Mechanistic Basis and Therapeutic Potential of a Novel TXNIP Inhibitor in Diabetes Treatment
Zhikuan Luo, Jun Han, Tao Zhong, Qiong Tian, Wanwan Ge, Zhongqi Liu, Xiangtong Li, Ming He, Shijun Zhou, Hongbin Jia, Weichen Xia, Ruijun Jing, Ao Dong, Yifeng Qi, Tinghong Lv, Yunkun Dang, Shili Chen, Xusheng Ma, Shaohua Wang, Haixue Zheng, Fan Lai, Xiaolei WangAbstract
Recently, inhibiting thioredoxin-interacting protein (TXNIP), a protein that plays critical roles in glucose metabolism, has emerged as a promising therapeutic strategy for diabetes. Through screening a compound library using a TXNIP reporter system, we identified an orally bioavailable small molecule (SKL-1223) that exhibits an excellent safety profile and potent glucose-lowering effects in streptozotocin-induced and db/db murine models. Notably, SKL-1223 promotes beta-cell formation and loss of alpha-cells in these disease models. Mechanistic studies indicate that SKL-1223 ameliorates hyperglycemia by directly modulating TXNIP transcription through attenuation of transcription factor binding. Compared with current therapies, SKL-1223 demonstrates improved efficacy in suppressing glucagon-mediated hepatic gluconeogenesis in diabetes treatment. Together, our findings not only identify a novel TXNIP inhibitor for controlling glucose production but also position SKL-1223 as a first-in-class therapeutic candidate addressing an unmet need in diabetes management.