Affinage

SLC16A3

Monocarboxylate transporter 4 · UniProt O15427

Length
465 aa
Mass
49.5 kDa
Annotated
2026-04-28
100 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC16A3 encodes MCT4, a proton-coupled monocarboxylate transporter that mediates high-capacity efflux of lactate and H⁺ from glycolytic cells, thereby maintaining intracellular pH homeostasis, sustaining NAD⁺ regeneration, and shaping the extracellular metabolic milieu. MCT4 requires the chaperone CD147/basigin for post-transcriptional stabilization and trafficking to the plasma membrane; without CD147, MCT4 protein is severely reduced despite normal mRNA levels (PMID:10921872, PMID:12601063). Transcription of SLC16A3 is directly activated by HIF-1α via a hypoxia-response element in its promoter and further de-repressed under hypoxia through NF-κB–mediated downregulation of the transcriptional repressor ZBTB7A/FBI-1, while promoter DNA methylation provides an additional layer of epigenetic silencing (PMID:16452478, PMID:31271899, PMID:23881922). Loss of MCT4 causes intracellular lactate accumulation that inhibits glycolysis, triggers histone lactylation-dependent transcriptional reprogramming in macrophages, impairs neuromuscular junction integrity in vivo, and—in tumors—restricts growth and restores sensitivity to immune checkpoint blockade (PMID:30540938, PMID:38733581, PMID:31837519, PMID:37327788).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Establishing that MCT4 cannot reach the plasma membrane alone resolved the question of why heterologous MCT4 expression often failed: CD147/basigin was identified as the obligate chaperone whose transmembrane domain physically interacts with MCT4 to enable surface delivery and transport activity.

    Evidence Reciprocal co-IP, chemical cross-linking, CD2-CD147 chimera mapping, and co-transfection reconstitution in mammalian cells

    PMID:10921872

    Open questions at the time
    • Stoichiometry of the MCT4–CD147 complex was not determined
    • Whether other auxiliary subunits participate in trafficking remains open
    • Structural basis of the transmembrane interaction was not resolved
  2. 2000 Medium

    Subcellular fractionation of skeletal muscle showed MCT4 is restricted to the sarcolemma (with an intracellular pool in triads/SR), distinguishing it from the dual sarcolemmal-mitochondrial localization of MCT1 and assigning MCT4 a dedicated plasma-membrane export role.

    Evidence Subcellular fractionation and isoform-specific Western blotting in rat skeletal muscle

    PMID:10827010

    Open questions at the time
    • Functional significance of the triad/SR pool was not tested
    • No immunogold EM confirmation was provided
  3. 2003 High

    In vivo validation in basigin-null mice showed that CD147 is required post-transcriptionally for MCT4 protein stability, not just trafficking—MCT4 protein was severely depleted despite normal mRNA, extending the chaperone model from cell lines to intact tissue.

    Evidence Bsg−/− knockout mice with immunofluorescence, Western blot, and RT-PCR in neural retina

    PMID:12601063

    Open questions at the time
    • Whether CD147 loss leads to proteasomal or lysosomal degradation of MCT4 was not determined
    • Rescue by CD147 re-expression was not performed
  4. 2006 High

    Identification of a functional HRE in the SLC16A3 promoter directly bound by HIF-1α established the molecular basis for hypoxia-induced MCT4 upregulation, explaining why MCT4 is the predominant lactate transporter in hypoxic and glycolytic tissues.

    Evidence Promoter-luciferase reporters, HRE deletion/point mutation, gel-shift and supershift assays in hypoxic HeLa cells

    PMID:16452478

    Open questions at the time
    • Contribution of HIF-2α was not addressed
    • Chromatin context (histone modifications at the HRE) was not examined
  5. 2011 High

    Functional studies in tumors demonstrated that MCT4 is a primary driver of intracellular alkalinization and lactate efflux required for tumor growth: MCT4 knockout reduced glycolytic flux, collapsed the pH gradient, and—combined with NHE-1 loss—caused tumor regression, while MCT4 re-expression rescued tumorigenicity in respiration-deficient cells.

    Evidence ZFN-mediated MCT4 KO in colon adenocarcinoma, in vivo MRS pH measurement in isogenic tumor variants, xenograft growth assays

    PMID:21484790 PMID:21930917

    Open questions at the time
    • Whether MCT4 loss selects for compensatory transporter upregulation in vivo was not examined
    • Immune microenvironment effects were not assessed in these xenograft (immunodeficient host) models
  6. 2013 High

    Genome-wide RNAi screening in renal clear cell carcinoma independently confirmed MCT4 as essential for the Warburg effect, showing that MCT4 silencing causes intracellular acidosis, ATP depletion, cell-cycle arrest, and apoptosis, while promoter DNA methylation was identified as an epigenetic regulator of SLC16A3 expression.

