DL-lactic acid

Overview

DL-lactic acid (Wikidata: Q161249) is the racemic mixture of the two enantiomers of lactic acid — the L-form (L-lactate) and the D-form (D-lactate) — sharing the molecular formula C₃H₆O₃. As a central metabolite of carbohydrate metabolism, lactic acid is produced primarily through anaerobic glycolysis, wherein pyruvate is reduced to lactate by L-lactate dehydrogenase in the cytoplasm. Under normal physiological conditions, circulating lactate serves as a critical energy substrate shuttled between tissues, fueling the tricarboxylic acid (TCA) cycle in the liver, heart, and brain. Beyond its classical role as a metabolic byproduct, lactate has emerged as a potent signaling molecule capable of modulating gene expression, immune function, and cellular fate through a post-translational modification known as lactylation — the direct acylation of lysine residues on histone and non-histone proteins by lactyl-CoA derived from lactate.

The biological significance of lactic acid extends across a wide spectrum of physiology and disease. Elevated lactate levels are well-established indicators of tissue hypoxia, sepsis, and mitochondrial dysfunction, making lactate a cornerstone clinical biomarker in critical care medicine. More recently, the field has recognized lactate's active participation in oncogenic reprogramming — the so-called Warburg effect — whereby cancer cells preferentially generate energy through aerobic glycolysis, producing abundant lactate even in the presence of oxygen. This metabolic phenotype not only fuels tumor growth but also reshapes the tumor microenvironment, suppresses anti-tumor immunity involving CD8+ T cells and dendritic cells, and drives epigenetic remodeling via histone lactylation. Collectively, these discoveries have repositioned lactic acid from a passive metabolic waste product to a master regulator of cellular signaling, making it a high-priority target in cancer, neurological disease, and metabolic research.

Focus of Latest Publications

Cancer Metabolism and the Warburg Effect

A substantial body of recent research has focused on lactate as a central driver of tumor progression across multiple malignancy types, including liver cancer and other solid tumors.

In hepatocellular carcinoma (HCC), a landmark study published in Gut (PMID 42114979) performed landscape screening to identify AARS2 — a lactate-modifying enzyme — as a master regulator of lactate metabolism and protein lactylation in HCC. The study demonstrated that lactate metabolism and the downstream epigenetic process of protein lactylation play key regulatory roles in HCC progression, establishing AARS2 as a promising therapeutic target and underscoring how lactate-driven epigenetic modification can fuel liver cancer.

In prostate cancer, an investigation published in the Journal of Molecular Histology (PMID 42185511) examined how icariin suppresses glycolysis by upregulating ALKBH5 to mediate EARS2 m6A demethylation. Glycolytic flux was directly quantified by measuring extracellular acidification rate (ECAR), oxygen consumption rate (OCR), and levels of glucose, lactate, and adenosine triphosphate (ATP), establishing lactate as a functional readout of glycolytic suppression in this context.

Colorectal cancer research (PMID 41966374), using integrated multi-omics analysis, demonstrated that TIMP1 and pyruvate kinase M (PKM) collectively drive immunosuppression and metabolic remodeling to promote tumor progression. Crucially, pharmacological inhibition of PKM significantly suppressed lactate production, linking the glycolytic enzyme directly to lactate-mediated immune evasion and highlighting lactate as a downstream effector of PKM activity.

In clear cell renal cell carcinoma, a study in the Balkan Medical Journal (PMID 42028950) identified that SLC16A3-induced lactate remodeling drives immune evasion via an autocrine GPR81-ERK-c-MYC feedback loop. This work directly implicated glycolytic reprogramming and lactate accumulation as mechanisms enabling tumor cells to escape immune surveillance, connecting lactate to the PD-1/PD-L1 immune checkpoint axis and regulatory T cell suppression.

