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Lactylation: A Novel Mechanism Regulating Disease

Cellular Stress Chronic Inflammation Tumor Microenvironment Metabolic Diseases

Lactylation is a lactate-derived lysine post-translational modification that connects glycolysis, chromatin regulation, and disease biology. It entered modern epigenetics when lactate-derived histone lysine lactylation was shown to directly stimulate gene transcription from chromatin, with 28 lactylation sites identified on core histones in human and mouse cells. This discovery turned lactate from a metabolic by-product into a signaling substrate for gene regulation, making lactylation a rapidly growing topic in cancer, inflammation, immunity, aging, fibrosis, cardiovascular disease, and regenerative biology[1][2][3].

Mechanistically, hypoxia, bacterial challenge, and glycolysis increase lactate production, and lactate acts as a precursor that stimulates histone lactylation. In bacterially challenged M1 macrophages, histone lactylation shows temporal dynamics distinct from acetylation, and late-phase lactylation induces homeostatic genes involved in wound healing, including Arg1. Enzymatic regulation adds druggable control points: p300 supports lactate-induced histone lactylation, while class I HDAC1-3 act as histone lysine delactylases and remove lactyl marks. These findings place LDHA-dependent lactate production, monocarboxylate transport, p300-mediated writing, HDAC-mediated erasing, and H3K18 lactylation at the center of disease-relevant lactylation signaling[1][4][5].

Disease applications now focus on tumor metabolism, macrophage polarization, immune suppression, inflammation, bone biology, and vascular pathology. In ovarian cancer, lactate activates CCL18 expression through H3K18 lactylation in macrophages and promotes tumorigenesis. In colorectal cancer, histone lactylation inhibits macrophage RARγ expression and promotes tumorigenesis through TRAF6-IL-6-STAT3 signaling. In atherosclerosis, lipid peroxidation increases lactate-dependent H3K18 lactylation during endothelial-to-mesenchymal transition. In osteoblast differentiation, lactate synthesized by LDHA supports BMP-2-induced differentiation and histone lactylation[6][7][8][9].

The main research gap is specificity: lactylation can mark histones and non-histone proteins, but the field still needs validated writers, erasers, readers, site-specific antibodies, quantitative proteomics, and causal disease models. Future drug discovery should test whether targeting lactate production, lactate transport, p300 activity, HDAC delactylation, or disease-specific lactylated proteins can separate protective repair programs from pathological inflammation, cancer immune evasion, vascular remodeling, and metabolic disease. The strongest clinical prospect is not global lactate suppression, but precision control of lactylation circuits in defined tissues, cell states, and disease stages[2][3][5][6][7][8][9].

