Aberrant Regulation of Key Enzymes in Hepatocellular Carcinoma: From Metabolic Reprogramming to Diagnostic Markers

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, with complex pathogenesis and limited treatment options. In recent years, the central role of enzymes in the proliferation of HCC has become increasingly prominent, beyond their traditional catalytic function. This review systematically describes the role of enzymes in HCC and their therapeutic potential. Firstly, review outlines some enzymes that drive HCC proliferation, invasion and metastasis, including metabolic enzymes (e.g. HK2, PKM2) in mediating Warburg effect; oxidative stress and detoxification enzymes (e.g. CYP450 family, SOD, PKM2) in accumulating of ROS and inducing of oncogenes; epigenetically modifying enzymes in silencing of tumor suppressor genes. Secondly, review discusses the potential of the enzyme as HCC diagnosis marker, emphasized the emerging markers (such as GP73) in make up for the traditional markers (AFP) lack of sensitivity and specificity of potential. Furthermore, we summarize the therapeutic strategies targeting enzymes, including approved multikinase inhibitors (sorafenib, lenvatinib), immunometabolism targets in clinical trials (IDO1 inhibitors), and preclinical hotspots (such as PKM2 inhibitors, HDAC inhibitors, and PARP inhibitors). Finally, we highlight the key challenges in the field, including the differences in enzyme expression profiles caused by tumor heterogeneity and the compensatory resistance mechanisms, then look forward to the future directions of combination therapy strategies integrated by new technologies such as single-cell sequencing and artificial intelligence. This review aims to highlight the great value and broad prospects of targeted enzyme systems as a precise and innovative strategy to overcome the clinical challenges of HCC.