Anti-PD-1 resistance — a major unresolved clinical challenge — was linked to lactate metabolism through the discovery of KSR2 as a metabolic checkpoint in cancer immunotherapy (PMID 42012646, Cancer Immunology, immunotherapy). KSR2 was found to drive profound glucose metabolic reprogramming in cancer cells, enhancing glucose uptake, potentiating the Warburg effect, promoting lactate accumulation, and disrupting the TCA cycle. This mechanistic cascade was shown to underpin resistance to anti-PD-1 therapy, positioning lactate as a mediator bridging cancer metabolism and immunotherapy failure.

In breast cancer, a study published in the Journal of Controlled Release (PMID 41679436) developed copper-based nanoplatforms (CPLL NPs) designed to synergistically deplete lactate, relieve hypoxia, restore mitochondrial vulnerability, and induce enhanced cuproptosis. The therapeutic strategy aimed at converting immunologically "cold" breast tumors into treatment-responsive lesions, with lactate depletion serving as a key mechanism to reverse tumor-associated immune suppression involving cancer-associated fibroblasts and regulatory T cells.

Importantly, a study employing AI-driven drug discovery (PMID 41833273, European Journal of Medicinal Chemistry) identified a selective dual-function inhibitor blocking both HK2 enzymatic activity and the HK2-VDAC1 interaction at the mitochondrial outer membrane. The lead compound reduced lactate and ATP levels and induced apoptotic markers including increased p-AMPK/AMPK ratio, elevated Bax, and decreased B-cell lymphoma 2 expression, demonstrating that targeting upstream glycolytic nodes translates directly into lactate suppression and cell death.

In papillary thyroid carcinoma (PTC), published in Cell Death & Disease (PMID 42045183), lactate was identified as a critical driver of tumor metastasis through a novel mechanism: lactylation of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme in fatty acid β-oxidation. This finding revealed that lactate not only fuels glycolysis but also epigenetically reprograms lipid metabolism to promote invasiveness, establishing a direct link between lactic acid accumulation and metastatic progression.

Neurological and Psychiatric Research

Beyond oncology, lactic acid has emerged as a significant metabolite in neurological disease and psychiatric conditions. In depression research (PMID 42023591, Gut Microbes), a study demonstrated that gut microbiota reshapes host energy metabolism to modulate depressive behaviors, with lactate and L-glutamic acid identified as core Metabolites associated with these alterations. Autologous fecal microbiota transplantation (FMT) served as an experimental intervention in a chronic social defeat stress mouse model, pointing to gut-derived lactate as part of the metabolic axis connecting the human gut flora to mood regulation.

In the context of age-related cognitive decline, a study in Signal Transduction and Targeted Therapy (PMID 42002550) reported that lactate, as a mitochondria-associated metabolite, facilitates histone lactylation of ferroptosis-related and aging-related genes — including Acsl4, Trp53 (TP53), and Cdkn1a — via the TEAD-YAP complex. This epigenetic mechanism was shown to promote transcription of genes that amplify neuronal ferroptosis, linking lactate directly to age-related neurodegeneration. Separately, in vascular cognitive impairment research (PMID 41837796, Journal of Alzheimer's Disease), CAP1 expression demonstrated a significant association with glycolysis-related Metabolites, particularly lactate and a complex glycolysis score, suggesting that lactate-linked glycolytic signaling may contribute to Alzheimer's disease and cognitive decline.

For neurocritical care, a near real-time multiplexed monitoring platform described in Science Translational Medicine (PMID 42127221) incorporated aptamer-based electrochemical biosensors and impedance-based flow sensors to continuously measure key cerebrospinal fluid (CSF) biomarkers including glucose, lactate, pH, and flow rate. The ability to track CSF lactate in real time was deemed essential for early detection of central nervous system infection and ventricular drain dysfunction.

Cardiovascular and Renal Disease

In the cardiovascular domain, a metabolomic study examining predictors of coronary artery calcification in postmenopausal women (PMID 41973512, American Journal of Physiology: Heart and Circulatory Physiology) identified significantly lower levels of lactic acid as part of an altered carbohydrate metabolism profile associated with elevated Agatston scores measured by computer tomography. Women with a history of preeclampsia showed plasma metabolite signatures — including reduced lactic acid alongside elevated proline, allothreonine, and ribitol — that predicted subclinical cardiovascular disease.

