Abstract Metabolic reprogramming is a hallmark of cancer, including hepatocellular carcinoma (HCC). Cancer cells exhibit enhanced glucose and glutamine uptake, increased glycolysis, pentose phosphate pathway activity, de novo lipogenesis, and altered amino acid metabolism. However, the metabolic crosstalk underlying cancer progression and the strategic directions for drug development remain insufficiently synthesized. This review systematically summarizes the functional mechanisms of key signaling regulators involved in cancer metabolic reprogramming, including mammalian target of rapamycin complex 1 (mTORC1), myelocytomatosis viral oncogene homolog (c-Myc), hypoxia-inducible factor-1α (HIF-1α), activating transcription factor 4 (ATF4), nuclear factor erythroid 2–related factor 2 (NRF2), and sterol regulatory element–binding protein 1 (SREBP1). Notably, we highlight the interconnections among metabolic pathways in cancer cells and the signaling hubs that orchestrate metabolic crosstalk, which together constitute an integrated network of metabolic pathways and their regulatory signals. Metabolic targets and metabolism-directed therapeutic agents with substantial developmental potential are comprehensively summarized, providing up-to-date insights and concrete directions for metabolism-targeted cancer therapy. Encouragingly, agents such as the fatty acid synthase inhibitor TVB-2640 and the glutaminase inhibitor CB-839 have already entered clinical trials. We recognize that adverse effects on normal tissues and drug resistance driven by metabolic plasticity represent major challenges for metabolism-targeted therapies. Accordingly, we systematically summarize innovative strategies that offer new therapeutic possibilities, including targeting multiple metabolic pathways through combination therapy to enhance efficacy, combining metabolic inhibitors to overcome resistance to conventional anticancer agents, leveraging metabolic reprogramming for early cancer detection, and exploring emerging approaches such as immunometabolism and metabolomics.
Yu et al. (Tue,) studied this question.