Oxaloacetate promotes the transition from glycolysis to gluconeogenesis through the Akt-FoxO1 and JNK/c-Jun-FoxO1 axes and inhibits the survival of liver cancer cells.

BACKGROUND

Unlike other gluconeogenesis activators, oxaloacetate serves as both a metabolic intermediate and a signaling molecule, offering unique advantages in cancer therapy. This study explores the therapeutic potential of oxaloacetate in hepatocellular carcinoma, focusing on its impact on glucose metabolism, cell apoptosis, and intracellular signaling pathways.

METHODS

Utilizing bioinformatics analysis, we evaluated the metabolic flux of glucose in tumors and conducted differential and prognostic analyses of gluconeogenesis genes. Techniques such as transfection were employed to manipulate FoxO1 expression and Akt activity. GSH and NAC were used as antioxidants. Key enzyme activities, FoxO1 expression, cell viability, apoptosis-related proteins, ROS levels, and cell cycle progression were measured. Additionally, TUNEL apoptosis staining was performed.

RESULTS

Oxaloacetate promotes a glucose metabolic shift toward gluconeogenesis and induces apoptosis in cancer cells via FoxO1. In a mouse xenograft model, oxaloacetate treatment significantly reduced tumor size. Notably, tumors overexpressing Akt were larger, but their growth was also diminished following oxaloacetate treatment. FoxO1 expression and apoptosis-related proteins were elevated in oxaloacetate treated tumors. Oxaloacetate inhibits Akt phosphorylation and activates the JNK/c-Jun pathway, enhancing FoxO1 activity through dual mechanisms.

CONCLUSIONS

Oxaloacetate not only inhibits tumor proliferation through metabolic pathways but also acts as a signaling molecule influencing tumor growth via multiple signaling cascades. It disrupts liver cancer cell energy homeostasis and selectively targets glycolysis-addicted cancer cells. Furthermore, its endogenous presence and prior demonstration of safety in humans at relatively high doses highlight its potential for clinical translation in cancer therapy.