dichloroacetate topical / Generic mfg. - LARVOL DELTA

A novel approach to reverse Warburg metabolism in patients with recurrent glioblastoma: A phase II pharmacodynamic study of dichloroacetate. (PubMed, Neurooncol Adv) - "It reduced markers of tumor cell proliferation and lowered plasma lactate. Although no clinical benefit was noted, further studies of combination therapy are indicated, given the known association between poor cancer outcomes and elevated PDK expression and lactate levels."

Journal • P2 data • PK/PD data • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • HIF1A • PCNA • PDHA1 • PDK4 • PGK1

Phase III trial of sodium dichloroacetate for pyruvate dehydrogenase complex deficiency in children. (PubMed, JCI Insight) - "DCA decreased plasma lactate -0.48 (0.82) mmol/L (-20%; P = 0.006). Survival of participants was significantly greater than that of a natural history cohort (log-rank P = 0.027).CONCLUSIONLonger-term treatment with DCA, dosed based on GSTZ1 haplotype, is safe and was associated with a statistically significant improvement in patient motor function, plasma lactate, and survival.FUNDINGNIH (R01FD005407; R42HD089804), University of Florida Department of Medicine, Saol Therapeutics."

Clinical • Journal • P3 data • Metabolic Disorders

BICC1 attenuates oxidative stress-induced osteogenic injury via regulation of the PDK/PDH axis in MC3T3-E1 cells. (PubMed, J Bioenerg Biomembr) - "Bicc1 over-expressing lentivirus and the pyruvate dehydrogenase kinase isozyme (PDK) inhibitor dichloroacetate (DCA) were used for intervention...Transcriptomic analysis showed that PDK1 was a key target molecule in Bicc1-regulated apoptosis and oxidative stress responses. Inhibition of PDK1 recapitulates the protective effect of BICC1 to oxidative stress injury in MC3T3-E1 cells. Bicc1 attenuates oxidative stress injury and promotes osteogenic differentiation in MC3T3-E1 cells, and may serve as a potential therapeutic target for osteoporosis."

Journal • Metabolic Disorders • Osteoporosis • Rheumatology • BICC1 • PDK1

Differential activation of TCA cycle activity and PDH flux by dichloroacetate in skeletal muscle measured by hyperpolarized [2-13C,3-2H3]pyruvate. (PubMed, iScience) - "A similar trend was also observed in ex vivo GC-MS analysis of skeletal muscle tissue collected from rats injected with [U-13C3]pyruvate. Together, these findings highlight the complex interplay between PDH and TCA cycle fluxes and establish hyperpolarized [2-13C,3-2H3]pyruvate as a robust agent for assessing mitochondrial metabolism in skeletal muscle."

Journal

Androgen-PDH axis modulates sexual dimorphism of mitochondrial respiration in visceral fat. (PubMed, Cell Rep) - "Furthermore, sodium dichloroacetate, a PDH activator, enhances mitochondrial respiration and reduces visceral fat in male mice. Multi-omics analyses reveal that the androgen-PDH axis orchestrates a male-specific chromatin-based transcriptional landscape that encompasses mitochondrial and metabolic pathways in visceral adipocytes. Collectively, this study identifies the androgen-PDH axis as a key regulator of sexual dimorphism in mitochondrial metabolism and adipose homeostasis in VAT."

Journal • Obesity • PDHB

Inflammatory-metabolic coupling in glia: LCN2-PDK axis as molecular mechanism and therapeutic paradigm. (PubMed, Biochem Pharmacol) - "Multi-level therapeutic opportunities include PDK inhibition with dichloroacetate, PPARβ/δ antagonism, LCN2 neutralization, and metabolic support strategies, although disease-specific dosing, timing, efficacy, and long-term safety (including the risk of peripheral neuropathy with dichloroacetate) require further clinical evaluation. Plasma LCN2 and hyperpolarized 13C-pyruvate magnetic resonance imaging represent promising, though still emerging, candidate biomarkers for patient stratification and target engagement monitoring. This mechanistic convergence across disorders positions the LCN2-PDK axis as a promising candidate therapeutic target, with diabetic neuropathy - where supporting evidence is currently strongest - representing the lead indication for clinical translation."