In acute kidney injury (AKI) following bee stings, a machine learning study in Renal Failure (PMID 42185747) developed and validated an early prediction model using data from 305 patients, identifying eight key predictors including lactate, creatinine, and dark urine. This work applied XGBoost, LightGBM, and artificial neural network models alongside the LASSO algorithm for feature selection, and referenced Kidney Disease: Improving Global Outcomes (KDIGO) criteria for AKI classification, demonstrating lactate's utility as a clinical triage biomarker in toxin-induced organ injury.

Key Publications

• May Icariin suppresses glycolysis in prostate cancer by upregulating ALKBH5 to mediate EARS2 m6A demethylation. (Journal of molecular histology, 2026, PMID 42185511): "Glycolysis was evaluated by measuring the extracellular acidification rate (ECAR), oxygen consumption rate (OCR), and levels of glucose, lactate, and adenosine triphosphate (ATP)."
• May Development and validation of an early prediction model for bee-sting-induced acute kidney injury using machine learning. (Renal failure, 2026, PMID 42185747): "identifying eight key predictors, including lactate, creatinine, and dark urine."
• May A platform for near real-time and multiplexed monitoring of cerebrospinal fluid biomarkers and flow in neurocritical care. (Science translational medicine, 2026, PMID 42127221): "...near real-time monitoring of key CSF (bio)markers, including glucose, lactate, pH, and flow rate, that are essential for detecting infection and drain dysfunction."
• May Landscape screening identifies the lactate-modifying enzyme AARS2 as a master regulator and therapeutic target in hepatocellular carcinoma. (Gut, 2026, PMID 42114979): "Lactate metabolism and protein lactylation play key roles in HCC progression; nevertheless, their regulatory mechanisms remain poorly understood."
• May Plasma metabolites, blood-borne microvesicles, and history of preeclampsia as predictors of coronary artery calcification in postmenopausal women. (American journal of physiology. Heart and circulatory physiology, 2026, PMID 41973512): "3) significantly higher levels of proline, allothreonine (amino acid metabolism), and ribitol (carbohydrate metabolism), and lower levels of lactic acid (carbohydrate metabolism);"
• May TIMP1 and PKM drive immunosuppression and metabolic remodeling to promote colorectal cancer progression through integrated multi-omics analysis. (International journal of biological macromolecules, 2026, PMID 41966374): "Functionally, treatment with a PKM inhibitor significantly suppressed lactate production."
• Apr Lactic acid promotes metastasis of papillary thyroid carcinoma by enhancing CPT1A lactylation. (Cell death & disease, 2026, PMID 42045183): "Here, we identify lactate as a critical driver of PTC metastasis through lactylation of carnitine palmitoyltransferase 1 A (CPT1A), the rate-limiting enzyme in fatty acid β-oxidation (FAO)."
• Apr SLC16A3-Induced Lactate Remodeling Drives Immune Evasion in Clear Cell Renal Cell Carcinoma via an Autocrine GPR81-ERK-c-MYC Feedback Loop. (Balkan medical journal, 2026, PMID 42028950): "Extensive studies have implicated glycolytic reprogramming and lactate accumulation in immune evasion."
• Apr Gut microbiota reshapes host energy metabolism to modulate depressive behaviors. (Gut microbes, 2026, PMID 42023591): "...and were associated with altered levels of core metabolites like lactate and L-glutamic acid."
• Apr KSR2 functions as a metabolic checkpoint for anti-PD-1 resistance by reprogramming glucose metabolism. (Cancer immunology, immunotherapy : CII, 2026, PMID 42012646): "Mechanistically, KSR2 functions as a central metabolic checkpoint, driving profound glucose metabolic reprogramming in cancer cells by enhancing glucose uptake, potentiating the Warburg effect, promoting lactate accumulation, and disrupting the tricarboxylic acid cycle."