Affinage

LDHA

L-lactate dehydrogenase A chain · UniProt P00338

Length
332 aa
Mass
36.7 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LDHA is the glycolytic enzyme catalyzing NADH-dependent conversion of pyruvate to lactate, and its expression and activity are tuned by an extensive regulatory network that drives aerobic glycolysis (the Warburg effect) in cancer and in tissue remodeling (PMID:24634381, PMID:28193910). Transcriptionally, LDHA is activated by hypoxia-responsive HIF-1α/HIF-2α binding an upstream HRE (PMID:28193910), by FOXM1 (PMID:24634381), by histone-demethylase–driven chromatin remodeling at its locus (JMJD2A, KDM6B) (PMID:28693517, PMID:33664867), and by c-Myc–containing complexes recruited with MTA1 or NUSAP1/HIF-1α (PMID:31570164, PMID:37354982), while it is directly repressed by KLF4 and by FOXO4 acting downstream of HIF-1α (PMID:24947925, PMID:33463054). Post-transcriptionally, METTL3-deposited m6A on the LDHA CDS promotes its translation via YTHDF1 (PMID:35832094). Enzymatic output is further controlled by post-translational modifications: tyrosine-10 phosphorylation by HER2/Src and FGFR1 activates LDHA and is scaffolded by FKBP10 and circVAMP3 (PMID:28218905, PMID:38233415, PMID:35525866); K155 succinylation, set by competition between SIRT5 and the lncRNA GLTC, raises activity (PMID:37031273); ZDHHC9-mediated C163 palmitoylation increases activity and lowers ROS (PMID:38331089); and BH4/NO-dependent S-nitrosylation at C163/C293 restrains LDHA-driven ROS (PMID:38689083). Beyond catalysis, LDHA performs noncanonical, lactate-independent functions: it binds active Rac1-GTP to shield it from GAPs and sustain Rac1 signaling (PMID:36536137), and it sequesters eEF2 in an NADH-dependent manner to control mRNA translation during megakaryocyte maturation (PMID:35176139). The lactate it produces acts as a signaling and epigenetic substrate, driving H3K18 histone lactylation at target promoters (JunB, TPI1) and lactylation of NLRP3 and NUSAP1 (PMID:35605402, PMID:39086231, PMID:39548367, PMID:37354982), and accumulating in the tumor microenvironment to suppress NFAT-dependent IFN-γ production and impair T/NK and CD8+ cytotoxic responses (PMID:27641098, PMID:36150745). Through these activities LDHA promotes cancer growth, invasion, and immune evasion and contributes to cardiomyocyte proliferation, vascular smooth-muscle remodeling, inflammatory chondrocyte catabolism, and trophoblast proliferation (PMID:32647171, PMID:36057161, PMID:34973467, PMID:36583693).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2014 High

    Established that LDHA expression is set by opposing transcription factors at its promoter, defining a bidirectional control point for aerobic glycolysis in tumors.

    Evidence ChIP and luciferase reporter assays with FOXM1 (activating) and KLF4 (repressing) in pancreatic cancer, with in vivo models

    PMID:24634381 PMID:24947925

    Open questions at the time
    • Did not resolve how activating and repressing inputs are integrated at the locus
    • Restricted to pancreatic cancer context
  2. 2016 High

    Showed that LDHA-derived lactate is not merely metabolic waste but an immunosuppressive signal, linking tumor glycolysis to immune evasion.

    Evidence Ldha-low tumor cells across immunocompetent, Rag2−/−γc−/−, and Ifng−/− mice with NFAT/IFN-γ readouts

    PMID:27641098

    Open questions at the time
    • Did not define the lactate sensor in T/NK cells
    • Mechanism of NFAT suppression by lactate not detailed
  3. 2017 High

    Identified hypoxic transcriptional induction (HIF-1α/HIF-2α) and activating Y10 phosphorylation (HER2/Src) as parallel routes that boost LDHA activity and promote metastasis via redox control.

    Evidence ChIP/luciferase for HIF binding; Y10F mutagenesis, kinase inhibitors, ROS/anoikis assays and xenograft metastasis models

    PMID:28193910 PMID:28218905

    Open questions at the time
    • Did not establish structural basis of Y10 phosphorylation on activity
    • Interplay between transcriptional and PTM control not addressed
  4. 2021 Medium

    Extended LDHA regulation to chromatin and signaling axes, showing histone-demethylase control at the locus and lactate-driven downstream signaling pathways.

    Evidence KDM6B/H3K27me3 ChIP in osteosarcoma; FOXO4 ChIP in gastric cancer; LDHA-NDRG3-ERK-MMP and AMPK/autophagy analyses in vascular and thyroid models

    PMID:33463054 PMID:33664867 PMID:33795650 PMID:34973467

    Open questions at the time
    • Single-lab studies in distinct disease contexts
    • Direct vs indirect effects of lactate on each signaling node not fully separated
  5. 2022 High

    Defined LDHA's noncanonical, glycolysis-independent moonlighting functions — sustaining Rac1 activity and sequestering eEF2 — separating its enzymatic from non-enzymatic oncogenic roles.

    Evidence Reciprocal Co-IP and activity-dead LDHA mutants for Rac1; NADH-dependent eEF2 Co-IP with MK-specific Ldha knockout mice and translation assays

    PMID:35176139 PMID:36536137

    Open questions at the time
    • Binding interfaces with Rac1 and eEF2 not structurally mapped
    • Extent of moonlighting functions across tissues unknown
  6. 2022 Medium

    Revealed PTM- and RNA-mediated layers (succinylation, m6A, scaffolding RNAs) that fine-tune LDHA activity and translation beyond transcription.

