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Here, this work screens the mevalonate metabolic pathway enzyme PMVK to stabilize <jats:italic>\u03b2<\/jats:italic>\u2010catenin signaling using a human genome\u2010wide library. On the one hand, PMVK\u2010produced MVA\u20105PP competitively binds to CKI<jats:italic>\u03b1<\/jats:italic> to prevent <jats:italic>\u03b2<\/jats:italic>\u2010catenin Ser45 phosphorylation and degradation. On the other hand, PMVK functions as a protein kinase to directly phosphorylate <jats:italic>\u03b2<\/jats:italic>\u2010catenin Ser184 to increase its protein nuclear localization. This synergistic effect of PMVK and MVA\u20105PP together promotes <jats:italic>\u03b2<\/jats:italic>\u2010catenin signaling. In addition, PMVK deletion impairs mouse embryonic development and causes embryonic lethal. PMVK deficiency in liver tissue alleviates DEN\/CCl<jats:sub>4<\/jats:sub>\u2010induced hepatocarcinogenesis. Finally, the small molecule inhibitor of PMVK, PMVKi5, is developed and PMVKi5 inhibits carcinogenesis of liver and colorectal tissues. These findings reveal a non\u2010canonical function of a key metabolic enzyme PMVK and a novel link between the mevalonate pathway and <jats:italic>\u03b2<\/jats:italic>\u2010catenin signaling in carcinogenesis providing a new target for clinical cancer therapy.<\/jats:p>","DOI":"10.1002\/advs.202204909","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T12:47:12Z","timestamp":1676983632000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Phosphomevalonate Kinase Controls <i>\u03b2<\/i>\u2010Catenin Signaling via the Metabolite 5\u2010Diphosphomevalonate"],"prefix":"10.1002","volume":"10","author":[{"given":"Zhiqiang","family":"Chen","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory of Cell Homeostasis College of Life Sciences Frontier Science Center for Immunology and Metabolism TaiKang Center for Life and Medical Sciences Wuhan University  Wuhan 430072 P. R. 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