Journal • Review • Alzheimer's Disease • Cardiovascular • CNS Disorders • Diabetic Neuropathy • Inflammation • Metabolic Disorders • Pain • Vascular Neurology • HIF1A • LCN2

Controlling chlorinated oxidation by-product formation during Fenton treatment of biologically treated landfill leachate: The role of flocculation pretreatment. (PubMed, Water Res) - "This suppression effect was most pronounced for polychlorinated HAAs, with the concentrations of dichloroacetic acid and trichloroacetic acid reduced by 76.00 % and 78.55 %, respectively...After treatment with the Flocculation-Fenton system, both the Cl-OBP-associated cytotoxicity and the phytotoxicity of the effluent were reduced. These findings provide mechanistic insight and practical guidance for advanced treatment and by-product control in high-chloride landfill leachate systems."

Journal

Predicting regulated and emerging disinfection byproducts in small drinking water catchments using machine learning. (PubMed, Environ Int) - "Ten DBP parameter concentrations, namely total trihalomethanes, total haloacetic acids, trichloromethane, bromodichloromethane, dibromochloromethane, dichloroacetic acid, trichloroacetic acid, dichloroacetonitrile, trichloronitromethane (chloropicrin) and trichloropropanone could be quantitatively predicted (average R2 = 0.86, root mean squared percent error = 27.9 %) with a further five species classified for binary presence-absence only (95.6 % average accuracy)...Inclusion of hydrochemical parameters (e.g., DOC) only marginally improved model performance. Our findings demonstrate a proof-of-concept for the utility of machine learning models trained on DOM spectroscopic variables using a relatively small sample size (n = 198) with a scalable workflow freely available to further data-driven, risk-based management of DBP formation in drinking water supplies globally."

Journal

Inhibition of PINK1/Parkin-mediated mitophagy enhances the susceptibility of breast cancer to cuproptosis. (PubMed, Oncogene) - "In this study, we induced cuproptosis of breast cancer cells using Elesclomol (ES) and assessed changes in mitochondrial reactive oxygen species, mitochondrial membrane potential, and oxygen consumption rate. The combination of dichloroacetate (DCA) and ES exhibited a synergistic antitumor effect without significant tissue damage on the brain, heart, liver, and kidneys in subcutaneous mouse xenograft models. Collectively, our findings reveal that inhibiting PINK1/Parkin-mediated mitophagy enhances the sensitivity of breast cancer to cuproptosis, offering a novel combined treatment strategy for breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • DLAT

Route-resolved priority risks of disinfection by-products in indoor pools: the underestimated role of buccal/sublingual exposure for the public and competitive swimmers. (PubMed, Front Public Health) - "This study evaluated carcinogenic and chronic toxic risks associated with chloroform (CF), dichloroacetic acid (DCAA), and trichloroacetic acid (TCAA) using annual monitoring data from two indoor pools with contrasting operational characteristics (SP-A and SP-B)...Overall, DBP-related risks were higher in SP-B, emphasizing the influence of pool chemistry, bather load, and ventilation. These findings highlight the need for regular multi-route-specific risk assessment especially for competitive athletes and improved operational controls, particularly reducing TCAA precursors and enhancing ventilation for CF."

Journal • Oncology

Chemical Bond-Orchestrated Energy Depletion to Augment Lung Cancer Chemo-Immunotherapy. (PubMed, Adv Sci (Weinh)) - "To address this, we herein grafted dichloroacetic acid into perylenediimide (PDI) skeleton via ionic or covalent bond to create PDIC-AC and PDIC-NAC...Superior PDHKs inhibiting efficacy and ROS generation capacity functionalize PDIC-AC as an efficient inhibitor to block glycolysis and OXPHOS, which not only repolarize macrophages toward anti-tumor M1 phenotype via suppression of lactate production, but also trigger immunogenic cell death via PERK-eIF2α-ATF4-CHOP axis to activate immune response, ultimately reaching effective chemo-immunotherapy against the primary and distant tumors. Overall, this work defines the unambiguous mechanism for PDI-triggered endogenous ROS generation, and meanwhile clarifies small-molecule regulators' energy metabolism intervention mechanism and establishes an innovative chemical bond engineering strategy for energy-targeted chemo-immunotherapy."