    Evidence Genome-wide RNAi screen, siRNA across 8 ccRCC lines, intracellular pH/ATP/lactate assays; bisulfite sequencing and promoter-luciferase assays

    PMID:22362593 PMID:23881922

    Open questions at the time
    • The methyltransferase(s) responsible for SLC16A3 promoter methylation were not identified
    • Whether demethylation agents restore MCT4 and sensitize tumors was not tested in vivo
  7. 2015 High

    Mutagenesis of His382 in the extracellular loop revealed the molecular basis for pH-dependent regulation of MCT4 transport, answering how extracellular acidification modulates lactate efflux kinetics.

    Evidence Site-directed mutagenesis (H382A), DEPC chemical modification, Zn²⁺ inhibition, Xenopus oocyte expression and uptake assays at varied pH

    PMID:25919709

    Open questions at the time
    • No crystal or cryo-EM structure was available to place His382 in a three-dimensional context
    • Whether His382 regulation is conserved across MCT family members was not tested
  8. 2018 High

    Pharmacological dual MCT1/MCT4 inhibition with syrosingopine revealed that blocking MCT4-dependent lactate export causes intracellular lactate accumulation sufficient to inhibit LDH and collapse NAD⁺ regeneration, establishing a metabolic vulnerability that is synthetically lethal with metformin.

    Evidence Syrosingopine treatment of cancer cells, intracellular lactate and NAD⁺/NADH measurements, exogenous NAD⁺ rescue, metformin combination lethality

    PMID:30540938

    Open questions at the time
    • Direct binding site of syrosingopine on MCT4 was not mapped
    • In vivo pharmacokinetics and toxicity of syrosingopine–metformin combination were not established
  9. 2019 High

    Revised kinetic analysis using intracellular FRET sensors corrected the MCT4 Km for lactate from ~30 mM to ~1 mM, fundamentally changing the understanding of MCT4 as a high-affinity rather than low-affinity transporter and explaining its efficacy even at modest intracellular lactate concentrations.

    Evidence FRET sensors (Laconic, Pyronic), CRISPR/Cas9 MCT4 deletion in MDA-MB-231 cells and macrophages, numerical simulation

    PMID:31719150

    Open questions at the time
    • Km under physiological intracellular ionic conditions and with native CD147 stoichiometry remains to be confirmed in intact tissue
    • Pyruvate transport kinetics were less thoroughly validated
  10. 2019 Medium

    A second layer of transcriptional control was uncovered: NF-κB represses ZBTB7A/FBI-1, which normally occupies the SLC16A3 promoter at both FBI-1 response elements and HREs, so that hypoxia simultaneously activates HIF-1α and removes FBI-1 repression, providing a dual-input logic gate for MCT4 induction.

    Evidence ChIP, oligonucleotide pulldown, promoter-luciferase reporters, siRNA knockdown of ZBTB7A and HIF-1α in colon cancer cells

    PMID:31271899

    Open questions at the time
    • Whether FBI-1 physically competes with HIF-1α for HRE occupancy or acts at distinct elements was not fully resolved
    • Single-lab finding; independent replication needed
  11. 2019 High

    Global MCT4 knockout mice exhibited exercise intolerance and structural NMJ degeneration with decremented compound muscle action potentials, demonstrating that MCT4-mediated lactate export from glycolytic muscle fibers is essential for neuromuscular junction integrity in vivo.

    Evidence MCT4 global knockout mice, treadmill testing, in vivo electrophysiology, NMJ immunofluorescence, comparison with muscle-specific basigin conditional KO

    PMID:31837519

    Open questions at the time
    • Whether the NMJ defect is due to lactate/pH imbalance in the muscle fiber or loss of lactate signaling to Schwann cells/motor neurons was not distinguished
    • Rescue by MCT4 re-expression in specific cell types was not performed
  12. 2023 High

    MCT4-mediated tumor lactate export was shown to create an immunosuppressive microenvironment: MCT4 knockout reversed M2 macrophage polarization, restored T-cell function, and sensitized LKB1-mutant tumors to anti-PD-1 therapy, connecting metabolic transport directly to immune evasion.

    Evidence MCT4 KO in syngeneic murine tumor models, PD-1 blockade, single-cell RNA profiling, GPR81 blockade epistasis, exogenous lactate rescue

    PMID:37327788

    Open questions at the time
    • Whether MCT4 inhibition benefits immunotherapy in non-LKB1-mutant contexts was not tested
    • Selective MCT4 inhibitors suitable for clinical translation were not available
  13. 2024 Medium

    MCT4 deficiency in macrophages was found to drive intracellular lactate accumulation that promotes histone H3K18 lactylation, activating anti-inflammatory and TCA cycle gene programs—revealing a cell-intrinsic epigenetic mechanism by which MCT4 loss reprograms macrophage identity toward an M2-like state.

