Aberrant activation of the PI3K/AKT/HIF‑1α pathway promotes glycolysis and lenvatinib resistance in liver cancer

Lenvatinib, a multi‑target tyrosine kinase inhibitor, has been approved as the first‑line treatment for advanced liver cancer (LC). However, its efficacy is markedly hindered by the rapid emergence of drug resistance. The phosphatidylinositol 3 kinase/protein kinase B/hypoxia‑inducible factor‑1 α (PI3K/AKT/HIF‑1α) signaling axis represents a key oncogenic pathway that regulates diverse biological processes, including aerobic glycolysis, and is closely associated with tumor progression and therapeutic resistance. However, the specific contribution of the PI3K/AKT/HIF‑1α pathway and aerobic glycolysis to lenvatinib resistance in LC, as well as the potential mechanistic interplay between these processes, remains inadequately elucidated. In the present study, colony formation, flow cytometry and Transwell assays were performed to evaluate the proliferative, apoptotic and invasive capabilities of LC cells. Cell aerobic glycolysis was assessed by detecting glucose uptake, lactate production, intracellular ATP levels and the expression of key glucose metabolism‑related genes. Compared with their parental counterparts, lenvatinib‑resistant (LR) Huh7 and HepG2 cells exhibited an enhanced glycolytic phenotype, characterized by increased glucose uptake, elevated lactate production, higher intracellular ATP levels and upregulated expression of key glycolysis‑related genes. Notably, aberrant activation of the PI3K/AKT/HIF‑1α signaling pathway was observed in LR LC cells. LY294002, a specific PI3K inhibitor, effectively inhibited the PI3K/AKT/HIF‑1α pathway and glycolytic activity in LR cells. Co‑administration of LY294002 with lenvatinib markedly suppressed the PI3K/AKT/HIF‑1α pathway and attenuated the glycolytic activity of Huh7‑LR/HepG2‑LR cells. Moreover, this combination treatment inhibited proliferation and invasion while inducing apoptosis and G₀/G₁ phase cell cycle arrest in LR cells. This evidence indicated that inhibition of the PI3K/AKT/HIF‑1α signaling pathway effectively restored the sensitivity of LR cells to lenvatinib. The findings in the present study demonstrate that aberrant activation of the PI3K/AKT/HIF‑1α pathway is required to enhance glycolysis and confers resistance to lenvatinib in LC. The combination of LY294002 with lenvatinib offers a promising strategic approach for overcoming resistance and enhancing the clinical efficacy of lenvatinib in patients with LC.