Journal • Lung Cancer • Oncology • Solid Tumor • ATF4

N-Acetylcysteine, Dichloroacetate, and Metformin Restore Mitochondrial Homeostasis by Counteracting Oxidative Stress and Fusion-Fission Imbalance in Palmitic Acid-Induced Lipotoxicity. (PubMed, J Oleo Sci) - "In an in vitro C2C12 model, PA-induced lipotoxicity is associated with oxidative stress and a fusion-fission imbalance favoring mitochondrial fragmentation. NAC, DCA, and metformin mitigate these alterations and help preserve mitochondrial homeostasis. These findings support targeting oxidative stress and mitochondrial dynamics as a potential approach to counteract mitochondrial dysfunction under lipotoxic conditions."

Journal • Metabolic Disorders • CAT • MFN1

Vincristine-induced alterations in ovarian function and oocyte quality: Modulation by dichloroacetate. (PubMed, Reprod Biol) - "Therefore, we propose that VCR induces significant alterations in ovarian function and oocyte quality that may persist beyond treatment. In contrast, DCA exhibits a dual effect, potentially aggravating follicular depletion while improving specific aspects of oocyte morphology."

Journal • CASP3 • CAT • FOXO3

Metabolic cell competition in the glioblastoma tumour microenvironment: glucose, glutamine, and lactate as determinants of immune exclusion and targets for pharmacological reprogramming. (PubMed, Front Oncol) - "Glioblastoma (GBM) remains the most lethal primary brain tumour, with median overall survival of 14 to 16 months despite maximal safe surgical resection, concurrent chemoradiotherapy, and adjuvant temozolomide...Disrupting glucose and glutamine metabolism through glutamine antagonism (DON and prodrugs JHU083/JHU395), dichloroacetate (DCA)-mediated PDK inhibition, intravenous pharmacological ascorbate-mediated GAPDH inactivation and HIF-1alpha destabilisation, systemic glucose restriction (SGLT2 inhibitors), sodium phenylbutyrate-mediated glutamine depletion, and monocarboxylate transporter inhibition can invert this competitive hierarchy, reprogramming the immunosuppressive myeloid compartment while preserving T cell fitness; mebendazole is additionally reviewed as a multi-target anti-parasitic repurposing candidate with demonstrated GBM preclinical survival benefit...GBM cells and immunosuppressive myeloid cells are proposed to constitute a substrate-dependent..."

Journal • Review • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • GAPDH • HIF1A • NLRP3

Metabolic Reprogramming in Oral Cancer: A Narrative Review of Therapeutic Perspectives with Emphasis on Dichloroacetate. (PubMed, Curr Issues Mol Biol) - "Oral squamous cell carcinoma (OSCC) represents a significant global health challenge characterized by high morbidity and mortality, frequently driven by therapeutic resistance and tumor aggressiveness. The review also examines the current translational limitations of DCA, including toxicity, pharmacokinetic constraints, and compensatory metabolic adaptations that restrict its efficacy as a standalone therapy. Furthermore, potential synergistic strategies are explored, particularly the combination of DCA with paclitaxel, which enhances therapeutic efficacy through concurrent disruption of cytoskeletal integrity and metabolic homeostasis, thereby increasing cellular susceptibility to apoptosis and overcoming chemoresistance."