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Cat. No. Product Name Information Application Publication
HY-13818 Stattic
Stattic is a potent STAT3 inhibitor and inhibits STAT3 phosphorylation (at Y705 and S727). Stattic inhibits the binding of a high affinity phosphopeptide for the SH2 domain of STAT3. Stattic ameliorates the renal dysfunction in Alport syndrome (AS) mice.
STAT   Apoptosis  
Lung Cancer   Breast Cancer   Prostate Cancer   Liver Cancer   Leukemia/Lymphoma/Myeloma   Pancreatic Cancer   Digestive System Inflammation   Obesity  
322
HY-10201 Sorafenib
Sorafenib (Bay 43-9006) is a potent oral active multikinase inhibitor. Sorafenib blocks autophosphorylation and activity of receptor tyrosine kinases (VEGFR-2, VEGFR-3) and RAF family kinases, thereby suppressing the RAF/MEK/ERK and PI3K/Akt pathways, inhibiting STAT3 phosphorylation, and selectively inhibiting the MAPK pathway in cancer cells. Sorafenib induces cell cycle arrest, autophagy, apoptosis, and PARP cleavage, reduces Bcl-2, Bcl-XL, cyclin D1 levels, and activates Bak and Bax. Sorafenib inhibits tumor growth and metastasis in mouse and rat models. Sorafenib can be used for cancer research, such as colon, breast, non-small-cell lung cancer (NSCLC), ovarian, pancreatic, melanoma, colorectal and hepatocellular carcinoma.
Raf   VEGFR   FLT3   Autophagy   Apoptosis   STAT   Akt   MMP   Cadherin   p38 MAPK   ERK   MEK   PI3K   PARP   Bcl-2 Family   Ephrin Receptor   PDGFR  
Gastric Cancer   Liver Cancer   Ovarian Cancer   Digestive System Inflammation   Small Cell Lung Cancer   Non-Small Cell Lung Cancer   Metastatic Breast Cancer   Metastatic Colorectal Cancer   Metastatic Prostate Cancer   Multiple Myeloma   Metastatic Pancreatic Cancer   SARS-CoV-2 Infection   Alzheimer's Disease   Parkinson's Disease   Obesity   Lung Fibrosis  
316
HY-B0075 Melatonin
Melatonin is a hormone made by the pineal gland that can activate melatonin receptor and inhibit PANoptosis. Melatonin plays a role in sleep and possesses important antioxidative and anti-inflammatory properties. Melatonin is a novel selective ATF-6 inhibitor and induces human hepatoma cell apoptosis through COX-2 downregulation. Melatonin attenuates palmitic acid-induced (HY-N0830) mouse granulosa cells apoptosis via endoplasmic reticulum stress.
Melatonin Receptor   Autophagy   Mitophagy   Endogenous Metabolite   Apoptosis   PANoptosis   Ligands for Target Protein for PROTAC   Histone Acetyltransferase  
Lung Cancer   Breast Cancer   Prostate Cancer   Liver Cancer   Viral Infection   Neurodegenerative Disease   Digestive System Inflammation   SARS-CoV-2 Infection  
149
HY-N0005 Curcumin
Curcumin (Diferuloylmethane), a natural phenolic compound, is a p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. Curcumin is a photosensitizer against microorganisms. Curcumin shows inhibitory effects on NF-κB and MAPKs, and has diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Curcumin induces stabilization of Nrf2 protein through Keap1 cysteine modification.
Histone Acetyltransferase   Epigenetic Reader Domain   Keap1-Nrf2   Autophagy   Mitophagy   Influenza Virus   Ferroptosis   Apoptosis  
Prostate Cancer   Leukemia/Lymphoma/Myeloma   Pancreatic Cancer   Viral Infection   Pain   Digestive System Inflammation   Glucose Metabolism   Metastatic Breast Cancer   SARS-CoV-2 Infection   Obesity   Lung Fibrosis  
138
HY-B0069 Fludarabine
Fludarabine (NSC 118218) is a DNA synthesis inhibitor and a fluorinated purine analogue with antineoplastic activity in lymphoproliferative malignancies. Fludarabine inhibits the cytokine-induced activation of STAT1 and STAT1-dependent gene transcription in normal resting or activated lymphocytes.
Nucleoside Antimetabolite/Analog   DNA/RNA Synthesis   STAT   Apoptosis  
Lung Cancer   Breast Cancer   Prostate Cancer   Leukemia/Lymphoma/Myeloma   Pancreatic Cancer   Viral Infection   Digestive System Inflammation   SARS-CoV-2 Infection   Obesity   Lung Fibrosis  
119
HY-107455 A-485
A-485, a chemical probe, is a potent and selective catalytic inhibitor of p300/CBP with IC50s of 9.8 nM and 2.6 nM for p300 and CBP histone acetyltransferase (HAT), respectively.
Epigenetic Reader Domain   Histone Acetyltransferase  
Leukemia/Lymphoma/Myeloma   Lung Fibrosis  
114
HY-40354 Tofacitinib
Tofacitinib (Tasocitinib) is an orally active, blood-brain barrier permeable selective inhibitor of JAK1/JAK3. Tofacitinib blocks the JAK-STAT/NF-κB signaling pathway, inhibits cytokine signal transduction, phosphorylation of STAT1/STAT5, and suppresses innate and adaptive immune responses. Tofacitinib can be used in research related to major depressive disorder, rheumatoid arthritis, pulmonary diseases, systemic lupus erythematosus, and immune-mediated liver injury.
JAK   STAT   NF-κB  
Depression   Pulmonary Disease   Systemic Lupus Erythematosus   Liver Injury   Rheumatoid Arthritis  
103
HY-13823 C646
C646 is a selective and competitive histone acetyltransferase p300 inhibitor with Ki of 400 nM, and is less potent for other acetyltransferases.
Histone Acetyltransferase   Autophagy   Epigenetic Reader Domain   Apoptosis  
Digestive System Disease   Leukemia/Lymphoma/Myeloma   Digestive System Inflammation   Glucose Metabolism  
98
HY-66005 Acetaminophen
Acetaminophen (Paracetamol) is a selective cyclooxygenase-2 (COX-2) inhibitor with an IC50 of 25.8 μM; is a widely used antipyretic and analgesic agent.. Acetaminophen is a potent hepatic N-acetyltransferase 2 (NAT2) inhibitor. Acetaminophen induces ferroptosis and leads to acute liver injury in mice model.
Environmental Pollutants   Histone Acetyltransferase   Ferroptosis   COX   Bacterial   Endogenous Metabolite   Parasite  
Inflammation or Immune System Disease   Breast Cancer   Lung Adenocarcinoma  
76
HY-16141 Cilengitide