    Evidence MCT4 gene manipulation and PROTAC degradation in macrophages, H3K18la ChIP, gene expression profiling, atherosclerosis mouse model

    PMID:38733581

    Open questions at the time
    • Whether lactylation-driven reprogramming occurs in other immune cell types was not tested
    • The writer enzyme for H3K18la in this context was not identified
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • No high-resolution structure of MCT4 (alone or in complex with CD147) has been determined, and no selective, clinically viable MCT4 inhibitor exists; the structural basis of substrate selectivity, the mechanism by which CD147 stabilizes MCT4, and whether MCT4 has non-transport (scaffolding) functions remain open.
  • No cryo-EM or crystal structure of MCT4 or MCT4–CD147 complex
  • No selective MCT4 inhibitor with demonstrated in vivo efficacy and safety
  • Whether MCT4 has transport-independent signaling or scaffolding functions is unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-1643685 Disease 4 R-HSA-382551 Transport of small molecules 4 R-HSA-168256 Immune System 2
Partners
BSGHIF1ASLC9A1ZBTB7A
Complex memberships
MCT4–CD147/basigin complex

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 MCT4 (SLC16A3) expression is transcriptionally upregulated by hypoxia through HIF-1α binding to hypoxia-response elements in the MCT4 promoter; mutation of a specific HRE (site 2) abolished the hypoxic response, and gel-shift/supershift assays confirmed direct HIF-1α binding. Promoter-luciferase reporter assays, deletion and mutation analysis, gel-shift and supershift analysis with nuclear extracts from hypoxic HeLa cells The Journal of biological chemistry High 16452478
2000 CD147 specifically interacts with MCT4 (and MCT1) via its transmembrane and cytoplasmic domains, and this interaction is required for proper cell-surface expression of MCT4; co-transfection of CD147 with MCT4 enabled plasma membrane localization and transport activity, whereas MCT4 alone accumulated in a perinuclear compartment. Co-immunoprecipitation, chemical cross-linking, CD2-CD147 chimera studies, co-transfection in mammalian cell lines, immunofluorescence co-localization, functional transport assay The EMBO journal High 10921872
2019 MCT4 is a high-affinity lactate transporter with Km ~0.7–1.7 mM for lactate (not ~30–40 mM as previously reported), and also transports pyruvate with Km ~4.2 mM. Previous high Km estimates were biased by pH-regulatory mechanisms. CRISPR/Cas9 deletion confirmed MCT4 as the dominant lactate transporter in MDA-MB-231 cells and macrophages. FRET sensors (Laconic, Pyronic) for real-time lactate/pyruvate dynamics, CRISPR/Cas9-mediated MCT4 deletion, pH-sensitive dye (BCECF), recombinant MCT4 expression in HEK293 cells, numerical simulation The Journal of biological chemistry High 31719150
2000 MCT4 localizes exclusively to the sarcolemmal membrane in skeletal muscle (not mitochondria), whereas MCT1 is found in both sarcolemmal and mitochondrial membranes, indicating distinct subcellular roles; MCT4 also has a significant intracellular pool in triads and sarcoplasmic reticulum. Subcellular fractionation (plasma membrane, triads, T-tubules, sarcoplasmic reticulum, intracellular membrane fractions), Western blotting with isoform-specific antibodies American journal of physiology. Endocrinology and metabolism Medium 10827010
2003 In basigin (CD147)-null mice, MCT4 protein is severely reduced in the neural retina despite normal mRNA levels, confirming that CD147/basigin is required post-transcriptionally for MCT4 protein stability and/or membrane targeting in vivo. Immunofluorescence microscopy, Western blot, and RT-PCR in Bsg−/− knockout mice Investigative ophthalmology & visual science High 12601063
2011 MCT4 mediates lactate/H+ efflux and is required for tumor glycolytic flux; zinc-finger nuclease knockout of MCT4 in LS174T colon adenocarcinoma cells reduced glycolytic flux and tumor growth, and MCT4 re-expression in respiration-deficient cells restored tumorigenicity. Zinc finger nuclease-mediated MCT4 knockout, inducible shRNA silencing, AR-C155858 MCT1/2 pharmacological inhibition, tumor xenograft growth assay, lactate secretion measurement Proceedings of the National Academy of Sciences of the United States of America High 21930917
2013 MCT4 silencing in renal clear cell carcinoma impairs lactate secretion, causes intracellular acidosis, reduces intracellular ATP, and induces cell-cycle arrest and apoptosis, establishing MCT4 as a functional regulator of the Warburg effect in this cancer. Genome-wide RNAi screen, siRNA knockdown in 8 ccRCC lines, lactate secretion assay, intracellular pH measurement, ATP quantification, flow cytometry (cell cycle and apoptosis) The Journal of pathology High 22362593
