Aerobic glycolysis-driven lactate accumulation and acidic tumor microenvironment in hepatocellular carcinoma: a vicious cycle promoting tumor progression

Background: Hepatocellular carcinoma (HCC) is a highly lethal malignancy with rising global incidence. Aberrantly activated aerobic glycolysis is a hallmark of HCC, driving excessive lactate production and the formation of an acidic tumor microenvironment (TME) that promotes malignant progression. Elucidating the underlying mechanisms of this metabolic axis is essential for developing targeted therapeutic strategies. Objective: This review systematically examines the role of the aerobic glycolysis-lactate-acidic TME axis in HCC progression, focusing on its molecular basis, multifaceted functions of lactate, and therapeutic implications. Key Findings: HCC progression is driven by a coordinated "production-efflux" mechanism involving glycolytic rate-limiting enzymes (such as HK2, PKM2, LDH) and the lactate transporter such as MCT4, which together facilitate lactate accumulation and TME acidification. Lactate exerts pleiotropic effects within the TME, including metabolic signaling via GPR81 and ASICs, epigenetic regulation through histone lactylation, and inter-organ crosstalk via the gut-liver axis. Current therapeutic strategies targeting GLUTs, glycolytic enzymes, LDH, and MCT4 are reviewed, along with approaches for direct TME alkalinization and combination regimens with targeted agents. Building upon this landscape, the present review is the first to systematically integrate emerging mechanisms such as histone lactylation and the gut-liver axis, and to explore the synergistic potential of combining metabolic inhibitors with immunotherapy, thereby offering a distinct framework that moves beyond traditional glycolysis-centric narratives in HCC. Challenges and Perspectives: Despite the substantial potential of targeting this metabolic axis, a considerable gap remains between preclinical findings and clinical translation. The pronounced heterogeneity of HCC, along with metabolic plasticity and insufficient drug selectivity, poses major challenges. Future efforts should prioritize the development of highly selective inhibitors and the optimization of combination therapies based on metabolic stratification.