Table 1 The function of lysine lactylation modification in physiology and disease
From: Post-translational protein lactylation modification in health and diseases: a double-edged sword
Study/Years of publication | Protein and Kla sites (if available) | Cell lines and animal models (if available) | Mechanisms and effects | Intervention and dose |
|---|---|---|---|---|
Dai SK et al., 2022 [63] | Histone H3 (K18) | P19 EC, neural stem/progenitor and 293T cells; ICR/CD−1 mice | Histone Kla existed extensively and changed significantly in the developing telencephalon to orchestrate gene expression changes and widely participate in neuronal differentiation and cell proliferation processes. HDAC1−3 acted as a novel “eraser” of H3K18la, affecting H3K18la levels | SAHA: 0.5 µM (for cells); VPA: 1 mM (for cells); MS−275: 1 µM (for cells), 20 mg/kg (for models); EX 527: 1 µM (for cells) |
Nian F et al., 2022 [73] | Histone H3 (K18) | HEK293FT and MC3T3-E1 cells | The increased expression levels of LDHA and its related H3K18lac during osteoblast differentiation promoted the formation of cellular mineralized nodules and ALP activity and played an important role in osteoblast differentiation | LA (unmentioned dosage) |
Wang J et al., 2022 [76] | Histone H4 (K8) | HCT116, HEK293T, RAW 264.7 and FHC cells infected with S. typhimurium | LPS decreased the negative regulatory efficiency of YY1 on LINC00152 through histone lactylation, thereby up-regulating LINC00152, which inhibited both Salmonella invasion and the inflammation response but also promoted tumor growth | Lactic acid: 25, 50, 75, 100 mM (for cells); LPS: 1, 5, 10 µg/ml |
Irizarry-Caro RA et al. 2020 [75] | Histone | Primary BMDMs isolated from femur and tibia; BCAPΔMϕ mice that specifically lack BCAP in macrophages | Macrophage-specific deletion of BCAP led to reduced histone lactylation through deficiency in aerobic glycolysis and lactate production and therefore attenuated expression of reparative macrophage genes such as ARG1 and KLF4 | LA: 25 mM (for cells) |
Zhang D et al., 2019 [14] | Histone H3 (K18) | MCF−7, MDA-MB−231, HeLa, A549, HepG2, MEF, and RAW 264.7 cells; Ldhafl/fl mice with LysMcre+/− or LysMcre−/− | Hypoxia and bacteria induced production of lactate through glycolysis, which stimulated histone lactylation and further promoted M2-like characteristics and the expression of homeostatic genes involved in the damage repair process | Glucose: 0, 1, 5, 25 mM (for cells); DCA: 0, 5, 10, 20 mM (for cells); Oxamate: 0, 5, 10, 20 mM (for cells); Rotenone: 0, 5, 10, 50 nM (for cells) |
Yao X et al., 2023 [85] | Histone H3 (K18) | N2a cells stimulated by OGD/R; Male Sprague Dawley rats as cerebral infarction models via the MCAO method | Upregulated LDHA facilitated the expression of IL−18 and IL−1β, and also induced cell pyroptosis by promoting the lactylation of histone H3K18la to upregulate the level of HMGB1. Conversely, LDHA knockdown relieved the cerebral infarction injury in the MCAO rat model | LA: 15 µM (for cells) |
Hagihara H et al., 2021 [87] | Histone H1 | Primary neuronal cells separated from C57BL/6J mice brains; C57BL/6J mice and ICR mice | Stress-associated neural excitation and social defeat stress increased brain lactate and histone lactylation levels, which was associated with a decrease in social behavior and an increase in anxiety-like behavior | LA: 2, 5, and 25 mM (for cells); Oxamate: 1 g/kg (for models); 4-CIN: 0.01 and 1 mM (for cells) |