    Evidence Mass-spec succinylation mapping with SIRT5/GLTC competition; METTL3 m6A MeRIP with YTHDF1; circVAMP3/FKBP10 scaffolding of Y10 phosphorylation

    PMID:35525866 PMID:35832094 PMID:37031273 PMID:38233415

    Open questions at the time
    • Cross-talk among multiple PTMs on the same enzyme not integrated
    • Most findings from single labs in individual cancer types
  7. 2024 Medium

    Cemented lactate as an epigenetic and protein-stability signal through histone and non-histone lactylation, and added lipid/nitrosylation PTM control of LDHA's redox output.

    Evidence H3K18la ChIP at TPI1/JunB promoters; NLRP3 K245 and NUSAP1 lactylation; ZDHHC9 C163 palmitoylation and BH4/NO C163/C293 S-nitrosylation with conditional mouse models

    PMID:38331089 PMID:38689083 PMID:38905316 PMID:39086231 PMID:39548367

    Open questions at the time
    • Whether lactylation targets are direct LDHA substrates or downstream of bulk lactate unresolved
    • Functional mutagenesis of nitrosylation sites not fully reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the dense, partly overlapping network of LDHA PTMs and transcriptional inputs is coordinated in a single cell, and which moonlighting functions dominate in physiological versus disease settings, remains unresolved.
  • No unified model integrating PTM cross-talk on residues such as C163 (palmitoylation vs S-nitrosylation)
  • Structural basis of non-enzymatic partner binding undefined
  • Relative contribution of enzymatic vs moonlighting roles in vivo unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 5 GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-4839726 Chromatin organization 3
Partners
EEF2FKBP10KCNK1NLRP3RAC1SIRT5TXNRD1ZDHHC9

