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Dihydrotanshinone I (DHT), a bioactive natural compound derived from\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Salvia miltiorrhiza<\/jats:italic>\n                    <\/jats:styled-content>\n                    , has been proposed as a potential therapeutic agent for HCC. This study aims to characterize DHT as a PGAM1\u2010targeting agent and investigate its anti\u2010HCC effects. We assessed the effects of DHT on PGAM1 regulation and glycolytic activity in\u00a0vitro and in\u00a0vivo. Using proteasomal degradation assays, we evaluated the role of Synoviolin 1 (SYVN1), an E3 ubiquitin ligase, in mediating the ubiquitination and degradation of PGAM1. The impact of DHT on key glycolytic enzymes, glucose consumption, lactate production, and ATP levels was also measured. In\u00a0vivo, orthotopic and subcutaneous xenograft HCC models were used to evaluate tumor growth suppression following DHT treatment. DHT induced SYVN1\u2010mediated K48\u2010linked polyubiquitination and proteasomal degradation of PGAM1, disrupting glycolytic flux by reducing hexokinase and pyruvate kinase activities, decreasing glucose consumption, lactate production, and ATP levels. In\u00a0vivo, DHT demonstrated dose\u2010responsive tumor suppression without observable short\u2010term toxicity. These findings establish DHT as a promising therapeutic agent for HCC by targeting PGAM1 degradation and disrupting glycolysis. The study provides a mechanistic framework for developing plant\u2010derived therapeutics targeting metabolic pathways in liver cancer.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70017","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T01:59:13Z","timestamp":1752199153000},"page":"3762-3783","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dihydrotanshinone I Targets\n                    <scp>PGAM1<\/scp>\n                    to Induce\n                    <scp>SYVN1<\/scp>\n                    \u2010Mediated Ubiquitination and Suppress Glycolysis in\u00a0Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"39","author":[{"given":"Ru","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Traditional Chinese Medicine, Jinshan Hospital Fudan University  Shanghai 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