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Coronavirus disease 2019 (COVID-19) infection has now reached a pandemic state, affecting more than a million patients worldwide. Predictors of disease outcomes in these patients need to be urgently assessed to decrease morbidity and societal burden. Lactate dehydrogenase (LDH) has been associated with worse outcomes in patients with viral infections. In this pooled analysis of 9 published studies (n = 1532 COVID-19 patients), we evaluated the association between elevated LDH levels measured at earliest time point in hospitalization and disease outcomes in patients with COVID-19. Elevated LDH levels were associated with a ~6-fold increase in odds of developing severe disease and a ~16-fold increase in odds of mortality in patients with COVID-19. Larger studies are needed to confirm these findings.

Although normally dormant, hair follicle stem cells (HFSCs) quickly become activated to divide during a new hair cycle. The quiescence of HFSCs is known to be regulated by a number of intrinsic and extrinsic mechanisms. Here we provide several lines of evidence to demonstrate that HFSCs utilize glycolytic metabolism and produce significantly more lactate than other cells in the epidermis. Furthermore, lactate generation appears to be critical for the activation of HFSCs as deletion of lactate dehydrogenase (Ldha) prevented their activation. Conversely, genetically promoting lactate production in HFSCs through mitochondrial pyruvate carrier 1 (Mpc1) deletion accelerated their activation and the hair cycle. Finally, we identify small molecules that increase lactate production by stimulating Myc levels or inhibiting Mpc1 carrier activity and can topically induce the hair cycle. These data suggest that HFSCs maintain a metabolic state that allows them to remain dormant and yet quickly respond to appropriate proliferative stimuli. Flores et al. show that hair follicle stem cells rely on the production of lactate via the LDHA enzyme to become activated. Inducing Ldha through Mpc1 inhibition or Myc activation successfully reactivates the hair cycle in quiescent follicles.

Elevated glycolysis remains a universal and primary character of cancer metabolism, which deeply depends on dysregulated metabolic enzymes. Lactate dehydrogenase A (LDHA) facilitates glycolytic process by converting pyruvate to lactate. Numerous researches demonstrate LDHA has an aberrantly high expression in multiple cancers, which is associated with malignant progression. In this review, we summarized LDHA function in cancer research. First, we gave an introduction of structure, location, and basic function of LDHA. Following, we discussed the transcription and activation mode of LDHA. Further, we focused on the function of LDHA in cancer bio‐characteristics. Later, we discussed the clinical practice of LDHA in cancer prevention and treatment. What we discussed gives a precise insight into LDHA especially in cancer research, which will contribute to exploring cancer pathogenesis and its handling measures. LDHA contributes to diverse bio‐characteristics of tumors via numerous mechanisms. LDHA has been used as a tumor biomarker for clinical diagnosis and treatment and is considered as a potential anticancer target.

Lactate dehydrogenase A (LDHA) is an important enzyme in fermentative glycolysis, generating most energy for cancer cells that rely on anaerobic respiration even under normal oxygen concentrations. This renders LDHA a promising molecular target for the treatment of various cancers. Several efforts have been made recently to develop LDHA inhibitors with nanomolar inhibition and cellular activity, some of which have been studied in complex with the enzyme by X-ray crystallography. In this work, we present a molecular dynamics (MD) study of the binding interactions of selected ligands with human LDHA. Conventional MD simulations demonstrate different binding dynamics of inhibitors with similar binding affinities, whereas steered MD simulations yield discrimination of selected LDHA inhibitors with qualitative correlation between the in silico unbinding difficulty and the experimental binding strength. Further, our results have been used to clarify ambiguities in the binding modes of two well-known LDHA inhibitors.

Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in breast cancer cells by binding to and activating lactate dehydrogenase A (LDHA), which promoted histones lysine lactylation to induce the expression of a series of downstream genes and LDHA itself. Notably, increased expression of LDHA served as a vicious positive feedback to reduce tumor cell stiffness and adhesion, which eventually resulted in the proliferation, invasion, and metastasis of breast cancer. In conclusion, our results suggest that KCNK1 may serve as a potential breast cancer biomarker, and deeper insight into the cancer-promoting mechanism of KCNK1 may uncover a novel therapeutic target for breast cancer treatment.

Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.

Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2−), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2− invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized [1-13C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized [1-13C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia.

Lactate dehydrogenase (LDH) catalyses the conversion of pyruvate to lactate and NADH to NAD + ; it has two isoforms, LDHA and LDHB. LDHA is a promising target for cancer therapy, whereas LDHB is necessary for basal autophagy and cancer cell proliferation in oxidative and glycolytic cancer cells. To the best of our knowledge, selective inhibitors for LDHB have not yet been reported. Here, we developed a high-throughput mass spectrometry screening system using an LDHB enzyme assay by detecting NADH and NAD + . As a result, we identified a small-molecule LDHB selective inhibitor AXKO-0046, an indole derivative. This compound exhibited uncompetitive LDHB inhibition (EC 50  = 42 nM). X-ray crystallography revealed that AXKO-0046 bound to the potential allosteric site away from the LDHB catalytic active site, suggesting that targeting the tetramerisation interface of the two dimers is critical for the enzymatic activity. AXKO-0046 and its derivatives can be used to validate LDHB-associated pathways in cancer metabolism.

One of the hallmarks of cancer cells is increased energy requirements associated with the higher rate of cellular proliferative activity. Metabolic changes in rapidly dividing cancer cells are closely associated with increased uptake of glucose and abnormal activity of lactate dehydrogenase (LDH), which regulates the processing of glucose to lactic acid. As serum LDH levels were found to be commonly increased in cancer patients and correlated with poor clinical outcome and resistance to therapy, the determination of LDH has become a standard supportive tool in diagnosing cancers or monitoring the effects of cancer treatment. The aim of this review is to summarize the current knowledge about methods and the practical utility for measuring both the total LDH and LDH isoenzymatic activities in the diagnosis, prognosis and prediction of cancer diseases.

Metastases remain the major cause of death from cancer. Recent molecular advances have highlighted the importance of metabolic alterations in cancer cells, including the Warburg effect that describes an increased glycolysis in cancer cells. However, how this altered metabolism contributes to tumour metastasis remains elusive. Here, we report that phosphorylation-induced activation of lactate dehydrogenase A (LDHA), an enzyme that catalyses the interconversion of pyruvate and lactate, promotes cancer cell invasion, anoikis resistance and tumour metastasis. We demonstrate that LDHA is phosphorylated at tyrosine 10 by upstream kinases, HER2 and Src. Targeting HER2 or Src attenuated LDH activity as well as invasive potential in head and neck cancer and breast cancer cells. Inhibition of LDH activity by small hairpin ribonucleic acid or expression of phospho-deficient LDHA Y10F sensitized the cancer cells to anoikis induction and resulted in attenuated cell invasion and elevated reactive oxygen species, whereas such phenotypes were reversed by its product lactate or antioxidant N-acetylcysteine, suggesting that Y10 phosphorylation-mediated LDHA activity promotes cancer cell invasion and anoikis resistance through redox homeostasis. In addition, LDHA knockdown or LDHA Y10F rescue expression in human cancer cells resulted in decreased tumour metastasis in xenograft mice. Furthermore, LDHA phosphorylation at Y10 positively correlated with progression of metastatic breast cancer in clinical patient tumour samples. Our findings demonstrate that LDHA phosphorylation and activation provide pro-invasive, anti-anoikis and pro-metastatic advantages to cancer cells, suggesting that Y10 phosphorylation of LDHA may represent a promising therapeutic target and a prognostic marker for metastatic human cancers.