Dihydrotanshinone I Targets PGAM1 to Induce SYVN1-Mediated Ubiquitination and Suppress Glycolysis in Hepatocellular Carcinoma.

Abstract

Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme frequently overexpressed in hepatocellular carcinoma (HCC), contributing to tumor progression through aberrant glycolysis. Dihydrotanshinone I (DHT), a bioactive natural compound derived from Salvia miltiorrhiza , has been proposed as a potential therapeutic agent for HCC. This study aims to characterize DHT as a PGAM1-targeting agent and investigate its anti-HCC effects. We assessed the effects of DHT on PGAM1 regulation and glycolytic activity in vitro and in vivo. 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 vivo, orthotopic and subcutaneous xenograft HCC models were used to evaluate tumor growth suppression following DHT treatment. DHT induced SYVN1-mediated K48-linked 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 vivo, DHT demonstrated dose-responsive tumor suppression without observable short-term 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-derived therapeutics targeting metabolic pathways in liver cancer.