Targeting aerobic glycolysis combats tyrosine kinase inhibitor resistance of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) represents the predominant form of primary liver cancer and is frequently identified at a late stage, necessitating systemic therapy. However, resistance to first‐line tyrosine kinase inhibitor therapies, such as sorafenib and lenvatinib, remains a significant clinical challenge. Recent research has revealed a strong link between aerobic glycolysis and drug resistance in HCC. Key enzymes in the glycolytic pathway, such as hexokinase, phosphofructokinase, and pyruvate kinase M, play central roles in the metabolic reprogramming of HCC cells. Aberrant activation of these enzymes not only promotes swift proliferation of tumor cells but also boosts adaptability. Lactate, the final product of glycolysis, is also pivotal in contributing to drug resistance in HCC. Moreover, signaling pathways, such as AMPK, HIF‐1, and c‐Myc, play key roles in tumor metabolic regulation, influencing energy balance, gene expression under hypoxia, and metabolic pathway control. These mechanisms interact synergistically, allowing HCC cells to endure and proliferate despite targeted therapies, ultimately resulting in drug resistance. Therefore, a deeper understanding of these metabolic and signaling regulatory mechanisms will help reveal the fundamental causes of drug resistance in HCC and provide new targets and directions for future therapeutic strategies.