A “DUBTAC” targeting GLUL deubiquitination promotes BMSC osteogenic differentiation and implant osseointegration in type 2 diabetes

作者：Lingxiao Wang, Zhanqiu Diao, Wanqing Wang, Y. Huang, Yang Liu, Zhenhua Gao, Pan Ma, Zhaochen Shan, Jie Li, Zhipeng Fan · 发表于：Journal of Advanced Research · 年份：2026 · DOI：10.1016/j.jare.2026.04.034 · 被引用次数：1 · 研究领域：Protein Degradation and Inhibitors、Connective tissue disorders research、Ubiquitin and proteasome pathways

This study found that GLUL plays a significant role in inhibiting the osteogenic differentiation of BMSCs and osseointegration in type 2 diabetes, revealing that SYVN1 mediates the ubiquitination of GLUL and highlighting the crucial role of maintaining GLUL protein homeostasis in the functioning of BMSCs. Moreover, deubiquitinase-targeted chimaeras were designed and synthesized on the basis of the ubiquitination sites of GLUL to explore targeted, safe and effective osteogenic treatment strategies based on the mechanism of GLUL ubiquitination. • This project focuses on the function of GLUL in the osteogenic differentiation and osseointegration of BMSCs and identifies new targets for intervening in the osteogenic differentiation and osseointegration of T2DM jawbone BMSCs. • These findings reveal that T2DM regulates SYVN1-mediated GLUL ubiquitination, disrupts GLUL protein homeostasis, and inhibits osteogenic differentiation and osseointegration in BMSCs. • This study is the first to report that the small-molecule ligand HY-126351 of GLUL can be used for the design of protein-targeted chimaeras. • In this study, GLUL-DUBTAC (HY-X3369) was designed and synthesized to verify its ability to maintain GLUL protein homeostasis. • HY-X3369 can be used to directly target the GLUL ubiquitin chain without affecting the programmed degradation of GLUL via non-ubiquitination pathways, resulting in the resynthesis of GLUL protein ligand target proteins. • The characteristics of the small mole...