Cilengitide (EMD 121974) is an integrin (integrin) inhibitor with blood-brain barrier permeability, with IC50 values against human targets as follows: 0.61 nM for αvβ3, 8.4 nM for αvβ5, 14.9 nM for α5β1, 5400 nM for αIIbβ3, 2050 nM for αvβ6, 2350 nM for αvβ8. Cilengitide inhibits the binding of integrins to vitronectin, fibronectin, fibrinogen and LAP (TGF-β), and serves as an internal standard for solid-phase integrin binding assays. Cilengitide inhibits tumor cell viability, induces apoptosis, reduces the phosphorylation levels of STAT3, AKT and mTOR, downregulates the expression of PD-L1, inhibits cell viability and angiogenesis, regulates anti-tumor immune responses and slows tumor growth. Cilengitide can be used in research related to glioblastoma, melanoma, advanced solid tumors and refractory brain tumors.
Integrin   TGF-β Receptor   Apoptosis   PD-1/PD-L1   STAT   Akt   mTOR  
Melanoma   Glioblastoma  
75
HY-N0193 Artesunate
Artesunate is an inhibitor of both STAT-3 and exported protein 1 (EXP1).
STAT   Ferroptosis   Parasite   Virus Protease  
Inflammation or Immune System Disease   Lung Cancer   Prostate Cancer   Liver Cancer   Leukemia/Lymphoma/Myeloma   Pancreatic Cancer   Viral Infection   Parasitic Infection   Metastatic Breast Cancer   Obesity  
43
HY-14944 Homoharringtonine
Homoharringtonine (Omacetaxine mepesuccinate;HHT) is a cytotoxic alkaloid with antitumor properties which acts by inhibiting translation elongation.
STAT  
Inflammation or Immune System Disease   Lung Cancer   Breast Cancer   Prostate Cancer   Liver Cancer   Leukemia/Lymphoma/Myeloma   Pancreatic Cancer   Obesity  
37
HY-117287 Deucravacitinib
Deucravacitinib (BMS-986165) is an orally active allosteric inhibitor of tyrosine kinase 2 (TYK2), with an IC50 of 0.2 nM and a Ki of 0.02 nM against the JH2 domain of TYK2, and it exhibits selectivity over other JAK subtypes and most of the kinome. Deucravacitinib blocks IL-23, IL-12, p-STAT1/3 and Type I IFN signaling, and inhibits Th17/Th1-mediated psoriasis inflammation. Deucravacitinib can be used in research related to moderate-to-severe plaque psoriasis, inflammatory bowel disease and systemic lupus erythematosus.
JAK   STAT   Interleukin Related   IFNAR  
Systemic Lupus Erythematosus   Psoriasis   Inflammatory Bowel Disease  
36
HY-15826 SGC-CBP30
SGC-CBP30, a chemical probe, is a potent and highly selective CBP/p300 bromodomain (Kds of 21 nM and 32 nM for CBP and p300, respectively) inhibitor, displaying 40-fold selectivity over the first bromodomain of BRD4 [BRD4(1)] bound. SGC-CBP30 strongly reduces secretion of IL-17A in Th17 cells and has anti-inflammatory effects.
Epigenetic Reader Domain   Histone Acetyltransferase  
Inflammation or Immune System Disease   Leukemia/Lymphoma/Myeloma   Depression   Lung Fibrosis  
24
HY-16706 Remodelin
Remodelin is an orally active and selective inhibitor of acetyltransferase NAT10. Remodelin inhibits NAT10 activitity and slows DNA replication and suppresses growth of prostate cancer cells. Remodelin inhibits the growth of prostate cancer and hepatocellular carcinoma in xenograft model. Remodelin enhances the healthspan in hutchinson-gilford progeria syndrome (HGPS) mouse model.
Histone Acetyltransferase  
Prostate Cancer   Liver Cancer   Non-Small Cell Lung Cancer  
24
HY-111784 Inobrodib
Inobrodib (CCS1477) is an orally active, potent, and selective inhibitor of the p300/CBP bromodomain. Inobrodib binds to p300 and CBP with Kd values of 1.3 and 1.7 nM, respectively, and with 170/130-fold selectivity compared with BRD4 with a Kd of 222 nM. CCS1477 inhibits cell proliferation in prostate cancer cell lines and decreases androgen receptor (AR)- and C-MYC-regulated gene expression.
Ligands for Target Protein for PROTAC   Epigenetic Reader Domain   Histone Acetyltransferase  
Leukemia/Lymphoma/Myeloma   Non-Small Cell Lung Cancer   Metastatic Breast Cancer   Metastatic Prostate Cancer  
13
HY-N0390S1 L-Glutamine-13C5
L-Glutamine-13C5 is the 13C-labeled L-Glutamine (HY-N0390). L-Glutamine is an orally active nutritional agent and cellular metabolism regulator. L-Glutamine is taken up in a Na+-dependent manner and targets multiple key molecules including glutaminase, mTORC1, NF-κB, STAT-3 and HIF-1α. L-Glutamine enhances glutaminolytic catabolism, drives the conversion of glutamate to α-ketoglutarate, thereby regulating gene expression, integrating metabolic signals, mediating glutamine flux and maintaining redox homeostasis. L-Glutamine also promotes cell proliferation, osteogenic differentiation and fracture healing, exerts neuroprotective and cardioprotective effects, and inhibits osteoarthritis. L-Glutamine can be applied to research related to osteoporosis, osteoarthritis, ischemic stroke and acute cantharidin-induced cardiotoxicity.
Isotope-Labeled Compounds   mGluR   Ferroptosis   Environmental Pollutants   Endogenous Metabolite   HIF/HIF Prolyl-Hydroxylase   mTOR   STAT   NF-κB  
Neurological, Eye or Ear Disease   Inflammation or Immune System Disease   Blood or Cardio-cerebrovascular Disease   Metabolic or Endocrine Disease  
13
HY-134901 WM-3835
WM-3835 is a potent and high-specific HBO1 (KAT7 or MYST2) inhibitor and binds directly to the acetyl-CoA binding site of HBO1. WM-3835 activates apoptosis while inhibits osteosarcoma (OS) cell proliferation, migration and invasion. WM-3835 has antitumor activity and potently inhibits pOS-1 xenograft growth in mice.
Histone Acetyltransferase   Apoptosis  
Cancer   Digestive System Disease   Digestive System Inflammation  
11
HY-107632 GYY4137
GY4137 is a sustained-release H2S donor possessing vasodilatory, antihypertensive, and anti-inflammatory activities. GY4137 can inhibit cell growth, induce apoptosis, and cause cell cycle arrest by blocking the STAT3 pathway, demonstrating potent anticancer activity.
Apoptosis   STAT   NF-κB   NO Synthase   COX   TNF Receptor   Interleukin Related  
Neurological, Eye or Ear Disease   Inflammation or Immune System Disease   Blood or Cardio-cerebrovascular Disease  
8
HY-132283 PF-9363
PF-9363 (CTx-648) is a first-in-class potent and high selective KAT6A/KAT6B inhibitor. PF-9363 can be used for the research of cancer.
Histone Acetyltransferase  
Cancer  
5

