LDH is a redox enzyme present in multiple tissues, participating in the ultimate stage of glycolysis by catalyzing the reversible conversion between pyruvate and lactate. LDH primarily consists of M and H subunits. These two subunits assemble into five distinct tetrameric isoforms: two homotetramers, LDHB (H4) and LDHA (M4), along with three heterotetramers, namely LDH-2 (H3M), LDH-3 (H2M2), and LDH-4 (HM3) (6). The expression patterns of LDH isoenzymes display considerable diversity among different tissues. LDHB and LDH-2 are the predominant forms found in cardiac muscle and erythrocytes. The LDH-3 demonstrates elevated expression in cerebral tissue. While LDHA and LDH-4 are primarily located within liver and skeletal muscle (10). Recent research has identified a novel protein, designated LDHAα, which is 3 kDa larger than LDHA and expresses in various cancer cells. This protein enhances glycolytic activity, significantly boosting glucose uptake, lactate production, and tumor growth capacity (11). Additionally, researchers have identified a specific isoenzyme in testicular tissue named as LDH-C4. Early studies have classified it as a cancer testis antigen (12).

The primary function of LDH is to catalyze the reversible redox reaction between lactate and pyruvate. Under sufficient oxygen supply, LDHB predominantly catalyzes the oxidation of lactate to pyruvate which is channeled into the mitochondrial TCA cycle, followed by the oxidative phosphorylation process, enabling efficient ATP production. In hypoxic conditions, pyruvate cannot enter the TCA cycle. Instead, it is reduced to lactate by LDHA, simultaneously oxidizing NADH to NAD⁺. This process ensures glycolysis can continue under oxygen-deprived conditions (6). Notably, even under normal oxygen partial pressure, tumor cells preferentially oxidize glucose to lactate via aerobic glycolysis to generate rapid, low-yield ATP rather than entering mitochondrial oxidative phosphorylation—a phenomenon termed the Warburg effect (5). Extensive research indicates that LDHA expression is mostly upregulated in cancer cells, potentially linked to the metabolic reprogramming of tumor cells (13). Related studies in T cells further reveal that the dynamic equilibrium between LDHA and LDHB is pivotal for governing normal cellular activities. Specific knockout of LDHA inhibits glycolytic flux, cell proliferation, and differentiation processes. Conversely, while knockout of LDHB partially boosts glycolysis but also impedes T cell differentiation. An appropriate ratio of LDHA to LDHB is crucial for maintaining glycolytic activity, redox homeostasis, and normal cellular physiological functions (14).

Unlike normal cells, tumor cells tend to take up large amounts of glucose and convert it into lactate even in oxygen-rich environments, while simultaneously reducing oxidative phosphorylation levels. Otto Warburg initially attributed this phenomenon to mitochondrial dysfunction (23). Subsequent research has progressively refined this understanding. Hypoxia emerges as a fundamental characteristic of the tumor microenvironment due to local blood supply insufficiency caused by rapid tumor growth (24). Furthermore, tumor cells exhibit biological traits such as unlimited proliferative potential, persistent angiogenesis, anti-apoptotic capacity, insensitivity to inhibitory signals, and invasive metastasis. To acquire the energy and nutrients required for survival and maintenance of these essential functions, tumor cells must undergo metabolic reprogramming (25). Tumor metabolic reprogramming encompasses multiple aspects including glucose utilization, glutamine breakdown, lipid uptake and oxidation, and branched-chain amino acid metabolism, with alterations in glucose metabolism being most prominent. This is because glycolysis produces essential biosynthetic substrates and intermediates required for the production of amino acid, nucleotide, and lipid synthesis beyond of providing energy (26). Although complete oxidative phosphorylation of glucose yields approximately 36 ATP molecules per glucose molecule, while glycolysis generates only 2 ATP molecules, lactate production occurs roughly two orders of magnitude faster than oxidative phosphorylation. This facilitates rapid fulfillment of the energy demands for tumor cell proliferation (27), providing a rational physiological explanation for tumors’ preference for aerobic glycolysis.

