Metabolic Reprogramming and Drug Resistance in Hepatocellular Carcinoma: the Emerging Role of SREBP2-driven Cholesterol Metabolism

Hepatocellular carcinoma (HCC) is the most common cancer and a leading cause of death. Multi-kinase inhibitors are vital for treating advanced HCC, yet drug resistance remains a major challenge. The molecular basis of metabolic adaptation to drug resistance is poorly understood. Evidence indicates that metabolic reprogramming, particularly dysregulated cholesterol metabolism, plays a key part in drug resistance. Sterol regulatory element-binding protein 2 (SREBP2) regulates cholesterol synthesis, stabilizes receptor tyrosine kinases (RTKs), promotes lipid raft formation, and reduces ATP-binding cassette transporter subfamily A member 1 (ABCA1) and cholesterol efflux, leading to increased intracellular cholesterol. Y-box binding protein 1 (YBX1), a DNA/RNA-binding protein, induces cancer metastasis and drug resistance by modulating ABC transporters, phosphoinositide 3-kinase (PI3K)/AKT, and lipid metabolism. This review discusses the role of cholesterol metabolism in resistance, focusing on SREBP2 and therapeutic strategies targeting cholesterol.