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 LDHA is phosphorylated at tyrosine 10 (Y10) by upstream kinases HER2 and Src; this phosphorylation activates LDHA enzymatic activity and promotes cancer cell invasion, anoikis resistance, and tumor metastasis through redox homeostasis (ROS regulation). Expression of phospho-deficient LDHA Y10F sensitized cells to anoikis and elevated ROS, while lactate or antioxidant NAC reversed these phenotypes. Site-directed mutagenesis (Y10F), kinase inhibitor treatment, shRNA knockdown, in vitro LDH activity assay, xenograft metastasis model, patient sample correlation Oncogene High 28218905
2022 LDHA interacts with active Rac1 (Rac1-GTP) to inhibit its interaction with GTPase-activating proteins (GAPs), thereby sustaining Rac1 activation independently of LDHA's glycolytic enzyme activity. This noncanonical oncogenic mechanism promotes cancer cell growth, and combination inhibition of LDHA enzyme activity plus Rac1 shows synergistic anti-tumor effects in breast cancer. Co-immunoprecipitation, pulldown assays, Rac1-GTP activity assays, glycolytic-activity-dead LDHA mutants, in vivo breast cancer models, clinical sample analysis Nature metabolism High 36536137
2020 Under inflammatory conditions, NF-κB activation in chondrocytes promotes metabolic reprogramming toward LDHA. LDHA binds NADH and promotes reactive oxygen species (ROS) generation, which stabilizes IκB-ζ, a pro-inflammatory mediator, inducing catabolic changes in chondrocytes relevant to osteoarthritis pathogenesis. NF-κB pathway modulation, LDHA knockdown/overexpression, ROS measurement, IκB-ζ protein stability assays, in vivo OA models Nature communications High 32647171
2022 LDHA interacts with eukaryotic elongation factor 2 (eEF2) in the cytoplasm in an NADH-dependent manner, sequestering eEF2 from ribosomes and thereby controlling translation. LDHA knockout in megakaryocytes releases eEF2 to participate in translation, accelerating megakaryocyte maturation and platelet production. This function is independent of LDHA's lactate-producing activity. Co-immunoprecipitation, MK/platelet-specific Ldha knockout mice, in vitro translation assays, NADH-competitive LDHA inhibitors, platelet count measurements, human cord blood MK differentiation Blood High 35176139
2023 The lncRNA GLTC binds LDHA and competitively inhibits the interaction between SIRT5 (a desuccinylase) and LDHA, thereby promoting succinylation of LDHA at lysine 155 (K155). K155 succinylation increases LDHA enzymatic activity and aerobic glycolysis; expression of a succinylation-mimetic LDHAK155E mutant rescues glycolysis in GLTC-depleted cells. Mass spectrometry identification of succinylation site, Co-immunoprecipitation, SIRT5 competition assay, site-directed mutagenesis (K155E succinylation mimetic), in vitro enzymatic activity assay, in vivo xenograft model Cell death and differentiation High 37031273
2024 LDHA is palmitoylated by the palmitoyltransferase ZDHHC9 at cysteine 163. This palmitoylation promotes LDHA enzymatic activity, increases lactate production, and reduces ROS generation. A palmitoylation-deficient LDHA mutant (C163A) reduces pancreatic cancer cell proliferation and tumor growth, and LDHA palmitoylation is upregulated in gemcitabine-resistant cells. Palmitoylation site mapping, ZDHHC9 knockdown/overexpression, palmitoylation-deficient mutant (C163A), in vitro LDHA activity assay, ROS measurement, xenograft tumor model Cancer letters High 38331089
2014 Transcription factor FOXM1 directly binds to the LDHA promoter and transcriptionally activates LDHA gene expression, thereby upregulating LDH enzymatic activity, lactate production, and glucose utilization in pancreatic cancer cells. Chromatin immunoprecipitation (ChIP) assay, luciferase reporter assay, FOXM1 overexpression/knockdown, LDH activity measurement, in vivo pancreatic cancer models Clinical cancer research High 24634381
2014 Transcription factor KLF4 directly binds to the LDHA gene promoter and negatively regulates its transcription, suppressing LDHA expression and aerobic glycolysis in pancreatic cancer cells. Chromatin immunoprecipitation (ChIP) assay, KLF4 overexpression/knockdown, LDHA promoter reporter assay, glycolysis measurements (glucose consumption, lactate production), orthotopic mouse model Clinical cancer research High 24947925
2017 HIF-1α and HIF-2α bind to the LDHA promoter at an HRE site 89 bp upstream under hypoxic conditions, directly activating LDHA transcription in pancreatic cancer cells. Knockdown of HIF-1α and HIF-2α decreases LDHA expression, lactate production, and glucose utilization even under hypoxia. Chromatin immunoprecipitation (ChIP) assay, luciferase reporter assay, HIF-1α/HIF-2α siRNA knockdown, lactate and glucose measurements, immunofluorescence in patient specimens Oncotarget High 28193910
2024 FKBP10 binds directly to LDHA through its C-terminal region and enhances LDHA phosphorylation at tyrosine 10 (Y10), resulting in hyperactive Warburg effect and accumulation of histone lactylation in clear cell renal cell carcinoma. Co-immunoprecipitation, domain mapping experiments, phospho-LDHA Y10 western blotting, FKBP10 knockdown/overexpression, in vivo xenograft models Cell death & disease Medium 38233415
2022 The circular RNA circVAMP3 directly interacts with LDHA and facilitates LDHA phosphorylation at tyrosine 10 (Y10) by the upstream kinase FGFR1, thereby increasing LDHA enzymatic activity and promoting aerobic glycolysis and proliferation in renal cell carcinoma. RNA pulldown assay, Co-immunoprecipitation, LDHA Y10 phosphorylation assay, FGFR1 inhibitor treatment, circVAMP3 knockdown/overexpression, glycolysis measurements Cell death & disease Medium 35525866
2018 PGC1β transcriptionally upregulates LDHA expression through the PGC1β/RXRβ axis acting on the LDHA promoter, promoting glycolytic metabolism and tumor growth in multiple myeloma. Chromatin immunoprecipitation (ChIP), luciferase reporter assay with LDHA deletion constructs, siRNA knockdown, stable overexpression cell lines, in vivo xenograft model Molecular oncology Medium 30051603
