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…
Read the paper
Related studies
- Metformin as an adjuvant in breast cancer treatment
- Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
- Aberrant HSF1 signaling activation underlies metformin amelioration of myocardial infarction in mice
- Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines
- Protein Interaction Network for Identifying Vascular Response of Metformin (Oral Antidiabetic)
- Preventing Long COVID With Metformin
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.