Targeting UXS1‐Dependent Glucuronate Detoxification Potentiates Metformin's Anti‐Tumor Efficacy in Lung Adenocarcinoma

ABSTRACT Despite the widely reported experimental anti‐tumor effects, metformin's role remains exceedingly complex, with contradictory results in clinical trials. Our study, based on metabolomics analysis of lung adenocarcinoma (LUAD) samples, xenografts, and cells, unveils a novel process that metformin promotes the conversion of UDP‐glucose (UDPG) to UDP‐glucuronic acid (UDPGA) in glucuronic acid metabolism. Mechanistically, metformin activates UDP‐glucose 6‐dehydrogenase (UGDH) through AMPK‐mediated phosphorylation of UGDH(S476), a previously unstudied phosphorylation site, impeding the binding of UDP‐Xyl to UGDH and the subsequent allosteric inhibition. Consequently, metformin‐treated cells are more reliant on UXS1, a downstream metabolic enzyme of UGDH, for detoxifying UDPGA based on the “kitchen‐sink” model. Through comprehensive virtual screening of a compound library, we identified that plantainoside is a potent UXS1‐targeting agent. Remarkably, when combined with metformin, plantainoside exhibits a superior synergistic lethal effect in LUAD cells, organoids, xenografts, and spontaneous models. Moreover, this combination not only directly targets tumor cells but also synergistically boosts CD8+ T cells and suppresses the differentiation of macrophages, thereby significantly enhancing immunotherapy efficacy. Collectively, our results shed light on metformin's complicated role by revealing its novel impact on glucuronic acid metabolism and dependence on UXS1; thus, targeting UXS1 combined with metformin represents a highly promising new strategy.