2013 SLC16A3/MCT4 promoter DNA methylation inversely regulates MCT4 expression in renal clear cell carcinoma; promoter activity assays in RCC cell lines confirmed that DNA methylation directly suppresses MCT4 transcription. Bisulfite sequencing, TCGA methylation analysis, promoter activity (luciferase) assays in RCC cell lines, mRNA and protein quantification Clinical cancer research Medium 23881922
2019 Under hypoxia, NF-κB (RelA/p65) represses ZBTB7A (encoding the repressor FBI-1), which normally binds FBI-1-response elements and HREs in the SLC16A3 promoter to suppress MCT4 transcription; loss of FBI-1 under hypoxia de-represses SLC16A3, while HIF-1α simultaneously activates it via an HRE. Transient transfection and luciferase reporter assays of SLC16A3 promoter, oligonucleotide pulldown, ChIP assays, siRNA knockdown of ZBTB7A and HIF-1α, NF-κB overexpression in colon cancer cells Biochimica et biophysica acta. Gene regulatory mechanisms Medium 31271899
2013 Hypoxia (1% O2 or DMOG treatment) induces MCT4 expression in cultured cortical astrocytes via HIF-1α; siRNA knockdown of HIF-1α prevented MCT4 induction, and MCT4 induction was necessary for increased lactate transport capacity and astrocyte survival under prolonged hypoxia. siRNA against HIF-1α, prolyl hydroxylase inhibitor DMOG, siRNA against MCT4, lactate release measurement, astrocyte survival assay under 1% O2 Glia Medium 24375723
2011 Nitric oxide induces MCT4 expression in astrocytes at mRNA and protein levels via a cGMP-independent transcriptional mechanism, increasing astrocytic lactate transport capacity; siRNA against MCT4 prevented the NO-induced increase in lactate transport. NO donor treatment, cGMP analog and guanylate cyclase inhibitor controls, siRNA against MCT4, lactate transport measurement, 24-h cumulative lactate release assay Glia Medium 21901758
2015 MCT4 histidine residue His382 in the extracellular loop is essential for pH regulation of MCT4-mediated lactate transport; H382A mutation abolished pH-dependent activity, and chemical modification of histidines (DEPC) removed pH regulation without fully inactivating transport. Site-directed mutagenesis (H382A), Xenopus oocyte expression system, DEPC chemical modification, Zn2+ inhibition, lactate uptake assay at varied pH PloS one High 25919709
2016 Diclofenac is a non-competitive inhibitor of MCT4-mediated lactate transport with Ki ~20 µM, as demonstrated in Caco-2 cells (endogenously expressing MCT4) and validated in the Xenopus oocyte expression system. Lactate uptake inhibition assay in Caco-2 cells, kinetic analysis (inhibition constant), Xenopus oocyte expression system with MCT4 Drug metabolism and pharmacokinetics Medium 27236641
2018 Syrosingopine is a dual MCT1/MCT4 inhibitor (60-fold higher potency on MCT4) that prevents lactate and H+ efflux; MCT4 inhibition causes intracellular lactate accumulation leading to end-product inhibition of lactate dehydrogenase, reducing NAD+ regeneration from NADH and blocking glycolysis, which is synthetically lethal with metformin. Pharmacological inhibition with syrosingopine, intracellular lactate measurement, NAD+/NADH ratio, ATP measurement, exogenous NAD+ rescue, metformin combination lethality assay in cancer cells Cell reports High 30540938
2019 MCT4 in colonic epithelial cells promotes NF-κB p65 nuclear translocation and enhances NF-κB-CBP interaction while dissolving the CREB-CBP complex, thereby increasing IL-6 transcription and reducing CREB-mediated ZO-1 expression, disrupting intestinal barrier function. Lentiviral MCT4 overexpression, luciferase reporter assays for IL-6 and ZO-1 promoters, co-immunoprecipitation of NF-κB-CBP and CREB-CBP complexes, ChIP assay, in vivo colitis model with MCT4 inhibitor CHC Cell proliferation Medium 31418947
2023 LKB1 loss enhances lactate production and secretion via MCT4, leading to M2 macrophage polarization and hypofunctional T cells; MCT4 knockout reversed immunotherapy resistance to PD-1 blockade in syngeneic murine models, and exogenous lactate recapitulated immunosuppression reversed by MCT4 knockdown. MCT4 knockout in murine tumor models, syngeneic PD-1 blockade tumor experiments, single-cell RNA profiling, GPR81 blockade, exogenous lactate treatment, MCT4 knockdown Cancer cell High 37327788
2024 MCT4 deficiency in macrophages results in intracellular lactate accumulation leading to histone H3 lysine 18 lactylation (H3K18la), which activates transcription of anti-inflammatory genes and TCA cycle genes, promoting M1-to-M2 transformation and protecting against atherosclerosis. MCT4 gene manipulation and protein hydrolysis-targeted chimerism (PROTAC), histone lactylation assays (H3K18la ChIP), gene expression profiling, atherosclerosis mouse model Cell reports Medium 38733581
