Metabolic reprogramming-driven resistance to multi-kinase inhibitors in hepatocellular carcinoma: molecular mechanisms and therapeutic opportunities

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is frequently diagnosed at advanced stages, limiting curative options. Multi-kinase inhibitors (MKIs), such as sorafenib and lenvatinib, serve as first-line therapies for unresectable HCC. However, the widespread development of drug resistance significantly diminishes the clinical efficacy of MKIs, and current treatments lack effective strategies to enhance MKI sensitivity. Metabolic reprogramming, a hallmark of cancer cells that facilitates unchecked growth and metastasis, has emerged as a critical mechanism driving MKI resistance in HCC. This review comprehensively examines the roles of glycolysis, lipid metabolism, and amino acid metabolism in promoting MKI resistance, with a focus on key molecular regulators that could serve as potential targets to reverse resistance. Additionally, this review synthesizes preclinical and clinical evidence of therapeutic agents that synergize with MKIs by modulating metabolic pathways, and discusses the regulatory role of metabolic reprogramming in the tumor immune microenvironment (TIME) of HCC, offering innovative strategies to improve treatment outcomes for patients with HCC. These findings highlight metabolic reprogramming as a crucial target for developing novel interventions aimed at overcoming MKI resistance in clinical practice.