Metabolic-extracellular matrix crosstalk in hepatocellular carcinoma: mechanisms and targeted intervention

Bidirectional crosstalk between metabolic reprogramming and extracellular matrix (ECM) remodeling in hepatocellular carcinoma (HCC) constitutes an important metabolic–ECM regulatory network that contributes to HCC progression. Metabolic derangements disrupt ECM deposition, crosslinking, and matrix mechanical properties, with downstream consequences for tumor invasion, immune evasion, and the establishment of pre-metastatic niches. Matrix remodeling in turn provides feedback via mechanotransduction and associated signaling networks that reprogram tumor cell glycolysis, lipogenesis, and amino acid metabolism, thereby forming a self-reinforcing malignant cycle. The network hubs in this cycle may represent candidate mechanobiological biomarkers for future patient stratification and longitudinal response monitoring, although their diagnostic and prognostic utility requires further clinical validation. Interventions are therefore shifting from single-target therapeutics toward coordinated, multi-node modulation aimed at decoupling the metabolic–ECM axis, including integrin-directed therapeutics combined with those that increase tumor microenvironment permeability; focal adhesion kinase (FAK) inhibitors, including those that disrupt functional coupling to epigenetic regulation; and the use of these regimens combined with anti-angiogenic agents, immunotherapies, or metabolic inhibitors to concurrently attenuate drug delivery barriers, mechanically driven cues, and metabolic plasticity. Collectively, therapeutic strategies aimed at decoupling the metabolic–ECM axis hold translational promise for limiting HCC progression, invasion, and metastasis, but their potential to improve long-term survival remains to be validated in clinical studies.