CHIN-YUAN HSIEH2026-10-162026-10-162025-12-01Pure ID: 15311728Pure UUID: cbed3cf7-89ff-4e02-ae3e-9f8a844de5bc10.1186/s40659-025-00604-7https://www.scopus.com/pages/publications/105003288286https://scholars.csmu.edu.tw/handle/123456789/22211Background: Stem cell therapies may potentially be used in regenerative and reconstructive medicine due to their ability for self-renewal and differentiation. Stressful conditions, such as hyperglycemia, adversely affect stem cell functions, impairing their function and promoting differentiation by opposing self-renewal. The carboxyl terminus of HSP70 interacting protein (CHIP), which is a cochaperone and E3 ligase, maintains protein homeostasis and performs quality control of the cell via ubiquitylation. However, the role of CHIP in regulating stemness remains unknown. Results: Hyperglycemia downregulated CHIP-induced p53, arrested the cell cycle at the gap (G1) phase, and promoted the loss of stemness in WJMSCs. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, immunofluorescence, and cell cycle analysis showed that CHIP-overexpressing WJMSCs downregulated the expression of phosphorylated p53 and shortened its half-life while enhancing self-renewal factors. Additionally, co-IP and Western blotting revealed that CHIP promoted the ubiquitination and proteasomal degradation of hyperglycemia-induced p53 through the chaperone system. Conclusions: CHIP may promote ubiquitin-mediated proteasomal degradation of hyperglycemia-induced p53 rescues self-renewal genes, which can maintain the long-term undifferentiated state of WJMSCs. CHIP may be an alternative therapeutic option in regenerative medicine for hyperglycemic-related complications in diabetes.enjournal article