Astrocytic GSTM2-STAT3 interaction ameliorates the diabetes associated cognitive dysfunction via targeting mitochondrial defects and oxidative stress

Diabetes associated cognitive dysfunction (DACD) present a substantial challenge to the management of diabetic patient. The pathogenesis of DACD is intricately associated with mitochondrial defects and oxidative stress. However, the exact molecular pathways implicated have not been comprehensively elucidated. This study aimed to characterize the mechanisms by which dysregulation of glutathione S transferase mu2 (GSTM2) contributes to the pathogenesis of DACD. Astrocytic GSTM2 expression is markedly downregulated in DACD mice hippocampus employed proteomic Sequencing. Hippocampal astrocytes specific GSTM2 overexpression alleviated cognitive dysfunction accompanied by inhibiting mitochondrial defects and oxidative stress in db/db mice. Conversely, astrocytic GSTM2 deficiency aggravated these dysfunctions. Immunoprecipitation-mass spectrometry and surface plasmon resonance were utilized to identify the GSTM2 - interacting proteins. The GSTM2 directly interacted with STAT3 and suppressed the phosphorylation of STAT3, thereby downregulating Drp1 signals and ultimately exerting a protective effect against mitochondrial defects and oxidative stress. Pharmacological intervention of STAT3 dysregulated mitochondrial function which influence the protective benefits conferred by GSTM2. Finally, we found that Icariin, which was explored by molecular docking and virtual screening from large-scale compound libraries, could activate the GSTM2/STAT3 pathway to improve cognitive impairment in DACD mice. Conclusively, the down regulation of GSTM2 impairs mitochondrial function and oxidative stress via the STAT3-Drp1 signaling pathway, further exacerbating DACD pathology. This discovery indicates that GSTM2 may serve as a promising and novel therapeutic target for the prevention and treatment of DACD.

Diabetes associated cognitive dysfunction; GSTM2; Icariin; Mitochondrial defects; Oxidative stress; STAT3.