2016 LDHA-associated lactic acid accumulation in tumors inhibits the function and survival of T and NK cells by preventing upregulation of NFAT, resulting in diminished IFN-γ production. This mechanism was established using Ldha-low tumor cells in immunocompetent vs. immunodeficient (Rag2−/−γc−/−) and Ifng−/− mice. Ldha knockdown tumor cells, immunocompetent and immunodeficient mouse models, genetic epistasis (Rag2−/−γc−/−, Ifng−/− mice), NFAT activity measurement, IFN-γ production assays, pathophysiological lactic acid treatment of T/NK cells Cell metabolism High 27641098
2022 LDHA-mediated metabolic reprogramming promotes cardiomyocyte (CM) proliferation by: (1) inhibiting succinylation-dependent ubiquitination of thioredoxin reductase 1 (Txnrd1) via succinyl-CoA reduction, thus alleviating ROS; and (2) driving lactate production that induces M2 macrophage polarization. CM-specific LDHA knockout inhibited CM proliferation; CM-specific overexpression promoted cardiac repair post-MI. CRISPR/Cas9 CM-specific knockout mice, CM-specific overexpression, metabolomics, proteomics, Co-immunoprecipitation (Txnrd1 interaction), flow cytometry for macrophage polarization, cardiac function measurements Redox biology Medium 36057161
2017 JMJD2A (a histone demethylase) binds to the LDHA promoter region and transcriptionally activates LDHA expression in nasopharyngeal carcinoma, promoting the Warburg effect. JMJD2A alteration selectively affects LDHA among glycolytic enzymes. Chromatin immunoprecipitation (ChIP) assay, JMJD2A knockdown/overexpression, glycolysis measurements (ATP, lactate production, glucose utilization), IHC in patient specimens BMC cancer Medium 28693517
2019 MTA1 (metastasis-associated protein 1) interacts with c-Myc and the MTA1-c-Myc complex is recruited to the LDHA promoter to regulate LDHA transcription in breast cancer, thereby controlling LDHA expression and subsequent cell migration. Co-immunoprecipitation (MTA1-c-Myc interaction), ChIP assay (promoter occupancy), LDHA siRNA knockdown in MTA1-overexpressing MCF7 cells, migration assays Biochemical and biophysical research communications Medium 31570164
2023 NUSAP1 binds to both c-Myc and HIF-1α to form a transcription regulatory complex that localizes to the LDHA promoter and enhances LDHA expression. In a feedforward loop, LDHA-produced lactate upregulates NUSAP1 by inhibiting its protein degradation through lysine lactylation (Kla) modification. ChIP-seq and CHIP-qPCR (complex localization to LDHA promoter), Co-IP (NUSAP1-c-Myc-HIF-1α complex), mass spectrometry (lactylation modification), RNA-seq, xenograft/spontaneous PDAC models Cancer letters Medium 37354982
2021 KDM6B histone demethylase directly mediates H3K27me3 demethylation at the LDHA locus, thereby increasing LDHA expression in osteosarcoma and promoting tumor metastasis. Overexpression of LDHA reversed the metastasis inhibition observed upon KDM6B knockdown. ChIP-seq + RNA-seq analysis identifying LDHA as KDM6B target, ChIP-qPCR validating H3K27me3 changes at LDHA locus, KDM6B knockdown with LDHA rescue experiments, in vivo lung metastasis model Theranostics Medium 33664867
2018 HIF1α aberrantly upregulates LDHA in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) under standard glucose-containing culture conditions. Chemical or siRNA inhibition of HIF1α or LDHA switches metabolism from aerobic glycolysis to oxidative phosphorylation and improves cardiomyocyte metabolic and functional maturation. HIF1α siRNA, LDHA small molecule inhibition, Seahorse metabolic flux analysis (OCR/ECAR), mitochondrial content measurement, contractility assessment Circulation research Medium 30355156
2021 LDHA knockdown in papillary thyroid carcinoma activated the AMPK pathway and induced protective autophagy. Additionally, the metabolic products of LDHA-catalyzed reactions induced EMT by increasing H3K27 acetylation of relevant EMT genes. LDHA knockdown (shRNA), AMPK pathway activation assays, autophagy flux measurement, H3K27 acetylation ChIP, EMT marker analysis, in vivo xenograft Cell death & disease Medium 33795650
2022 METTL3 enhances LDHA expression via two mechanisms: (1) stabilizing HIF-1α mRNA to increase HIF-1α-driven LDHA transcription; and (2) direct m6A methylation of the LDHA mRNA CDS region, promoting its translation through YTHDF1 recruitment. METTL3 knockdown/overexpression, m6A MeRIP assay, YTHDF1 interaction studies, HIF-1α mRNA stability assay, luciferase reporter, glycolysis measurements, in vivo xenograft Theranostics Medium 35832094
2021 FOXO4 directly binds to the LDHA promoter and transcriptionally inactivates LDHA expression in a dose-dependent manner in gastric cancer cells, regulating glycolysis. FOXO4 is itself a transcriptional target of HIF-1α, placing FOXO4 between HIF-1α and LDHA in a HIF-1α→FOXO4→LDHA axis. Chromatin immunoprecipitation (ChIP), luciferase reporter assay, FOXO4 overexpression/silencing, glycolysis measurement (glucose uptake, lactate), in vivo 18F-FDG PET in mouse models, patient specimens Clinical and translational medicine Medium 33463054
2016 Capsaicin directly binds to and inhibits both PKM2 and LDHA, suppressing the Warburg effect in inflammatory macrophages. This was identified using activity-based protein profiling (ABPP) with capsaicin-based chemical probes. Activity-based protein profiling (ABPP) with designed capsaicin probes, direct binding validation, LDH enzymatic activity assay in macrophages, in vivo endotoxemia/sepsis models Cell chemical biology Medium 35858615
2024 LDHA mediates lactylation of NLRP3 at lysine 245 (K245), increasing NLRP3 protein stability and promoting cardiomyocyte pyroptosis during myocardial ischemia-reperfusion injury. LDHA knockout attenuated infarct size and myocardial damage, and NLRP3 overexpression counteracted LDHA-knockout protection. LDHA siRNA knockdown, LDHA knockout in vivo (I/R mouse model), site-specific lactylation assay (K245), NLRP3 protein stability measurement, pyroptosis assays, genetic epistasis (NLRP3 rescue of LDHA KO phenotype) BMC cardiovascular disorders Medium 39548367
2022 LDHA-mediated histone lactylation (H3K18la) during osteoblast differentiation drives expression of the transcription factor JunB. LDHA knockdown decreases H3K18la enrichment at the JunB promoter; exogenous lactate treatment rescues this effect, suggesting LDHA controls osteogenic differentiation via histone lactylation. LDHA knockdown, ChIP for H3K18la at JunB promoter, RNA-sequencing, exogenous lactate rescue experiments, ALP activity and mineralized nodule formation assays Biochemical and biophysical research communications Medium 35605402
