Metformin Attenuates Glucose‐Driven Hepatocellular Carcinoma Progression by Targeting GPD2‐Mediated Metabolic Plasticity

Glucose metabolism is crucial for cancer cell survival and proliferation. Hepatocellular carcinoma (HCC) cells exhibit distinct metabolic adaptations that support tumor progression under nutrient‐limited conditions. The study examines the impact of glucose availability and GPD2‐mediated metabolic adaptation on HCC progression, as well as how these processes are modulated by glucose transport inhibitors and metformin. Cell proliferation and migration of HCC cells (HepG2 and Huh7) and lung cancer cells (A549) were examined under different glucose concentrations using MTT, colony formation, and scratch assays. The impacts of glucose transporter 1 (GLUT1) inhibitors and metformin were also evaluated. Gene and protein expression data were analyzed from TCGA/CPTAC datasets, and GPD2 expression was validated by immunohistochemistry. High glucose enhanced proliferation and migration of liver cancer cells. Unlike A549, HepG2 and Huh7 cells maintained growth under glucose deprivation, indicating metabolic plasticity. GPD2 was markedly upregulated in HCC tissues and correlated with poor survival. Metformin suppressed cell proliferation and migration in a dose‐dependent manner, with stronger effects under low‐glucose conditions. Mechanistically, metformin downregulated Cyclin D1 and XIAP, induced Caspase‐3 cleavage, and reduced the EMT marker, Slug. Correlation analyses revealed positive associations between GPD2 and CCND1 or SNAI2, indicating a link between GPD2 and cell cycle and EMT signaling. In conclusion, HCC cells utilize GPD2‐mediated metabolic adaptation to sustain growth under glucose‐limiting conditions. GPD2 represents a prognostic biomarker and therapeutic target in HCC. Metformin effectively inhibits HCC progression by disrupting GPD2‐linked pro‐survival and EMT pathways.