The Dual Role of Human UDP-Glucuronosyltransferase-Mediated Metabolism in Tumor Drug Resistance: Mechanisms and Prospects

UDP-glucuronosyltransferases (UGTs) are a key family of phase II metabolic enzymes in humans that play a central role in maintenance of metabolic homeostasis and drug disposition by catalyzing glucuronidation of endogenous and exogenous substances. UGT-mediated metabolism of antitumor drugs plays a dual role in tumor drug resistance, emerging as a hotspot in cancer therapy. This review outlines the structural characteristics, classification system, tissue distribution, and multilevel regulation of UGTs, with a focus on their bidirectional roles in tumor drug resistance, i.e., promotion of resistance through metabolic clearance and inhibition of resistance through metabolic activation. This review also discusses strategies of multidimensional tumor resistance intervention based on UGTs, and we also discussed the challenges in the clinical translation of current UGT-targeting strategies. To date, most data on UGTs were derived from in vitro and preclinical models; clinical validation remains limited, and the dual roles of UGTs are highly context-dependent. This review article provides a perspective for comprehensive understanding of UGT-mediated tumor resistance and offers theoretical foundations and practical directions for development of novel antitumor strategies.