of therapeutic effect of electroacupuncture (EA) on POCD. EA at acupoints ST36, GV20, and GV24 significantly enhanced cognitive behaviors of POCD mice. IL‐12p70, downregulated in POCD mice but rescued by EA treatment, is the cytokine closely associated with EA's therapeutic effect. Clinically, IL‐12p70 is downregulated in older adults’ serum post‐surgery. Furthermore, IL‐12p70 exerts a potent neuroprotective effect in both neuronal cell lines and primary hippocampal neurons. The PI3K‐AKT‐BCL2 axis enriched by in silico analysis is validated as the signaling mechanism underlying IL‐12p70‐induced neuroprotection. In vivo, beneficial effects of EA treatment on the activation of PI3K‐AKT‐BCL2 axis and POCD are reproduced by IL‐12p70 administration but attenuated by IL‐12p70 knockdown. The findings reveal a novel mechanism underlying the therapeutic effect of EA on POCD, demonstrating that IL‐12p70 exerts a neuroprotective effect by activating PI3K‐AKT‐BCL2 axis in hippocampal neurons. The newly‐discovered function and mechanism of IL‐12p70 highlight its potential in treating cognitive disorders.