Pan RY et al., 2022 [86] | Histone H4 (K12) | Primary microglia separated from mouse brains, and microglial BV2 cell line; Microglia-specific Pkm2 knockout mice as an Alzheimer’s disease model induced by tamoxifen | Elevated lactate and histone lactylation levels in AD further promoted the expression of glycolytic gene PKM2, thus forming a positive feedback loop that contributes to the abnormal activation and dysfunction of microglia | LA: 20 mM (for cells); Shikonin: 0.5 µM (for cells) and 0.5 mM (for models); compound 3 K: 5 µM (for cells) and 1 mM (for models) |
Li X et al., 2022 [88] | Histone H3 (K18) | HTR−8/SVneo and TEV−1 cells exposed to hypoxia | Hypoxia increased the expression of fibrosis-related genes, FN1 and SERPINE1, through lactate-induced histone lactylation in trophoblast cells | LA: 0, 1, 5, 25 mM (for cells); Lactic acid: 0, 1, 5 mM (for cells); Oxamate: 0, 5, 10, 20 mM (for cells) |
Cui H et al., 2021 [89] | Histone | Primary mouse alveolar macrophages and BMDMs; Male C57BL/6 mice as lung fibrosis models via intratracheal instillation of bleomycin or adenovirus expressing TGF-β1 | TGF-β1 stimulated the increase of lactate production in myofibroblasts and secreted it into the extracellular milieu to promote histone lactylation in macrophages, thereby inducing the expression of some profibrotic mediators. And, p300 as a “writer” mediated lactate-induced histone lactylation | LA: 20 mM (for cells) |
Wang N et al., 2022 [91] | Histone H3 (K18) | Mouse aortic endothelial cells, and primary mouse peripheral blood monocytes and cardiac fibroblasts; Male C57BL/6 mice as MI models via ligation of the left coronary artery | Histone lactylation in monocytes increases rapidly after MI and promoted activation of reparative genes Lrg1, Vegf-a, and IL−10, which is conducive to the reparative environment and the improvement of cardiac function after MI. GCN5, as a writer of histone lactylation, promoted H3K18la in an IL−1β-dependent manner | LA: 20 mM (for cells); Rotenone: 5 nM (for cells); FX−11: 40 µM (for cells); DCA: 5 mM (for cells) |
He Y et al., 2023 [99] | Histone H3 (K18) | LNCaP, NCI-H660, LAPC−4, VCaP, A549, LNCaP/AR, PC9/ER and NCI-H1688 cells; Pbsn-Cre4 mice models | NEPC exhibited preferential utilization of aerobic glycolysis due to an impairment of the Parkin-mediated mitophagy, which subsequently led to histone lactylation and upregulation of transcription of neuroendocrine associated genes. However, the cell fate determinant Numb reversed this process by binding to Parkin | DCA or oxamate: 10 mM (for cells); CCCP: 10 mM (for cells); Rapamycin: 10 nM and 50 nM (for cells) |
Jiang J et al., 2021 [100] | Histone H3 | Human lung bronchial epithelial cell line BEAS−2B, NSCLC cell lines including A549 and H1299 | Lactate regulated cellular metabolism at least in part through up-regulation of HK−1 and IDH3G gene expression mediated by histone lactylation in NSCLC cells | LA: 5 or 10 mM (for cells) |
Yang J et al., 2022 [101] | Histone H3 (K18) | Human renal epithelial cell HK2, and human RCC cell lines 786-O, A498, Caki−1 and ACHN; BALB/c nude mice and NSG mice via subcutaneous injection of sectioned ccRCC tissues | Inactive VHL induced histone lactylation in a HIFs-dependent manner, thereby transcriptionally activating the expression of PDGFRβ to promote ccRCC progression. In addition, overexpression of PDGFRβ positively stimulated histone lactylation | Oxamate: 8 mM (for cells), 60 mg/kg (for models); 2-DG: 4 mM (for cells) |
Pan L et al., 2021 [102] | Histone H3 (K9/56) | LCSCs, human hepatoma cell lines including HCCLM3 and Hep3B; Female nude mice via subcutaneous injection of 3B-LCSCs cells | DML reduced the lactate level of LCSCs by regulation of the glycolytic metabolic pathway to attenuate histone lactylation, thus playing an anti-cancer role | NA |
