Journal: International Journal of Oncology

Article Title: Multifaceted roles of lactate dehydrogenase in liver cancer (Review)

doi: 10.3892/ijo.2025.5756

Figure Lengend Snippet: LDH subtypes and associated distribution. LDH is a tetrameric enzyme composed of A (M) and/or B (H) subunits. LDHA and LDHB are encoded by the LDHA gene and LDHB gene, respectively . By altering the combination of A and B subunits, five isoenzyme forms can be produced: LDH-1, H4; LDH-2, H3M; LDH-3, H2M2; LDH-4, HM3; and LDH-5, M4 ( , ). LDH-1 and LDH-2 are primarily detected in the heart and red blood cells, while LDH-3 is found in the brain, and LDH-5 and LDH-4 are found in both liver and skeletal muscle . Among these subtypes, LDHA (LDH-5) and LDHB (LDH-1) have a notable association with liver cancer, particularly LDHA. LDHA is highly expressed in liver cancer cells, catalyzing the conversion of lactic acid to pyruvate, maintaining metabolic balance and regulating the tumor microenvironment, thereby promoting invasion and metastasis. High LDHA expression is associated with the invasiveness and resistance to treatment in liver cancer. By contrast, low expression of LDHB in liver cancer may be related to metabolic status and treatment sensitivity. In liver cancer diagnosis, the ratio of serum LDH isoenzymes can reflect the origin of the tumor and its pathological type ( , ). In liver cancer treatment, gene editing techniques such as RNAi or CRISPR to inhibit LDH-5 expression may be used ( - ). In the evaluation of prognosis of liver cancer, serum LDH levels can be used to assess the risk of progression and recurrence of liver cancer ( , ). LDH, lactate dehydrogenase; RNAi, RNA interference.

Article Snippet: Catalysis of the conversion of pyruvate to lactate by LDH helps to regulate the intracellular NADH/NAD + ratio, and a normal intracellular NADH/NAD + ratio is essential for various cellular processes, including the oxidative stress response, DNA repair and cell signaling ( ).

Techniques: Produced, Expressing, Biomarker Discovery, CRISPR

Journal: International Journal of Oncology

Article Title: Multifaceted roles of lactate dehydrogenase in liver cancer (Review)

doi: 10.3892/ijo.2025.5756

Figure Lengend Snippet: Metabolic reprogramming of HCC cells. HCC cells meet the needs of rapid cell proliferation through metabolic reprogramming and aerobic glycolysis of hepatoma cells is enhanced . By reducing pyruvate to lactate, LDH maintains the dynamic balance of NADH/NAD + in cells and ensures the stability of the intracellular redox environment . Glycolysis may also provide the PPP substrate required for nucleotide synthesis ( , ). LDH regulates lipid metabolism through the regulation of NAD + /NADH balance, with increased de novo fat synthesis and increased FA β-oxidation in hepatocellular carcinoma cells ( , ). Lactate can enter mitochondria through the lactate shuttle mechanism and be converted to pyruvate under the reverse catalysis of LDH. LDH participates in the TCA and provides more energy to cells . HCC, hepatocellular carcinoma; LDH, lactate dehydrogenase; GLUT1, glucose transporter; SGLT2, glucose transporter sodium-glucose cotransporter 2; P, phosphate; G-6-P, glucose-6-P; PPP, pentose phosphate pathway; R-5-P, ribose-5-P; G-3-P, glyceraldehyde-3-P; ATP, adenosine triphosphate; TCA, Tricarboxylic acid cycle; FA, fatty acid.

Article Snippet: Catalysis of the conversion of pyruvate to lactate by LDH helps to regulate the intracellular NADH/NAD + ratio, and a normal intracellular NADH/NAD + ratio is essential for various cellular processes, including the oxidative stress response, DNA repair and cell signaling ( ).

Techniques:

Journal: International Journal of Oncology

Article Title: Multifaceted roles of lactate dehydrogenase in liver cancer (Review)

doi: 10.3892/ijo.2025.5756

Figure Lengend Snippet: Roles of LDH in the occurrence and development of liver cancer. (A) LDH is involved in numerous aspect of metabolic reprogramming of liver cancer: i) Glycolysis: LDH catalyzes the conversion of pyruvate to lactate, which supports the energy metabolism of HCC cells under hypoxic conditions; ii) pentose phosphate pathway: LDH, through NADH, promotes ribosome, regenerates NADH and supports the biosynthetic requirements of cancer cells; iii) redox balance: LDH maintains the redox homeostasis of the tumor microenvironment through lactate metabolism and promotes cancer cell survival. (B) Roles of LDH in the tumor microenvironment of liver cancer are as follows: i) lactate levels increase in the tumor microenvironment, leading to metabolic abnormalities, acidic environment and fibrosis; ii) immunosuppression: LDH regulates T-cell function through lactate metabolism, whereby the accumulation of lactic acid changes the acidic pH of the tumor microenvironment, inhibits the activity of CD8 + T cells, and promotes the recruitment of Tregs and the polarization of tumor-associated macrophages to the M2-like phenotype ( - ); iii) angiogenesis: Lactate promotes the expression of VEGF by activating the HIF-1 α signaling pathway and then induces VEGF-mediated angiogenesis ( , ); iv) fibrosis: Lactate metabolites promote fibroblast activation, leading to tumor-associated fibrosis; and v) cancer cell properties: HCC cells with high LDH expression showed greater proliferative capacity, invasiveness and metastatic capacity . HCC, hepatocellular carcinoma; LDH, lactate dehydrogenase; TAM, tumor-associated macrophages; HIC-1α, hypoxia-inducible factor 1α; regulatory T cells, Tregs.

Article Snippet: Catalysis of the conversion of pyruvate to lactate by LDH helps to regulate the intracellular NADH/NAD + ratio, and a normal intracellular NADH/NAD + ratio is essential for various cellular processes, including the oxidative stress response, DNA repair and cell signaling ( ).

Techniques: Cell Function Assay, Activity Assay, Expressing, Activation Assay