Journal • Review • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma

Dual compartment lipid carriers hijack exocytosis to empower natural killer cells against solid tumours. (PubMed, Nat Commun) - "Lipid nanoparticles deliver nicotinamide mononucleotide to restore intracellular nicotinamide adenine dinucleotide, while endoplasmic reticulum targeted carriers exploit the endoplasmic reticulum to Golgi pathway to achieve trafficking directed exocytic dichloroacetate export, enabling precise lactate depletion without systemic toxicity...Endoplasmic reticulum engineered natural killer cells achieve potent tumour suppression through spatiotemporal metabolic reprogramming, a platform strategy that also extends to conventional T cell and macrophage therapies for enhanced therapeutic efficacy across adoptive cell systems. Our work establishes exocytosis co option as a strategy to empower cellular therapies and improve antitumour efficacy against lactate rich solid cancers."

Journal • Oncology • Solid Tumor • IFNG

Selective targeting of cancer and senescence via shared metabolic shifts extends lifespan of old mice. (PubMed, Aging (Albany NY)) - "To overcome these limitations, we combined dichloroacetate and metformin with a 10-fold reduced dose of Navitoclax (ABT-263) and show that this pharmacology, termed, DMA, selectively targets the metabolic vulnerabilities underlying senescent and malignant cells. Notably, the treatment is well tolerated by healthy human cells and in mice in vivo, and in fact improves the functional performance of aged mice after acute administration and extends lifespan after prolonged dosing. While the in vivo effects of DMA are yet to be fully explored, our findings suggest that it might represent a new, clinically viable way to combat cancer and senescence without toxicity to healthy cells and tissues."

Journal • Preclinical • Hematological Disorders • Oncology • Thrombocytopenia

Dichloroacetate improves animal survival, growth, neuromuscular activity, mitochondrial stress and physiology, and elevated lactate in C. elegans pdha-1 and dld-1 RNAi models of pyruvate dehydrogenase complex deficiency (PDCD). (PubMed, bioRxiv) - "These data further confirm that DCA's therapeutic effect correlates with PDHc disease phenotype severity in dld-1(RNAi) animals. SYNOPSIS: Dichloroacetate (DCA) treatment demonstrated significant preclinical beneficial effect on survival, neuromuscular function, linear growth, tissue lactate, and mitochondrial metabolism in two C. elegans models with variable degrees of pyruvate dehydrogenase complex (PDHc) deficiency (PDCD), providing confirmatory evidence to support its therapeutic potential in human PDCD patients."

Journal • CNS Disorders • Developmental Disorders • Metabolic Disorders • Psychiatry • PDHA1

Inhibition of mitochondrial complex I impedes zygotic genome activation via PDH-histone modification retrograde signaling. (PubMed, Biochem Biophys Res Commun) - "In addition, dichloroacetic acid enhanced the nuclear localization of PDH in 2-cell embryo, thereby augmenting TCA flux and promoting preimplantation development. In conclusion, RTN has the potential to exert cytotoxic effects on mammalian reproduction, and electron transport chain complex I inhibitors should be used with caution when applied to the treatment of reproductive diseases. Furthermore, this study enhances our comprehension of the interplay between mitochondrial metabolism and epigenetic regulation in early embryos."

Journal • Metabolic Disorders

Targeting Warburg effect in Chinese hamster ovary cell culture with pyruvate dehydrogenase kinase inhibitors. (PubMed, Biotechnol Prog) - "Therefore, the present study explores the use of pyruvate dehydrogenase kinase (PDK) inhibitors dichloroacetate (DCA), metformin (M), (S)-3,3,3-trifluoro-2-hydroxy-2-methyl propionic acid (TPP), and 4-phenylbutyrate (PB) to counteract this metabolic bottleneck. Validation in Trastuzumab-producing CHO-S cells confirmed a 30% increase in mAb yield and a 10% improvement in cell density. These outcomes demonstrate that the combination of DCA + TPP is a promising metabolic intervention to mitigate the Warburg effect and enhance recombinant protein production in mammalian systems."