Yu J et al., 2021 [103] | Histone H3 (K18) | PIG1 and HEK293T cells, and human melanoma cell lines (92.1, MUM2B, OCM1, MEL290, OMM1, CRMM1, CRMM2, and CM2005.1); Male BALB/c nude mice via choroid injection of ocular melanoma cells | Elevated histone lactylation (modulated by EP300, a “writer”) effectively promoted the tumorigenesis of ocular melanoma through up-regulating the transcription of YTHDF2 and further inducing the degradation of PER1 and TP53 mRNAs via binding to their respective m6A sites | LA: 1, 5, and 25 mM (for cells); Oxamate: 5, 10, and 20 mM (for cells); 2-DG: 1, 10, and 20 mM (for cells) |
Xiong J et al., 2022 [104] | Histone H3 (K18) | HEK293T, LLC, B16F10, and MC38 cells, and primary bone marrow cells and MDSCs; C57BL/6 mice via subcutaneous injection of MC38, B16F10, or LLC cells | Elevated lactate in tumor-infiltrating myeloid cells induced METTL3 expression by promoting histone lactylation, and further m6A modification on Jak1 mRNA, which promoted its protein translation and strengthened downstream STAT3 signal that enhanced immunosuppressive functions of myeloid cells | LA: 25 mM (for cells); C646: 100 µM (for cells); Trichostatin A: 1 µM (for cells) |
Yang Q et al., 2022 [106] | Histone H3 (K18) | Ishikawa cells; Chinese Small Tail Han ewes as pregnancy models | During pregnancy, increased levels of H3K18 lactylation and lactate helped to maintain glutathione-based redox homeostasis and apoptotic balance, which are essential for successful embryo implantation | LA: 0.04, 0.2, 1, 5, 10, 50, 100 mM (for cells); Oxamate: 10, 25 mg/ml (for cells) |
Chen J et al., 2023 [109] | Histone H3 (K18) | Primary PASMCs isolated from from adult male Sprague Dawley rats; Male Sprague Dawley rats as pulmonary hypertension models via exposure to hypoxia | Hypoxia-induced mROS further triggered lactate accumulation and histone lactylation in PASMCs by upregulating HIF−1α/PDK1&2/p-PDH-E1α axis, which promoted the proliferation of PASMCs | LA: 10 mM (for cells); DCA: 10 mM (for cells); Oxamate: 50 µM (for cells), 750 mg/kg (for models) |
Yang W et al., 2021 [107] | Histone H3 (K18/23) | Oocytes/embryos collected from ICR mice | Inhibition of LDHA activity reduced histone lactylation, thereby impairing embryonic pre-implantation development | GSK2837808A: 100 pmol (for cells) |
Wang J et al., 2022 [77] | PKM2 (K62) | Primary mouse BMDMs separated from C57BL/6 mice femurs; Male C57BL/6 mice made with two full-thickness skin wounds (9-mm) on the back | Lactate increased the lactylation level of PKM2 and inhibited its tetramer-to-dimer transition, activating pyruvate kinase and promoting the transition of LPS-induced macrophages to a reparative phenotype | LA: 20 mM (for cells and models) |
Yang K et al., 2022 [59] | HMGB1 | RAW 264.7 macrophages; Macrophage-specific YAP knockout mice as a polymicrobial sepsis model via cecal ligation and puncture | Elevated lactate levels during polymicrobial sepsis promoted the secretion of HMGB1 from macrophage exosomes and its lactylation in a p300/CBP-dependent mechanism, further inducing endothelial dysfunction | LA: 10 mM (for cells); Oxamate: 20 mM (for cells) |
Zhang W et al., 2023 [83] | LCP1 | Neurocytes (PC12) stimulated by OGD/R; Male Sprague Dawley rats as cerebral infarction models via the MCAO method | The elevated lactylation of LCP1 in cerebral infarction reduced its own degradation and cell viability and enhanced the apoptosis rate of PC12 cells. However, LCP1 knockdown or inhibiting the glycolysis relieved the cerebral infarction injury | LA: 15 µM (for cells); 2-DG: 20 mM (for cells) |