References

[1]. Zhang D, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574(7779):575-580.  [Content Brief]

[2]. Wang J, et al. Ubiquitous protein lactylation in health and diseases. Cell Commun Signal. 2024;22(1):101.  [Content Brief]

[3]. Gong H, et al. Post-translational protein lactylation modification in health and diseases. Cell Death Discov. 2024;10(1):62.  [Content Brief]

[4]. Minami E, et al. Lactate-induced histone lactylation by p300 promotes osteoblast differentiation. PLoS One. 2023;18(12):e0293676.  [Content Brief]

[5]. Moreno-Yruela C, et al. Class I histone deacetylases (HDAC1-3) are histone lysine delactylases. Sci Adv. 2022;8(3):eabi6696.  [Content Brief]

[6]. Sun J, et al. Lactate activates CCL18 expression via H3K18 lactylation in macrophages to promote tumorigenesis of ovarian cancer. Acta Biochim Biophys Sin (Shanghai). 2024;56(9):1373-1386.  [Content Brief]

[7]. Li XM, et al. Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling. Cell Rep. 2024;43(2):113730.  [Content Brief]

[8]. Dong M, et al. ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes endothelial-to-mesenchymal transition and atherosclerosis. Nat Cardiovasc Res. 2024;3:1013-1029.  [Content Brief]

[9]. Merkuri F, et al. Histone lactylation couples cellular metabolism with chromatin organization and gene regulatory networks. Nat Commun. 2024;15(1):1043.  [Content Brief]

Keywords

lactylation, histone lactylation, lysine lactylation, lactate metabolism, H3K18la, p300, HDAC1, cancer metabolism, macrophage polarization, inflammatory disease