Journal • Preclinical

Central lactate uptake during exercise contributes to hypothalamic fibroblast growth factor 21 induction and systemic fat mobilization. (PubMed, Mol Cell Endocrinol) - "Male Wistar rats received intracerebroventricular (ICV) administration of FGF21 or lactate, or performed acute endurance exercise under three conditions: standard exercise, exercise with inhibited brain lactate transport using α-cyano-4-hydroxycinnamate (4-CIN), or exercise with reduced systemic lactate production via dichloroacetate (DCA)...ICV FGF21 increased catecholamines, adipose cAMP, and HSL phosphorylation, effects blocked by the FGF21 receptor antagonist BGJ-398. Inhibiting brain lactate uptake before exercise attenuated hypothalamic FGF21 induction, sympathetic activation, and fat mobilization, whereas systemic lactate reduction had a weaker effect, suggesting that brain lactate uptake contributes importantly to exercise-induced hypothalamic FGF21 regulation and fat mobilization. Taken together, these findings support a role for central lactate uptake in the activation of hypothalamic GPR81-p38-MAPK-FGF21 signaling and suggest that this pathway contributes to..."

Journal • Metabolic Disorders • FGF21

Targeting metabolic reprogramming in HPV-associated oral squamous cell carcinoma: current advances, challenges, and clinical prospects. (PubMed, J Mol Histol) - "Emerging studies suggest that glycolytic inhibition, mitochondrial modulation, and repurposed agents such as metformin and dichloroacetate (DCA) may suppress tumor growth and enhance therapeutic sensitivity in HPV-positive models. Advancing this approach may require a biomarker-guided patient stratification and rational combination strategies. Overall, this review provides an integrated overview of HPV-driven metabolic alterations and current therapeutic progress while emphasizing the need for clinically grounded and mechanistically informed translational research."

IO biomarker • Journal • Review • Head and Neck Cancer • Metabolic Disorders • Oncology • Oral Cancer • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma

Reshaping glycometabolic reprogramming to suppress M1 macrophage polarization for diabetic wound therapy (PubMed, Sheng Li Xue Bao) - "Metabolism-based therapeutic strategies for diabetic wounds include: 1) targeting lactate dehydrogenase A (LDHA) to inhibit lactate production; 2) modulating monocarboxylate transporter (MCT) to maintain intracellular pH homeostasis; 3) stabilizing pyruvate kinase M2 (PKM2) tetramers to restore pyruvate metabolism; 4) applying mitochondria-targeted antioxidants to intervene in oxidative stress; and 5) utilizing specific small molecule inhibitors (including dichloroacetate as a pyruvate dehydrogenase kinase 4 inhibitor, dimethyl malonate as a succinate dehydrogenase inhibitor, and tanshinone IIA). These strategies provide novel approaches for restoring metabolic-immune balance."

Journal • Review • Diabetes • Inflammation • LDHA • NLRC5 • NLRP3 • PDK4 • PKM

PDK4 drives time-dependent physical endurance impairment during acute hypoxia by disrupting carbohydrate metabolism. (PubMed, Nutr Metab (Lond)) - "These findings suggest that acute hypoxia impairs endurance, in part through PDK4-mediated alterations in pyruvate metabolism, providing a mechanistic basis for optimizing nutritional and therapeutic strategies under hypoxic stress."

Journal • PDK4

COOPERATIVE GENETIC LESIONS INDUCE AEROBIC GLYCOLYSIS IN B-ALL, CREATING A THERAPEUTICALLY EXPLOITABLE METABOLIC VULNERABILITY (EHA 2026) - "Dichloroacetic acid (DCA) (0.1-10 mM) and venetoclax (1 nM-10 µM) effects were evaluated in murine cells and human B-ALL cell lines (SUP-B15, SD-1, 697, NALM-6). Summary/Conclusion Fusion oncogenes cooperate with secondary alterations to induce aerobic glycolysis during B-ALL leukemogenesis, representing a therapeutically exploitable vulnerability. Targeting the Warburg regulator PDK1 via DCA induces mitochondrial apoptosis preferentially in fully transformed leukemia cells and robustly potentiates venetoclax across multiple genomic drivers, supporting combined metabolic-BCL2 directed therapy to target relapse-associated glycolytic B-ALL cells."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • ABL1 • BCL2 • BCL2L1 • CDKN2A • IKZF1 • PDK1 • STAT5 • STAT5AWqe