2019 MCT4 mediates lactate-dependent stabilization and glycosylation of PD-L1 via the WNT pathway in triple-negative breast cancer cells; MCT4 knockout reduced extracellular lactate, and lactate treatment of MCT4-KO cells restored PD-L1 glycosylation. CRISPR/Cas9 MCT4 knockout, lentiviral MCT4 overexpression, exogenous lactate treatment, Western blot for PD-L1 glycosylation, multiple immunohistochemical staining Journal of oncology Medium 36199799
2019 MCT4 in hypothalamic tanycytes is required for metabolic signaling that regulates feeding behavior; adenoviral shRNA knockdown of MCT4 in the third ventricle decreased food intake and altered orexigenic neuropeptide responses to intracerebroventricular glucose. Adenovirus-mediated shRNA knockdown of MCT4 in rat third ventricle, food intake measurement, neuropeptide expression analysis, intracerebroventricular glucose administration Molecular neurobiology Medium 31578706
2019 MCT4 (and its chaperone CD147) are required for lactate export from Sertoli cells during spermatogenesis; cadmium exposure reduces MCT4 and CD147 protein levels and disrupts MCT4/CD147 co-localization at the cell membrane, thereby reducing lactate export. Co-localization fluorescence microscopy of MCT4-CD147 complex in mouse Sertoli cells, Western blot, mRNA analysis, extracellular/intracellular lactate measurement, LDH activity assay Toxicology in vitro Low 30615929
2008 PGC-1α overexpression in skeletal muscle specifically increases MCT1 (and its chaperone CD147) expression but not MCT4 or MCT2, establishing PGC-1α as a transcriptional regulator upstream of MCT1/CD147 in oxidative skeletal muscle. In vivo plasmid transfection of PGC-1α-pcDNA into rat muscle, Western blot for MCT1/MCT4/CD147, lactate uptake assay in transfected muscle, chronic stimulation model Physiological genomics Medium 18523157
2019 NF-κB/miR-425-5p/MCT4 axis mediates diabetic endothelial injury: NF-κB activation in high-glucose conditions increases miR-425-5p, which directly targets MCT4 mRNA, reducing MCT4 expression, causing intracellular lactate accumulation and apoptosis in endothelial cells. miR-425-5p target validation (MCT4 as direct target), NF-κB activation/inhibition, miR-425-5p overexpression in HUVECs, lactate accumulation measurement, apoptosis assay Molecular and cellular endocrinology Medium 31711985
2019 MCT4 (not MCT4's transport activity alone) promotes actin cytoskeleton reorganization, cell migration, and invasion in glioma cells; MCT4 overexpression enhanced these processes while MCT4 inhibition mitigated angiogenesis induction. Stable MCT4 overexpression and knockdown in F98 glioma cells, migration/invasion assays, actin cytoskeleton imaging, angiogenesis assay, organotypic brain slice model, extracellular lactate/pH measurement Journal of oncology Medium 33936203
2019 Global MCT4 knockout mice exhibit exercise intolerance and structural degeneration of neuromuscular junctions (NMJs) with decremented compound muscle action potentials, demonstrating that MCT4-mediated lactate export from glycolytic fibers is required for motor unit integrity. Global MCT4 knockout mice, treadmill exercise testing, compound muscle action potential recording in vivo, immunofluorescence of NMJ morphology, comparison with muscle-specific basigin conditional KO iScience High 31837519
2011 MCT4 expression in Ras-transformed tumor cells in vivo markedly increases the pH gradient between intracellular and extracellular compartments (from 0.14 to 0.43 units), and genetic loss of MCT4 combined with NHE-1 deficiency caused tumor regression, establishing MCT4 as a primary proton/lactate co-transporter driving intracellular alkalinization in tumors. In vivo MRS measurement of intracellular/extracellular pH in tumor xenografts, isogenic CCL39 variants with MCT4 and/or NHE-1 genetic deficiency, tumor growth and necrosis measurement International journal of cancer High 21484790
2010 Wounding of RPE monolayers causes dedifferentiation with loss of MCT3 and concomitant upregulation of MCT4 in migrating cells at the wound edge; re-epithelialization restores MCT3 expression, indicating that MCT4 expression marks the dedifferentiated/migratory state of RPE cells. Scratch wounding of chick RPE/choroid explants and human fetal RPE monolayers, immunofluorescence microscopy, Western blot for MCT3 and MCT4 during wound healing and re-epithelialization Investigative ophthalmology & visual science Medium 20505202

