Molecular regulatory network of glycolytic reprogramming in hepatocellular carcinoma and its clinical implications

Hepatocellular carcinoma (HCC) ranks among the most prevalent malignant tumors worldwide, exhibiting persistently high incidence and mortality rates. Metabolic reprogramming, particularly the 'Warburg effect' characterized by aberrantly enhanced glycolysis, serves as a hallmark feature of HCC and various other malignancies. Even under oxygen-sufficient conditions, tumor cells preferentially utilize the glycolytic pathway to convert glucose into lactate. This metabolic mode not only supplies essential energy (ATP) for rapid tumor cell proliferation but, more critically, provides key intermediate metabolites for synthesizing macromolecules such as nucleic acids, lipids, and amino acids. It concurrently regulates the pH and redox status of the tumor microenvironment, thereby robustly supporting tumor growth, invasion, and metastasis. Recent years have witnessed significant advances in research on glycolytic regulatory mechanisms in HCC, revealing an exceptionally complex regulatory network composed of diverse molecules and signaling pathways. This review aims to systematically organize and elucidate the multi-layered molecular mechanisms regulating glycolytic reprogramming in HCC. We will comprehensively examine the multidimensional regulation of key enzymes and glucose transporters within the glycolytic pathway, encompassing transcriptional control, post-translational modifications, and other regulatory layers; We will conduct an in-depth analysis of the central role played by non-coding RNAs (ncRNAs)-including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs)-within the glycolytic regulatory network of HCC; Elucidate how classical signaling pathways and key transcription factors synergistically interact to precisely regulate the glycolytic process; Analyze how post-translational modifications fine-tune the activity of glycolytic enzymes; And discuss how various components within the tumor microenvironment and intercellular communication mechanisms reshape the metabolic phenotypes of HCC. Furthermore, this review summarizes the clinical application value of positron emission tomography (PET) technology based on glycolytic activity in the diagnosis, staging, and prognostic evaluation of HCC. Through a comprehensive elucidation of these complex regulatory networks, this work aims to enhance comprehension of HCC metabolic characteristics and provide a theoretical foundation for exploring novel therapeutic targets and clinical strategies.