2024 LDHA-mediated H3K18 lactylation at the TPI1 promoter enhances TPI1 transcription and promotes glycolysis in chondrocytes in osteoarthritis. Mutation of K69 on H3K18 ameliorated LPS-induced glycolysis. LDHA knockout in vivo recovered cartilage injury. ChIP for H3K18la at TPI1 promoter, H3K18 K69 site-directed mutagenesis, LDHA knockdown and knockout (in vivo OA model), glycolysis assays, LPS-induced OA cell model Autoimmunity Medium 39086231
2023 APOL3 binds LDHA and promotes its ubiquitylation-related degradation in colorectal cancer cells, reducing lactate production and facilitating ferroptosis and CD8+ T cell antitumor activity. Co-immunoprecipitation (APOL3-LDHA interaction), ubiquitylation assay, APOL3 overexpression/knockdown, ferroptosis assays (MDA, Fe2+), CD8+ T cell co-culture, in vivo tumor model International journal of biological sciences Medium 36923931
2021 LDHA promotes MMP2/9 expression and extracellular matrix degradation in aortic vascular smooth muscle cells through the LDHA-NDRG3-ERK1/2-MMP2/9 signaling pathway, promoting phenotypic switching from contractile to synthetic phenotype. LDHA knockdown/overexpression in HAVSMCs, LDHA inhibitor (oxamate) treatment, pathway analysis (NDRG3, p-ERK1/2, MMP2/9 western blotting), in vivo aortic dissection model (BAPN+Ang II) Pharmacological research Medium 34973467
2023 LDHA deficiency in trophoblasts decreases phosphorylation of PI3K, AKT, and FOXO1, resulting in downregulation of CyclinD1, causing G0/G1 cell cycle arrest and increased apoptosis. RNA sequencing identified PI3K/AKT as a downstream pathway of LDHA in trophoblast biology. LDHA knockdown/overexpression, RNA-seq, KEGG pathway analysis, phospho-PI3K/AKT/FOXO1 western blotting, AKT inhibitor and FOXO1 inhibitor epistasis, cell cycle analysis FASEB journal Medium 36583693
2024 LDHA-mediated lactate production in pulmonary artery smooth muscle cells activates Akt signaling, promoting PASMC proliferation and migration and pulmonary vascular remodeling under hypoxia. LDHA knockdown suppressed Akt phosphorylation in vitro and in vivo, and Akt overexpression reversed the inhibitory effect of LDHA knockdown. LDHA knockdown (shRNA) in PASMCs, Akt overexpression rescue, phospho-Akt western blotting, in vivo hypoxic mouse PH model (Sugen/hypoxia, MCT-induced rat), LDHA inhibitor treatment, CCK8/EdU proliferation assays Journal of translational medicine Medium 39103838
2024 BH4 (tetrahydrobiopterin) controls S-nitrosylation of LDHA at Cys163 and Cys293 via NO. S-nitrosylation at these sites restricts LDHA-mediated ROS generation. Loss of S-nitrosylation after irradiation increases LDHA-driven ROS and radiosensitivity. iodoTMT-based quantitative mass spectrometry identifying S-nitrosylation sites, GCH1 knockout/knockin conditional lung mice, BH4 supplementation, NO pathway manipulation, ROS measurements Experimental & molecular medicine Medium 38689083
2024 SIRT2 deacetylates LDHA; inhibition of NAD+ synthesis (via FK866) enhances acetylation of LDHA in 293T cells, as shown by Co-IP. The Nampt/SIRT2/LDHA pathway mediates lactate production in granulosa cells relevant to follicular development. Co-immunoprecipitation (acetylated LDHA detection), FK866 inhibitor treatment, SIRT2 knockdown, NMN supplementation in PCOS rat model, lactate and glycolysis measurements Free radical biology & medicine Low 39489197
2015 FOXM1 transcriptionally activates LDHA expression in gastric cancer by binding to the LDHA promoter, regulating the glycolytic phenotype, proliferation, migration, and invasion via LDHA. FOXM1 knockdown/overexpression, glycolytic enzyme expression profiling, LDHA promoter analysis, LDH activity and lactate measurement International journal of clinical and experimental pathology Low 26261559
2023 SIX1 transcription factor directly binds to the LDHA promoter region (confirmed by ChIP assay) and activates LDHA expression, promoting lactate accumulation and NK cell dysfunction in pancreatic cancer. Chromatin immunoprecipitation (ChIP), SIX1 overexpression, LDHA inhibitor treatment, NK cell co-culture functional assays, in vivo tumor model Journal of immunology research Medium 36937004
2022 USP1 deubiquitinase interacts with and deubiquitinates PLK1, and elevated PLK1 increases LDHA expression. Inhibition of PLK1 reduces LDHA expression and abrogates USP1-mediated glycolysis; LDHA overexpression rescues USP1-silencing-induced growth suppression, placing LDHA downstream of the USP1-PLK1 axis in T-ALL. Co-immunoprecipitation (USP1-PLK1), deubiquitination assay, PLK1 inhibition, LDHA rescue overexpression, proliferation and glycolysis assays, in vivo leukemia mouse model Blood advances Medium 36912760
2024 KCNK1 binds to and activates LDHA, increasing glycolysis and lactate production in breast cancer cells. Elevated lactate then promotes histone lysine lactylation (H3K18la), driving expression of downstream genes including LDHA itself in a positive feedback loop. Increased LDHA activity also reduces tumor cell stiffness and adhesion. Co-immunoprecipitation (KCNK1-LDHA binding), LDHA activity measurement, H3K18 lactylation western blotting, KCNK1 knockdown/overexpression, in vivo breast cancer model PLoS biology Medium 38905316
2021 NAC1 transcription factor positively regulates LDHA expression at the transcriptional level in melanoma cells, leading to higher lactate accumulation in the tumor microenvironment that inhibits cytokine production and induces exhaustion/apoptosis of CD8+ cytotoxic T lymphocytes, impairing antitumor immunity. CRISPR/Cas9 NAC1 depletion, LDHA expression measurement, lactic acid measurement in TME, adoptive CTL transfer in immunocompetent/immunodeficient mouse melanoma models, CTL function assays, retroviral transduction Journal for immunotherapy of cancer Medium 36150745
2017 LDHA inhibition (via oxamate or siRNA) impairs TNF-α-dependent tumor cell migration and reduces TNF-α-induced MMP9 expression in esophageal cancer cells. These effects are associated with disruption of ERK1/2 signaling pathway activation. Lactic acid synergizes with TNF-α to stimulate MMP9 expression. siRNA-mediated LDHA knockdown, sodium oxamate (LDHA inhibitor), wound healing assay, gelatin zymography (MMP9 activity), ERK1/2 phosphorylation western blotting, lactate measurement International journal of molecular sciences Medium 36555705