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. The Journal of biological chemistry 748 16452478
2000 CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression. The EMBO journal 569 10921872
2011 CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors. Proceedings of the National Academy of Sciences of the United States of America 364 21930917
2011 Evidence for a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell cycle (Georgetown, Tex.) 353 21558814
2018 Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD+ Depletion in Cancer Cells. Cell reports 307 30540938
2000 Endurance training, expression, and physiology of LDH, MCT1, and MCT4 in human skeletal muscle. American journal of physiology. Endocrinology and metabolism 265 10751188
1998 Lactic acid efflux from white skeletal muscle is catalyzed by the monocarboxylate transporter isoform MCT3. The Journal of biological chemistry 231 9632638
2001 The expression of lactate transporters (MCT1 and MCT4) in heart and muscle. European journal of applied physiology 217 11820324
2013 Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer. Cell cycle (Georgetown, Tex.) 197 23574725
2003 Loss of MCT1, MCT3, and MCT4 expression in the retinal pigment epithelium and neural retina of the 5A11/basigin-null mouse. Investigative ophthalmology & visual science 197 12601063
2016 MCT1 Modulates Cancer Cell Pyruvate Export and Growth of Tumors that Co-express MCT1 and MCT4. Cell reports 191 26876179
2003 Highly differential expression of the monocarboxylate transporters MCT2 and MCT4 in the developing rat brain. Neuroscience 181 14622911
2011 Metabolic markers in relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1α, CAIX, LDH-5, GLUT-1, MCT1 and MCT4. BMC cancer 178 21569415
2019 Monocarboxylate transporter 4 (MCT4) is a high affinity transporter capable of exporting lactate in high-lactate microenvironments. The Journal of biological chemistry 159 31719150
1998 Monocarboxylate transporter MCT1 is located in the apical membrane and MCT3 in the basal membrane of rat RPE. The American journal of physiology 135 9841555
2023 MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma. Cancer cell 133 37327788
1997 Identification of a unique monocarboxylate transporter (MCT3) in retinal pigment epithelium. Biochemical and biophysical research communications 108 9168967
2001 Mouse MCT3 gene is expressed preferentially in retinal pigment and choroid plexus epithelia. American journal of physiology. Cell physiology 101 11287345
2014 Expression of the hypoxia-inducible monocarboxylate transporter MCT4 is increased in triple negative breast cancer and correlates independently with clinical outcome. Biochemical and biophysical research communications 95 25058459
2018 An overview of MCT1 and MCT4 in GBM: small molecule transporters with large implications. American journal of cancer research 94 30416849
2000 Isoform-specific regulation of the lactate transporters MCT1 and MCT4 by contractile activity. American journal of physiology. Endocrinology and metabolism 94 11052969
2011 In vivo pH in metabolic-defective Ras-transformed fibroblast tumors: key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH. International journal of cancer 93 21484790
2014 Acute exercise increases brain region-specific expression of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins. Journal of applied physiology (Bethesda, Md. : 1985) 91 24610532
2012 Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target. The Journal of pathology 91 22362593
2013 DNA methylation of the SLC16A3 promoter regulates expression of the human lactate transporter MCT4 in renal cancer with consequences for clinical outcome. Clinical cancer research : an official journal of the American Association for Cancer Research 88 23881922
2011 Effects of acute and chronic exercise on sarcolemmal MCT1 and MCT4 contents in human skeletal muscles: current status. American journal of physiology. Regulatory, integrative and comparative physiology 87 22012699
2000 Abundance and subcellular distribution of MCT1 and MCT4 in heart and fast-twitch skeletal muscles. American journal of physiology. Endocrinology and metabolism 86 10827010
2016 The MCT4 Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 83 26755530
2023 MCT4 blockade increases the efficacy of immune checkpoint blockade. Journal for immunotherapy of cancer 81 37880183
2019 Inhibition of CREB-mediated ZO-1 and activation of NF-κB-induced IL-6 by colonic epithelial MCT4 destroys intestinal barrier function. Cell proliferation 80 31418947
2005 Immunohistochemical analysis of MCT1, MCT2 and MCT4 expression in rat plantaris muscle. The Journal of physiology 80 15932892
2024 Macrophage MCT4 inhibition activates reparative genes and protects from atherosclerosis by histone H3 lysine 18 lactylation. Cell reports 77 38733581
2016 Monocarboxylate Transporters MCT1 and MCT4 Regulate Migration and Invasion of Pancreatic Ductal Adenocarcinoma Cells. Pancreas 77 26765963
2015 Functional screening identifies MCT4 as a key regulator of breast cancer cell metabolism and survival. The Journal of pathology 77 25965974
2017 MCT1 and MCT4 Expression and Lactate Flux Activity Increase During White and Brown Adipogenesis and Impact Adipocyte Metabolism. Scientific reports 76 29026134