Fan M et al., 2023 [90] | Snail1 | HUVEC cells and HCMECs; Sex-matched C57BL/6 mice as MI models via MI surgery | After MI, high lactate levels induced the association between p300/CBP and Snail1, which promoted the lactylation of Snail1 and thereby activated the TGF-β/Smad2 pathway and further endothelial-to-mesenchymal transition | 2-DG: 0.5 g/kg (for models); LA: 5 or 10 mM (for cells), 0.5 g/kg (for models) |
Yao G et al., 2023 [94] | c-myc | HCC cell lines including Huh7 and HCCLM3 exposed to hypoxia | GPC3 knockdown alleviates viability, migration, invasion and glycolysis of HCC cells by inhibiting the lactylation of c-myc to promote itself degradation | LA: 15 µM (for cells); 2-DG: 10 mM (for cells) |
Miao Z et al., 2023 [96] | β-catenin | CRC cell lines including SW620 and RKO exposed to hypoxia; Male BALB/c nude mice via subcutaneous injection of infected SW620 cells | Hypoxia-induced glycolysis promotes the lactylation of β-catenin in CRC cells to further enhance the protein stability and expression of β-catenin, thereby aggravating the progression of CRC through the Wnt signaling pathway | LA: 15 µM (for cells); 2-DG: 10 mM (for cells); Wnt agonist1: 20 µM (for cells) |
Luo Y et al., 2022 [97] | HIF−1α | PC−3 and DU145 cell lines; Male BALB/c nude mice via subcutaneous injection of infected PC−3 cells | Elevated lactate in prostate cancer promoted lactylation of HIF1α to induce KIAA1199-mediated angiogenesis, vasculogenic mimicry and depolymerized hyaluronic acid levels | LA: 10 mM (for cells) |
Yang Z et al., 2023 [95] | AK2 (K28) | HepG2 or Hep3B cells | High lactylation of AK2 in HCC could significantly reduce its own activity, mediate perturbation of ATP metabolism and down-regulate the intrinsic apoptosis pathway to promote cancer cell proliferation and migration, and predict poor prognosis in HCC patients | LA: 10 mM (for cells); Glucose: 10, 25 mM (for cells) |
Gu J et al., 2022 [98] | MOESIN (K72) | Naive CD4 + T and CD3 + T cells separated from murine leukocytes from lymph nodes and spleens; Male C57BL/6 mice via axillary injection of mouse Hepa1−6 tumor cells | Lactylation of MOESIN at Lys72 enhanced TGF-β and downstream SMAD3 signaling in Treg cells through TGF-βRI to regulate the development and function of Treg cells to control tumorigenesis and antitumor therapy | LA: 10, 20 mM (for cells); GSK2837808A: 20 mg/kg (for models) |
Sun Y et al., 2022 [105] | PARP1 (K498/505/506/508/518/521/524) | HEK293T cells | Hyperlactylation of PARP1 regulated its ADP-ribosylation activity and may contribute to DNA repair | LA: 10 or 25 mM (for cells) |
Wang X et al., 2023 [110] | YY1 (K183) | HMC3 cells exposed to hypoxia; Male and female C57BL/6 J mice as OIR models via placing them into a glass oxygen chamber | Hyperlactylation of non-histone YY1 under hypoxia was regulated by p300 as a “writer”. YY1 was directly bound to the promoter of FGF2 and promoted the transcription of FGF2 through its high lactylation, thus promoting the formation of neovascularization. This situation was reversed by the p300 inhibitor A−485 | DCA: 1.5 mg/kg/day (for models), 20 mM (for cells); Rotenone: 200 mg/kg/day (for models), 50 nM (for cells); A−485: 5, 10, and 20 µM (for cells) |
Gao R et al., 2023 [108] | FASN (K673) | AML−12, HepG2, 293T and RAW 264.7 cells; Male MPC1+/- and wildtype C57/BL6J mice fed with a HFD or a LFD | MPC1 knockout induced lactate accumulation, promoted the lactylation of FASN in hepatocytes, and lactylation at the K673 site of FASN inhibited own activity, thereby mediating the down-regulation of liver lipid accumulation | GSK2837808A: 10 µM (for cells) |