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell metabolism 1554 27641098
2022 Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics. Seminars in cancer biology 329 36371026
2020 LDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis. Nature communications 324 32647171
2019 Unappreciated Role of LDHA and LDHB to Control Apoptosis and Autophagy in Tumor Cells. International journal of molecular sciences 232 31035592
2017 Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis. Oncogene 225 28218905
2016 Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition. Nature chemical biology 220 27479743
2014 FOXM1 promotes the warburg effect and pancreatic cancer progression via transactivation of LDHA expression. Clinical cancer research : an official journal of the American Association for Cancer Research 203 24634381
2022 EIF4A3-Induced circARHGAP29 Promotes Aerobic Glycolysis in Docetaxel-Resistant Prostate Cancer through IGF2BP2/c-Myc/LDHA Signaling. Cancer research 182 34965937
2018 Metabolic Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes by Inhibition of HIF1α and LDHA. Circulation research 182 30355156
2014 A novel KLF4/LDHA signaling pathway regulates aerobic glycolysis in and progression of pancreatic cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 162 24947925
2023 NUSAP1-LDHA-Glycolysis-Lactate feedforward loop promotes Warburg effect and metastasis in pancreatic ductal adenocarcinoma. Cancer letters 146 37354982
2017 HIF1/2α mediates hypoxia-induced LDHA expression in human pancreatic cancer cells. Oncotarget 142 28193910
2015 Inhibition of LDHA suppresses tumor progression in prostate cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 116 25983002
2012 LDHA is necessary for the tumorigenicity of esophageal squamous cell carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 113 22961700
2016 The miR-34a-LDHA axis regulates glucose metabolism and tumor growth in breast cancer. Scientific reports 111 26902416
2022 Capsaicin ameliorates inflammation in a TRPV1-independent mechanism by inhibiting PKM2-LDHA-mediated Warburg effect in sepsis. Cell chemical biology 96 35858615
2022 LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ROS and inducing M2 macrophage polarization. Redox biology 96 36057161
2022 N6-methyladenosine-mediated LDHA induction potentiates chemoresistance of colorectal cancer cells through metabolic reprogramming. Theranostics 95 35832094
2022 LDHA promotes osteoblast differentiation through histone lactylation. Biochemical and biophysical research communications 91 35605402
2019 LDHA Promotes Oral Squamous Cell Carcinoma Progression Through Facilitating Glycolysis and Epithelial-Mesenchymal Transition. Frontiers in oncology 90 31921691
2021 LDHA induces EMT gene transcription and regulates autophagy to promote the metastasis and tumorigenesis of papillary thyroid carcinoma. Cell death & disease 84 33795650
2022 Metabolic enzyme LDHA activates Rac1 GTPase as a noncanonical mechanism to promote cancer. Nature metabolism 81 36536137
2015 JQ1 suppresses tumor growth through downregulating LDHA in ovarian cancer. Oncotarget 81 25762632
2021 STAT3/LINC00671 axis regulates papillary thyroid tumor growth and metastasis via LDHA-mediated glycolysis. Cell death & disease 78 34404767
2024 KCNK1 promotes proliferation and metastasis of breast cancer cells by activating lactate dehydrogenase A (LDHA) and up-regulating H3K18 lactylation. PLoS biology 76 38905316
2021 KDM6B-mediated histone demethylation of LDHA promotes lung metastasis of osteosarcoma. Theranostics 73 33664867
2018 LDHA is a direct target of miR-30d-5p and contributes to aggressive progression of gallbladder carcinoma. Molecular carcinogenesis 72 29569755
2017 LDHA promotes tumor metastasis by facilitating epithelial‑mesenchymal transition in renal cell carcinoma. Molecular medicine reports 72 28983605
2021 Hypoxia-induced FOXO4/LDHA axis modulates gastric cancer cell glycolysis and progression. Clinical and translational medicine 70 33463054
2018 miR-142-3p inhibits aerobic glycolysis and cell proliferation in hepatocellular carcinoma via targeting LDHA. Biochemical and biophysical research communications 70 29360449
2022 Trophoblast-derived Lactic Acid Orchestrates Decidual Macrophage Differentiation via SRC/LDHA Signaling in Early Pregnancy. International journal of biological sciences 67 35002512
2023 LncRNA GLTC targets LDHA for succinylation and enzymatic activity to promote progression and radioiodine resistance in papillary thyroid cancer. Cell death and differentiation 61 37031273
2023 Apolipoprotein L3 enhances CD8+ T cell antitumor immunity of colorectal cancer by promoting LDHA-mediated ferroptosis. International journal of biological sciences 57 36923931
2024 FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation. Cell death & disease 53 38233415
2023 Glucose transporter 3 (GLUT3) promotes lactylation modifications by regulating lactate dehydrogenase A (LDHA) in gastric cancer. Cancer cell international 53 38041125
2022 Inhibition of LDHA suppresses cell proliferation and increases mitochondrial apoptosis via the JNK signaling pathway in cervical cancer cells. Oncology reports 53 35191522
