UPro^1A8: A Specific Fluorescent Probe for Functional Imaging and Inhibitor Screening of UGT1A8

UDP-glucuronosyltransferase 1A8 (UGT1A8), a key human phase II metabolic enzyme, is related to the pathogenesis of endometrial and breast cancers. Nevertheless, its roles in drug–drug interactions and disease mechanisms remain unclear due to the lack of selective real-time monitoring tools. In this work, we developed UPro1A8, the first “off-on” fluorescent probe specifically targeting UGT1A8, designed via a “single-end modification strategy”. UPro1A8 demonstrates excellent selectivity and sensitivity for UGT1A8 over other UGT isoforms. It enables real-time visualization of endogenous UGT1A8 activity in living cells, tissue slices, and zebrafish, providing a flexible platform for precise inhibitor evaluation. Screening of a compound library using this probe identified four natural products, namely Ginkgetin, Silibinin, Ledebouriellol, and Antcin C (R), as potent UGT1A8 inhibitors. Collectively, these findings position UPro1A8 as a robust molecular tool for advancing UGT1A8 functional studies.