2006 Testosterone increases lactate transport, monocarboxylate transporter (MCT) 1 and MCT4 in rat skeletal muscle. The Journal of physiology 76 16959859
2008 PGC-1alpha increases skeletal muscle lactate uptake by increasing the expression of MCT1 but not MCT2 or MCT4. Physiological genomics 74 18523157
2013 Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment: RAS and NFκB target stromal MCT4. Cell cycle (Georgetown, Tex.) 72 23860378
2013 Oxygen tension controls the expression of the monocarboxylate transporter MCT4 in cultured mouse cortical astrocytes via a hypoxia-inducible factor-1α-mediated transcriptional regulation. Glia 71 24375723
2005 Inactivation of monocarboxylate transporter MCT3 by DNA methylation in atherosclerosis. Circulation 65 16116050
2018 The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms. International journal of cancer 64 29363134
2018 Selective Inhibition of the Lactate Transporter MCT4 Reduces Growth of Invasive Bladder Cancer. Molecular cancer therapeutics 63 30262589
2004 Exercise rapidly increases expression of the monocarboxylate transporters MCT1 and MCT4 in rat muscle. The Journal of physiology 62 15388779
2000 Determination of transport kinetics of chick MCT3 monocarboxylate transporter from retinal pigment epithelium by expression in genetically modified yeast. Biochemistry 62 10924129
2012 Butyrate activates the monocarboxylate transporter MCT4 expression in breast cancer cells and enhances the antitumor activity of 3-bromopyruvate. Journal of bioenergetics and biomembranes 59 22350013
2018 Targeting MCT4 to reduce lactic acid secretion and glycolysis for treatment of neuroendocrine prostate cancer. Cancer medicine 57 29905005
2007 Expression, cellular localization, and functional role of monocarboxylate transporter 4 (MCT4) in the gastrointestinal tract of ruminants. Gene 53 17289302
2007 Effects of high-intensity training on MCT1, MCT4, and NBC expressions in rat skeletal muscles: influence of chronic metabolic alkalosis. American journal of physiology. Endocrinology and metabolism 50 17609257
2018 Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma. Cancer medicine 48 30051648
2022 TGF-β1 induced autophagy in cancer associated fibroblasts during hypoxia contributes EMT and glycolysis via MCT4 upregulation. Experimental cell research 47 35561786
2021 Targeting Lactate Metabolism by Inhibiting MCT1 or MCT4 Impairs Leukemic Cell Proliferation, Induces Two Different Related Death-Pathways and Increases Chemotherapeutic Sensitivity of Acute Myeloid Leukemia Cells. Frontiers in oncology 46 33614502
2018 MCT4 Expression Is a Potential Therapeutic Target in Colorectal Cancer with Peritoneal Carcinomatosis. Molecular cancer therapeutics 44 29483215
2013 MCT1 and MCT4 expression during myocardial ischemic-reperfusion injury in the isolated rat heart. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 43 24030048
2024 Targeting tumor-intrinsic SLC16A3 to enhance anti-PD-1 efficacy via tumor immune microenvironment reprogramming. Cancer letters 41 38522774
2016 Effect of diclofenac on SLC16A3/MCT4 by the Caco-2 cell line. Drug metabolism and pharmacokinetics 41 27236641
2018 Monocarboxylate Transporter 4 (MCT4) Knockout Mice Have Attenuated 4NQO Induced Carcinogenesis; A Role for MCT4 in Driving Oral Squamous Cell Cancer. Frontiers in oncology 40 30211114
2016 Butyric acid increases transepithelial transport of ferulic acid through upregulation of the monocarboxylate transporters SLC16A1 (MCT1) and SLC16A3 (MCT4). Archives of biochemistry and biophysics 38 26854723
2013 Expression of monocarboxylate transporter (MCT)-4 in colorectal cancer and its role: MCT4 contributes to the growth of colorectal cancer with vascular endothelial growth factor. Anticancer research 38 23780984
2019 Hypoxia-induced RelA/p65 derepresses SLC16A3 (MCT4) by downregulating ZBTB7A. Biochimica et biophysica acta. Gene regulatory mechanisms 36 31271899
2013 Loss of caveolin-1 and gain of MCT4 expression in the tumor stroma: key events in the progression from an in situ to an invasive breast carcinoma. Cell cycle (Georgetown, Tex.) 36 23907124
2021 Novel strategies to improve tumour therapy by targeting the proteins MCT1, MCT4 and LAT1. European journal of medicinal chemistry 35 34517305
2013 Effect of AMPK activation on monocarboxylate transporter (MCT)1 and MCT4 in denervated muscle. The journal of physiological sciences : JPS 32 24081524
2001 Tissue-specific and isoform-specific changes in MCT1 and MCT4 in heart and soleus muscle during a 1-yr period. American journal of physiology. Endocrinology and metabolism 31 11551851
2021 The tissue expression of MCT3, MCT8, and MCT9 genes in women with breast cancer. Genes & genomics 30 34097251
2010 Modulation of MCT3 expression during wound healing of the retinal pigment epithelium. Investigative ophthalmology & visual science 30 20505202
2010 Effect of training and detraining on monocarboxylate transporter (MCT) 1 and MCT4 in Thoroughbred horses. Experimental physiology 29 21148623
2006 Expression of CD147 and monocarboxylate transporters MCT1, MCT2 and MCT4 in porcine small intestine and colon. Veterinary journal (London, England : 1997) 29 16901736