2017 PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a. Journal of experimental & clinical cancer research : CR 51 28915924
2015 FOXM1-LDHA signaling promoted gastric cancer glycolytic phenotype and progression. International journal of clinical and experimental pathology 49 26261559
2024 Palmitoylation alters LDHA activity and pancreatic cancer response to chemotherapy. Cancer letters 45 38331089
2024 NAT10 mediated ac4C acetylation driven m6A modification via involvement of YTHDC1-LDHA/PFKM regulates glycolysis and promotes osteosarcoma. Cell communication and signaling : CCS 44 38233839
2020 ANXA2P2/miR-9/LDHA axis regulates Warburg effect and affects glioblastoma proliferation and apoptosis. Cellular signalling 44 32707073
2017 Blocking LDHA glycolytic pathway sensitizes glioblastoma cells to radiation and temozolomide. Biochemical and biophysical research communications 44 28756228
2023 LDHA deficiency inhibits trophoblast proliferation via the PI3K/AKT/FOXO1/CyclinD1 signaling pathway in unexplained recurrent spontaneous abortion. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 42 36583693
2023 FOXQ1 promotes pancreatic cancer cell proliferation, tumor stemness, invasion and metastasis through regulation of LDHA-mediated aerobic glycolysis. Cell death & disease 42 37875474
2021 Coptis chinensis and dried ginger herb combination inhibits gastric tumor growth by interfering with glucose metabolism via LDHA and SLC2A1. Journal of ethnopharmacology 42 34737010
2021 Long noncoding RNA HAGLR sponges miR-338-3p to promote 5-Fu resistance in gastric cancer through targeting the LDHA-glycolysis pathway. Cell biology international 41 34658120
2020 CDKN2A inhibits cell proliferation and invasion in cervical cancer through LDHA-mediated AKT/mTOR pathway. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 40 32594303
2018 PGC1β regulates multiple myeloma tumor growth through LDHA-mediated glycolytic metabolism. Molecular oncology 40 30051603
2016 Pharmacological or genetic inhibition of LDHA reverses tumor progression of pediatric osteosarcoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 40 27261617
2024 LDHA-induced histone lactylation mediates the development of osteoarthritis through regulating the transcription activity of TPI1 gene. Autoimmunity 38 39086231
2023 LDHA as a regulator of T cell fate and its mechanisms in disease. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 38 36916398
2022 Associations between local acidosis induced by renal LDHA and renal fibrosis and mitochondrial abnormalities in patients with diabetic kidney disease. Translational research : the journal of laboratory and clinical medicine 36 35788054
2021 LDHA mediated degradation of extracellular matrix is a potential target for the treatment of aortic dissection. Pharmacological research 35 34973467
2017 The miR-383-LDHA axis regulates cell proliferation, invasion and glycolysis in hepatocellular cancer. Iranian journal of basic medical sciences 34 28293396
2020 PCK1 Regulates Glycolysis and Tumor Progression in Clear Cell Renal Cell Carcinoma Through LDHA. OncoTargets and therapy 33 32280238
2018 MiR-323a-3p suppressed the glycolysis of osteosarcoma via targeting LDHA. Human cell 32 30088225
2023 Glycolysis-related lncRNA TMEM105 upregulates LDHA to facilitate breast cancer liver metastasis via sponging miR-1208. Cell death & disease 31 36737428
2016 Inhibition of LDHA Deliver Potential Anticancer Performance in Renal Cell Carcinoma. Urologia internationalis 31 27027898
2017 JMJD2A promotes the Warburg effect and nasopharyngeal carcinoma progression by transactivating LDHA expression. BMC cancer 30 28693517
2023 The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic Cancer. Journal of immunology research 28 36937004
2022 Effect of LDHA Inhibition on TNF-α-Induced Cell Migration in Esophageal Cancers. International journal of molecular sciences 28 36555705
2022 CDKN3 Overcomes Bladder Cancer Cisplatin Resistance via LDHA-Dependent Glycolysis Reprogramming. OncoTargets and therapy 27 35388272
2022 Circular RNA circVAMP3 promotes aerobic glycolysis and proliferation by regulating LDHA in renal cell carcinoma. Cell death & disease 26 35525866
2022 Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion. Journal for immunotherapy of cancer 26 36150745
2024 Inhibition of xanthine oxidase alleviated pancreatic necrosis via HIF-1α-regulated LDHA and NLRP3 signaling pathway in acute pancreatitis. Acta pharmaceutica Sinica. B 25 39220867
2023 Pancreatic stellate cell-induced gemcitabine resistance in pancreatic cancer is associated with LDHA- and MCT4-mediated enhanced glycolysis. Cancer cell international 25 36658582
2022 LDHA: The Obstacle to T cell responses against tumor. Frontiers in oncology 25 36518315
2024 Lactate dehydrogenase A (LDHA)-mediated lactate generation promotes pulmonary vascular remodeling in pulmonary hypertension. Journal of translational medicine 24 39103838
2024 LRPPRC promotes glycolysis by stabilising LDHA mRNA and its knockdown plus glutamine inhibitor induces synthetic lethality via m6 A modification in triple-negative breast cancer. Clinical and translational medicine 23 38372449
