AFP confers the resistance of lenvatinib in hepatocellular carcinoma by activating PI3K/AKT/LDHA signaling axis

This study aimed to explore whether alpha-fetoprotein (AFP) promotes resistance of hepatocellular carcinoma (HCC) cells to lenvatinib by regulating the activity of lactate dehydrogenase A (LDHA) and triggering the Warburg effect. Analysis of 30 clinical HCC samples revealed that the expression of AFP and LDHA in cancer tissues was significantly higher than that in adjacent tissues and that there was a positive correlation between their expression levels. Cell function experiments (such as MTT and colony formation assays) confirmed that AFP significantly enhances the resistance of HCC cells to lenvatinib. Mechanistic studies have found that AFP can promote glycolysis in HCC cells (manifested as an enhanced Warburg effect, increased glucose consumption, lactate production, and ATP production) and upregulate the expression of glycolysis-related proteins, which is dependent on LDHA. Further mechanistic studies indicated that AFP regulates LDHA activity by activating the PI3K/AKT signaling pathway. Therefore, this study revealed that AFP enhances glycolysis by stimulating the activation of the PI3K/AKT/LDHA signaling axis, thereby inducing resistance of HCC cells to lenvatinib. This study provided a new theoretical basis for overcoming lenvatinib resistance by targeting AFP and inhibiting LDHA expression.