Glucose metabolic reprogramming is regulated by multifaceted mechanisms, including critical metabolic enzyme activities, transcriptional regulator actions, the triggering of signaling cascades and the modulation of metabolic feedback. Within the group of glycolysis-related enzymes, HK2 and LDHA play particularly prominent roles. The binding of HIF-1α to a Hypoxia-Response HRE present in the HK2 promoter leads to the subsequent activation of this gene’s transcription. This allows tumor cells to sustain an elevated glycolytic flux despite the presence of adequate oxygen (28). As a core regulator of tumor invasion and energy metabolism adaptation, HIF-1α directly binds to HREs of glycolysis-related genes (GLUT1, HK2, PDK1, LDHA, etc.), increasing expression of key glycolytic enzymes and suppressing mitochondrial aerobic metabolism, playing a pivotal role in cancer cell growth and metastasis (29). Moreover, HIF-1α serves as a central node integrating multiple transcriptional regulation and signaling pathways (30). Ma et al. demonstrated that CREB1 activates the HIF-1 signaling axis by upregulating WNK1, thereby promoting proliferation and metastatic behavior in ovarian cancer cells (31). Furthermore, acting as a key regulator, Myc drives the expression of numerous glycolysis-related genes through direct transcriptional upregulation, including LDHA, significantly enhancing tumor cell glycolytic capacity (32).

LDH not only directly promotes tumor cell proliferation by catalyzing glycolytic reprogramming, but its enzymatic activity and downstream glycolytic metabolites also play a pivotal role in shaping and maintaining the tumor microenvironment (TME). TME, a complex cellular ecosystem, chiefly comprises malignant tumor cells alongside diverse non-malignant cells including fibroblasts, macrophages, various immune cells, mesenchymal stem cells, and endothelial cells. These cells collectively sustain tumor growth and proliferation through metabolic crosstalk (33). Verma et al. demonstrated that LDHA expression is significantly higher in cancer cells than in non-cancerous cells. LDH inhibitors can rebalance glycolytic competition between tumor cells and infiltrating regulatory Tregs, disrupting Tregs functional stability (34). Within tumor tissues and their microenvironments, Tregs suppress the activity of other immune cells, aiding tumor immune evasion and promoting growth (35).

The substantial lactate produced during glycolysis further promotes the progression of gynecological malignancies by modulating the tumor microenvironment (36). Microenvironment acidification directly impairs the function of CD8⁺ and CD4⁺ T lymphocytes, and suppresses T cell proliferation and weakens the cytotoxicity of NK cells, consequently promoting the evasion of immune surveillance by malignant cells (37). Tumor-associated macrophages (TAMs), abundant in the TME, serve as key mediators of immunosuppression. Xiao die Li et al. found that in endometrial cancer, lactate drives M2 polarization of TAMs, which enhances tumor aggressiveness by facilitating EMT and angiogenesis (38). Lactic acid generated via LDH-mediated pathways also modulates interactions between tumor cells and vascular endothelial cells (36). Studies indicate that lactic acid enhances HIF1α stability in tumor-associated endothelial cells, subsequently inducing the expression of VEGF, which facilitates angiogenesis in ovarian cancer (39, 40). Cancer-associated fibroblasts (CAFs), one of the mainly matrix cell types in the TME, extensively communicate with cancer cells through signaling molecule secretion or intercellular adhesion. They also remodel the extracellular matrix and modulate immune cells, collectively promoting tumor proliferation, metastasis, and immune evasion (41). Additionally, PARP-1 activation by reducing the NAD⁺/NADH ratio and downregulates p62 expression which acts as an inhibitor of CAF activation and tumor progression (42). Conversely, overexpression of GLUT1 in CAFs enhances glucose transport and accelerates glycolysis and elevates lactate output, promoting ovarian cancer cell proliferation and migration via the TGF-β1/p38/MMP2/MMP9 signaling pathway (43). Accumulated lactate in the TME also enhances tumor cell resistance to ferroptosis, making a contribution to tumor cell proliferation, metastasis, and drug resistance (44).

Lactate is not merely a metabolic byproduct, but also serves as a precursor for epigenetic modifications. Lactylation, a novel post-translational modification where lactate binds lysine residues, drives tumor progression by accelerating proliferation, dissemination and chemoresistance (37). A study in investigating ovarian cancer resistance to niraparib revealed that H4K12 lactylation upregulates RAD23A via super-enhancers, potentiating DNA repair and fostering chemoresistance (15). Another study indicated that L-lactic acid increases lactylation modification of the DCBLD1 protein, directly stabilizing DCBLD1 and enhancing its transcription and expression, ultimately boosting cervical cancer cell growth, invasion, and treatment resistance (45).