2024 LDHA exacerbates myocardial ischemia-reperfusion injury through inducing NLRP3 lactylation. BMC cardiovascular disorders 22 39548367
2024 Nampt/SIRT2/LDHA pathway-mediated lactate production regulates follicular dysplasia in polycystic ovary syndrome. Free radical biology & medicine 21 39489197
2022 circRNA PLOD2 promotes tumorigenesis and Warburg effect in colon cancer by the miR-513a-5p/SIX1/LDHA axis. Cell cycle (Georgetown, Tex.) 21 36071678
2021 LDH-A negatively regulates dMMR in colorectal cancer. Cancer science 21 34110068
2019 MiR-1271 inhibits cell proliferation and metastasis by targeting LDHA in endometrial cancer. European review for medical and pharmacological sciences 21 31298316
2023 The mRNA and protein levels of the glycolytic enzymes lactate dehydrogenase A (LDHA) and phosphofructokinase platelet (PFKP) are good predictors of survival time, recurrence, and risk of death in cervical cancer patients. Cancer medicine 20 37326348
2022 MYC Promotes LDHA Expression through MicroRNA-122-5p to Potentiate Glycolysis in Hepatocellular Carcinoma. Analytical cellular pathology (Amsterdam) 20 36033372
2019 miR-489 suppresses multiple myeloma cells growth through inhibition of LDHA-mediated aerobic glycolysis. Genes & genomics 20 31872383
2024 Low level exposure to BDE-47 facilitates the development of prostate cancer through TOP2A/LDHA/lactylation positive feedback circuit. Environmental research 19 39362459
2023 USP1 promotes the aerobic glycolysis and progression of T-cell acute lymphoblastic leukemia via PLK1/LDHA axis. Blood advances 19 36912760
2022 Genetic and Drug Inhibition of LDH-A: Effects on Murine Gliomas. Cancers 19 35565435
2019 MTA1 coregulator regulates LDHA expression and function in breast cancer. Biochemical and biophysical research communications 19 31570164
2024 Fibroblast growth factor pathway promotes glycolysis by activating LDHA and suppressing LDHB in a STAT1-dependent manner in prostate cancer. Journal of translational medicine 18 38764020
2023 Targeting the monocarboxylate transporter MCT2 and lactate dehydrogenase A LDHA in cancer cells with FX-11 and AR-C155858 inhibitors. European review for medical and pharmacological sciences 18 37522672
2022 Inhibition of LDHA to induce eEF2 release enhances thrombocytopoiesis. Blood 17 35176139
2022 Circ-CSNK1G1 promotes cell proliferation, migration, invasion and glycolysis metabolism during triple-negative breast cancer progression by modulating the miR-28-5p/LDHA pathway. Reproductive biology and endocrinology : RB&E 17 36109751
2022 4-OI Protects MIN6 Cells from Oxidative Stress Injury by Reducing LDHA-Mediated ROS Generation. Biomolecules 17 36139075
2021 LDHA is enriched in human islet alpha cells and upregulated in type 2 diabetes. Biochemical and biophysical research communications 17 34217973
2015 Expression of SIP1 is strongly correlated with LDHA and shows a significantly poor outcome in gastric cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 17 25913622
2024 The opposite role of lactate dehydrogenase a (LDHA) in cervical cancer under energy stress conditions. Free radical biology & medicine 16 38307156
2024 Tetrahydrobiopterin metabolism attenuates ROS generation and radiosensitivity through LDHA S-nitrosylation: novel insight into radiogenic lung injury. Experimental & molecular medicine 16 38689083
2022 GLUT1, LDHA, and MCT4 Expression Is Deregulated in Cervical Cancer and Precursor Lesions. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 16 35615882
2019 MiR-638 Repressed Vascular Smooth Muscle Cell Glycolysis by Targeting LDHA. Open medicine (Warsaw, Poland) 16 31989041
2022 Anticancer Effects of Cinnamaldehyde Through Inhibition of ErbB2/HSF1/LDHA Pathway in 5637 Cell Line of Bladder Cancer. Anti-cancer agents in medicinal chemistry 15 34315398
2022 YY1 transcription factor induces proliferation and aerobic glycolysis of neuroblastoma cells via LDHA regulation. Experimental and therapeutic medicine 15 36569438
2021 Long, Noncoding RNA SRA Induces Apoptosis of β-Cells by Promoting the IRAK1/LDHA/Lactate Pathway. International journal of molecular sciences 14 33572095
2018 miR‑199a‑3p/Sp1/LDHA axis controls aerobic glycolysis in testicular tumor cells. International journal of molecular medicine 14 30015851
2025 Oxamate, an LDHA Inhibitor, Inhibits Stemness, Including EMT and High DNA Repair Ability, Induces Senescence, and Exhibits Radiosensitizing Effects in Glioblastoma Cells. International journal of molecular sciences 13 40565174
2024 LDHA-mediated M2-type macrophage polarization via tumor-derived exosomal EPHA2 promotes renal cell carcinoma progression. Molecular carcinogenesis 13 38780182
2023 Single-cell sequencing of the retina shows that LDHA regulates pathogenesis of autoimmune uveitis. Journal of autoimmunity 13 38160538
2021 E2F1-Induced FTH1P3 Promoted Cell Viability and Glycolysis Through miR-377-3p/LDHA Axis in Laryngeal Squamous Cell Carcinoma. Cancer biotherapy & radiopharmaceuticals 13 33571038

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