Epigen-Mediated Mechanisms to Alleviate Glucose Homeostasis Disruptions in Diet-Induced Obese and STZ-Induced Diabetic Mice

Ka-Ying Chan; Chu-Jun Deng; Dilun Chen; Tak-Ho Lo; Shiqi Jia; Pauline Po Yee Lui; Chi-Ming Wong

doi:10.1016/j.ymthe.2025.06.044

Epigen-Mediated Mechanisms to Alleviate Glucose Homeostasis Disruptions in Diet-Induced Obese and STZ-Induced Diabetic Mice

Mol Ther. 2025 Jun 30:S1525-0016(25)00534-9. doi: 10.1016/j.ymthe.2025.06.044. Online ahead of print.

Authors

Ka-Ying Chan¹, Chu-Jun Deng¹, Dilun Chen², Tak-Ho Lo³, Shiqi Jia⁴, Pauline Po Yee Lui⁵, Chi-Ming Wong⁶

Affiliations

¹ Department of Health Informatics and Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China.
² Department of General Surgery Ward II, Foshan Sanshui District People's Hospital, China.
³ Department of Health Informatics and Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China; School of Life Science, The Guangzhou University, Guangzhou, Guangdong Province, China.
⁴ Institutes of Biomedical Sciences, Inner Mongolia University, China.
⁵ Department of Orthopaedics and Traumatology, Chinese University of Hong Kong, Hong Kong SAR, China.
⁶ Department of Health Informatics and Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China; State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong SAR, China; Hong Kong Polytechnic University, Shenzhen Research Institute, China. Electronic address: chi-ming.cm.wong@polyu.edu.hk.

PMID: 40598771
DOI: 10.1016/j.ymthe.2025.06.044

Abstract

Epidermal growth factor receptor (EGFR) plays a crucial role in cellular processes such as development and tissue repair, with dysregulation linked to various diseases, including those affecting energy metabolism. Previous studies have reported that EGFR ligands enhance glucose homeostasis through various mechanisms across different tissues. However, epigen, the latest EGFR ligand, has not been thoroughly investigated regarding its impact on energy metabolism. In this study, we employed both in vivo gain-of-function and loss-of-function approaches to investigate the role of epigen in metabolic regulation using diet-induced obesity (DIO) and streptozotocin (STZ)-induced diabetic mice. Our findings, which align with previous research on other EGFR ligands, provide the first evidence that epigen is crucial for glucose homeostasis. It promotes the release of endogenous insulin, enhances glucose uptake in adipocytes and muscle, improves glycolysis and respiration utilization in adipose tissues of DIO mice, and increases pancreatic beta cell mass in STZ-induced diabetic mice. Overall, our findings suggest that epigen could be a potential therapeutic target for managing both type 2 and type 1 diabetes, warranting further exploration in clinical settings.