The elevated expression of LDH in tumor tissue provides valuable information for cancer diagnosis. In its initial phases, ovarian carcinoma frequently demonstrates a lack of characteristic clinical manifestations (46). CA125 and HE4 are commonly used in clinical practice for ovarian cancer diagnosis. While serum CA125 is elevated in most patients, its sensitivity for early-stage disease is low (47). HE4, as a more specific biomarker, is often combined with CA125 to improve accuracy (48). Unlike these conventional markers that indicate tumor origin or monitor recurrence, LDH reflects metabolic reprogramming and immunosuppressive microenvironment features, collectively representing tumor metabolic activity and invasiveness, thereby complementing traditional biomarkers. Studies indicate that combining ovarian malignant tumor risk prediction models with LDH testing aids in distinguishing early-stage ovarian cancer from benign ovarian lesions, combining LDH with traditional biomarkers may enhance early ovarian cancer detection (49). However, existing evidence mainly derives from retrospective studies in diagnosed patients, likely missing undetected early cases due to diagnostic challenges. Thus, LDH remains a preliminary screening candidate, lacking prospective validation in asymptomatic populations. Research on LDH is more established in ovarian than in cervical or endometrial cancers. Although LDHA shows diagnostic potential for endometrial carcinoma (17), current in vitro evidence is inadequate to support its clinical reliability as a novel biomarker.

As an indicator of tumor metabolic activity and burden, LDH demonstrates prognostic potential in ovarian cancer. A study revealed that serum LDH concentrations in ovarian cancer patients are significantly higher than in those with benign tumors, and these levels correlate closely with tumor clinical staging and pathological grading (50). Numerous studies have confirmed that elevated LDH levels are closely associated with adverse outcomes in cervical cancer. A study involving 908 cervical cancer cases demonstrated that serum LDH was universally elevated, with higher LDHA expression typically associated with poorer prognosis (51). A multivariate logistic regression analysis by Qiuyuan Huang et al. revealed a significant positive correlation between LDH levels and lymphatic metastasis in cervical cancer cohort. Elevated LDH was associated with increased likelihood of deep stromal invasion and lymphovascular invasion, suggesting its potential as a tumor marker and treatment monitoring indicator (52). Further research indicates that regardless of FIGO stage in cervical cancer, overexpression of both LDHA and PFKP is significantly correlated with poorer overall survival, elevated likelihood of recurrence, and higher mortality risk, suggesting their importance in assessing disease progression and prognosis (53). In light of this, clinicians can accurately assess disease progression by integrating LDH levels with gynecological malignancy-specific markers and imaging data.

Treatment modalities for gynecologic malignancies principally include surgery, systemic chemotherapy, radiotherapy, and immunotherapy (54). For advanced or recurrent cases post-surgery, chemotherapy and immunotherapy often serve as core strategies. However, low drug sensitivity remains a major challenge (55). The development of drug resistance is a key factor in treatment failure and disease recurrence (56), making the need for personalized treatment strategies increasingly urgent. Multiple studies suggest associations between serum LDH levels and drug efficacy and resistance. As a case in point, Asami Ikeda et al. reported that elevated serum LDH and NLR may predict platinum resistance and poor prognosis in ovarian cancer patients, providing reference for personalized treatment (57). The KELIM score serves as a reliable indicator for assessing chemotherapy sensitivity in ovarian cancer, with higher scores suggesting better treatment response (58). Among patients with poor KELIM scores, those with elevated LDH levels derive minimal benefit from first-line bevacizumab therapy. Lower LDH levels (≤ 210 U/L) serve as an independent predictor of therapeutic benefit from this agent in advanced ovarian cancer (59). Thus, dynamic monitoring of LDH levels before or during treatment may provide crucial guidance for optimizing chemotherapy regimens.

As a key enzyme regulating glycolysis in tumor cells, LDHA is emerging as a promising and prospective focus in developing novel anticancer therapeutics overcoming drug resistance (9). Studies indicate that isoprolactone reduces glucose uptake and lactate production in cisplatin-resistant ovarian cancer cells by targeting LDHA inhibition, increasing the susceptibility of cisplatin, suppressing tumor growth and overcoming resistance (60). Research by Y Tian et al. indicates that miR-1271 suppresses proliferation and metastatic capacity in endometrial cancer cells by downregulating LDHA expression, providing theoretical support for developing novel biomarkers and therapeutic strategies (61). In cervical cancer, inhibiting LDHA induces G2/M phase cell cycle arrest and activates the mitochondrial-mediated apoptosis pathway (62). On the contrary, Chaoran Jia et al. demonstrated that LDHA deficiency paradoxically suppresses glucose-starvation-induced ferroptosis, consequently stimulating cell multiplication and the process of oncogenesis (20). Accordingly, whether LDHA inhibition strategies are applicable for targeted therapy in cervical cancer warrants further investigation.