A Novel Therapeutic Strategy for Ameliorating Hyperglycemia-Induced Liver Injury via Overexpression of the Carboxyl Terminus of HSP70-Interacting Protein in Wharton's Jelly Mesenchymal Stem Cells

Diabetes is a widespread metabolic disorder that significantly affects modern society. The liver plays a vital role in metabolism; however, hyperglycemia can induce liver damage and disrupt its normal functions. Wharton's jelly mesenchymal stem cells (WJMSCs) engineered to express the carboxyl terminus of HSP70-interacting protein (CHIP) have demonstrated protective effects against hyperglycemia-induced damage in various organs. Nonetheless, the potential hepatoprotective effects and underlying mechanisms of these modified stem cells in diabetic livers remain unclear. Therefore, this study aimed to evaluate the efficacy of CHIP-transfected WJMSCs in mitigating hyperglycemia-induced hepatic injury in diabetic rats and to elucidate the associated protective mechanisms. Diabetic rats received tail vein injections of WJMSCs either overexpressing or silenced for CHIP. Seven weeks post-transplantation, all rats were sacrificed, and liver tissues were harvested for histological staining and Western blot analysis. The findings indicated that CHIP-overexpressing WJMSCs significantly reversed hyperglycemia-induced liver damage, reducing tissue injury, fibrosis, and glycogen deposition. These cells also alleviated hepatic inflammation and apoptosis. Moreover, they regulated oxidative stress pathways by lowering gp91-phox, Rac1, and phosphorylated PKCζ levels, while enhancing phosphorylated Nrf2 and SOD-2 expression. Additionally, the modified WJMSCs suppressed STAT3 activation and downregulated FOXO3a, suggesting a role in attenuating fibrosis and triglyceride accumulation in diabetic livers. Overall, CHIP-overexpressing WJMSCs reversed hyperglycemia-induced hepatic alterations by mitigating inflammation and oxidative stress while also modulating pathways related to fibrosis and lipid metabolism. These results highlight the therapeutic potential of CHIP-modified WJMSCs in managing diabetic liver complications and offer promising avenues for future treatment strategies.