2005 Expression of MCT1, MCT2 and MCT4 in the rumen, small intestine and liver of reindeer (Rangifer tarandus tarandus L.). Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 29 15953554
2020 Disrupted function of lactate transporter MCT1, but not MCT4, in Schwann cells affects the maintenance of motor end-plate innervation. Glia 28 32686211
2019 The NF-κB/miR-425-5p/MCT4 axis: A novel insight into diabetes-induced endothelial dysfunction. Molecular and cellular endocrinology 28 31711985
2013 Possible involvement of AMPK in acute exercise-induced expression of monocarboxylate transporters MCT1 and MCT4 mRNA in fast-twitch skeletal muscle. Metabolism: clinical and experimental 27 23886299
2003 T3 increases lactate transport and the expression of MCT4, but not MCT1, in rat skeletal muscle. American journal of physiology. Endocrinology and metabolism 27 12900382
2022 Lactate Transporter SLC16A3 (MCT4) as an Onco-Immunological Biomarker Associating Tumor Microenvironment and Immune Responses in Lung Cancer. International journal of general medicine 26 35509603
2021 Therapy-induced DNA methylation inactivates MCT1 and renders tumor cells vulnerable to MCT4 inhibition. Cell reports 26 34077729
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 Formosanin C inhibits non-small-cell lung cancer progression by blocking MCT4/CD147-mediated lactate export. Phytomedicine : international journal of phytotherapy and phytopharmacology 25 36610137
2019 New Insights into the Lactate Shuttle: Role of MCT4 in the Modulation of the Exercise Capacity. iScience 25 31837519
2003 Distribution of monocarboxylate transporter isoforms MCT1, MCT2 and MCT4 in porcine muscles. Acta physiologica Scandinavica 24 12492781
2008 Characterization and regulation of monocarboxylate cotransporters Slc16a7 and Slc16a3 in preimplantation mouse embryos. Biology of reproduction 23 18385447
2022 MCT4/Lactate Promotes PD-L1 Glycosylation in Triple-Negative Breast Cancer Cells. Journal of oncology 22 36199799
2011 Nitric oxide induces the expression of the monocarboxylate transporter MCT4 in cultured astrocytes by a cGMP-independent transcriptional activation. Glia 22 21901758
2019 A novel MCT1 and MCT4 dual inhibitor reduces mitochondrial metabolism and inhibits tumour growth of feline oral squamous cell carcinoma. Veterinary and comparative oncology 21 31661586
2019 Exposure to Pb and Cd alters MCT4/CD147 expression and MCT4/CD147-dependent lactate transport in mice Sertoli cells cultured in vitro. Toxicology in vitro : an international journal published in association with BIBRA 20 30615929
2014 Upregulation of CD147 protects hepatocellular carcinoma cell from apoptosis through glycolytic switch via HIF-1 and MCT-4 under hypoxia. Hepatology international 19 26202642
2019 MCT4 promotes cell proliferation and invasion of castration-resistant prostate cancer PC-3 cell line. EXCLI journal 18 31217781
2015 Involvement of Histidine Residue His382 in pH Regulation of MCT4 Activity. PloS one 18 25919709
2023 Functional heterogeneity of MCT1 and MCT4 in metabolic reprogramming affects osteosarcoma growth and metastasis. Journal of orthopaedic surgery and research 17 36814318
2021 MCT4 Promotes Tumor Malignancy in F98 Glioma Cells. Journal of oncology 17 33936203
2019 Inhibition of Hypothalamic MCT4 and MCT1-MCT4 Expressions Affects Food Intake and Alters Orexigenic and Anorexigenic Neuropeptide Expressions. Molecular neurobiology 17 31578706
2024 Exercise influence on monocarboxylate transporter 1 (MCT1) and 4 (MCT4) in the skeletal muscle: A systematic review. Acta physiologica (Oxford, England) 16 38240467
2012 Expression and role of GLUT-1, MCT-1, and MCT-4 in malignant pleural mesothelioma. Virchows Archiv : an international journal of pathology 16 23187830
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 15 35615882
2014 MCT1 and MCT4 kinetic of mRNA expression in different tissues after aerobic exercise at maximal lactate steady state workload. Physiological research 15 25470525
2006 MCT-4, A511/Basigin and EF5 expression patterns during early chick cardiomyogenesis indicate cardiac cell differentiation occurs in a hypoxic environment. Developmental dynamics : an official publication of the American Association of Anatomists 15 16110503
2021 MCT4 is induced by metastasis-enhancing pathogenic mitochondrial NADH dehydrogenase gene mutations and can be a therapeutic target. Scientific reports 14 34172808
2013 The Expression of Glut-1, CAIX, and MCT4 in Mucinous Carcinoma. Journal of breast cancer 14 23843845
2011 Expression of monocarboxylate transporter (MCT) 1 and MCT4 in overloaded mice plantaris muscle. The journal of physiological sciences : JPS 14 21826525
2007 Rapid upregulation of GLUT-4 and MCT-4 expression during 16 h of heavy intermittent cycle exercise. American journal of physiology. Regulatory, integrative and comparative physiology 14 18056982
2022 Involvement of SLC16A1/MCT1 and SLC16A3/MCT4 in l-lactate transport in the hepatocellular carcinoma cell line. Biopharmaceutics & drug disposition 13 36104287
1998 Genomic structure and developmental expression of the chicken nonocarboxylate transporter MCT3 gene. Experimental eye research 13 9820789