Microglia lactylation in relation to central nervous system diseases

The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous system homeostasis,injury response,and neurodegenerative diseases.Lactate has been considered a metabolic waste product,but recent studies are revealing ever more of the physiological functions of lactate.Lactylation is an important pathway in lactate function and is involved in glycolysis-related functions,macrophage polarization,neuromodulation,and angiogenesis and has also been implicated in the development of various diseases.This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation,histone versus non-histone lactylation,and therapeutic approaches targeting lactate.Finally,we summarize the current research on microglia lactylation in central nervous system diseases.A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.

Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma

BACKGROUND Lactate,previously considered a metabolic byproduct,is pivotal in cancer progression and maintaining the immunosuppressive tumor microenvironment.Further investigations confirmed that lactate is a primary regulator,introducing recently described post-translational modifications of histone and non-histone proteins,termed lysine lactylation.Pancreatic adenocarcinomas are characterized by increased glycolysis and lactate accumulation.However,our understanding of lactylation-related genes in pancreatic adenocarcinomas remains limited.AIM To construct a novel lactylation-related gene signature to predict the survival of patients with pancreatic cancer.METHODS RNA-seq and clinical data of pancreatic adenocarcinoma(PDAC)were obtained from the GTEx(Genotype-Tissue Expression)and TCGA(The Cancer Genome Atlas)databases via Xena Explorer,and GSE62452 datasets from GEO.Data on lactylation-related genes were obtained from publicly available sources.Differential expressed genes(DEGs)were acquired by using R package“DESeq2”in R.Univariate COX regression analysis,LASSO Cox and multivariate Cox regressions were produced to construct the lactylation-related prognostic model.Further analyses,including functional enrichment,ESTIMATE,and CIBERSORT,were performed to analyze immune status and treatment responses in patients with pancreatic cancer.PDAC and normal human cell lines were subjected to western blot analysis under lactic acid intervention;two PDAC cell lines with the most pronounced lactylation were selected.Subsequently,RT-PCR was employed to assess the expression of LRGs genes;SLC16A1,which showed the highest expression,was selected for further investigation.SLC16A1-mediated lactylation was analyzed by immunofluorescence,lactate production analysis,colony formation,transwell,and wound healing assays to investigate its role in promoting the proliferation and migration of PDAC cells.In vivo validation was performed using an established tumor model.RESULTS In this study,we successfully identified 10 differentially expressed lactylation-related genes(LRGs)with prognostic value.Subsequently,a lactylation-related signature was developed based on five OS-related lactylationrelated genes(SLC16A1,HLA-DRB1,KCNN4,KIF23,and HPDL)using Lasso Cox hazard regression analysis.Subsequently,we evaluated the clinical significance of the lactylation-related genes in pancreatic adenocarcinoma.A comprehensive examination of infiltrating immune cells and tumor mutation burden was conducted across different subgroups.Furthermore,we demonstrated that SLC16A1 modulates lactylation in pancreatic cancer cells through lactate transport.Both in vivo and in vitro experiments showed that decreasing SLC16A1 Level and its lactylation significantly inhibited tumor progression,indicating the potential of targeting the SLC16A1/Lactylation-associated signaling pathway as a therapeutic strategy against pancreatic adenocarcinoma.CONCLUSION We constructed a novel lactylation-related prognostic signature to predict OS,immune status,and treatment response of patients with pancreatic adenocarcinoma,providing new strategic directions and antitumor immunotherapies.

Histone lactylation promotes cell proliferation,migration and invasion through targeting HMGB1 in endometriosis

Endometriosis is defined as a condition with endometrium-like tissues migrating outside of the pelvic cavity.However,the mechanism of endometriosis is still unclear.Lactate can be covalently modified to lysine residues of histones and other proteins,which is called lactylation.The results showed that the higher level of lactate and lactate dehydrogenase A enhanced the histone H3 lysine 18 lactylation(H3K18lac)in ectopic endometrial tissues and ectopic endometrial stromal cells than that in normal endometrial tissues and normal endometrial stromal cells.Lactate promoted cell proliferation,migration,and invasion in endometriosis.Mechanistically,lactate induced H3K18lac to promote the expression of high-mobility group box 1(HMGB1)in endometriosis,and HMGB1 knockdown significantly reduced the cell proliferation,migration,and invasion of the lactate-treated cells through the phosphorylation of AKT.In conclusion,lactate could induce histone lactylation to promote endometriosis progression by upregulating the expression of HMGB1,which may provide a novel target for the prevention and treatment of endometriosis.

The function and mechanism of lactate and lactylation in tumor metabolism and microenvironment

Lactate is an end product of glycolysis.Owing to the lactate shuttle concept introduced in the early 1980s,increasing researchers indicate lactate as a critical energy source for mitochondrial respiration and as a precursor of gluconeogenesis.Lactate also acts as a multifunctional signaling molecule through receptors expressed in various cells,resulting in diverse biological consequences including decreased lipolysis,immune regulation,and anti-inflammation wound healing,and enhanced exercise performance in association with the gut microbiome.Furthermore,increasing evidence reveals that lactate contributes to epigenetic gene regulation by lactylating lysine residues of histones,which accounts for its key role in immune modulation and maintenance of homeostasis.Here,we summarize the function and mechanism of lactate and lactylation in tumor metabolism and microenvironment.

Protein Lactylation and Metabolic Regulation of the Zoonotic Parasite Toxoplasma gondii

The biology of Toxoplasma gondii,the causative pathogen of one of the most widespread parasitic diseases(toxoplasmosis),remains poorly understood.Lactate,which is derived from glucose metabolism,is not only an energy source in a variety of organisms,including T.gondii,but also a regulatory molecule that participates in gene activation and protein function.Lysine lactylation(Kla)is a type of post-translational modifications(PTMs)that has been recently associated with chromatin remodeling;however,Kla of histone and non-histone proteins has not yet been studied in T.gondii.To examine the prevalence and function of lactylation in T.gondii parasites,we mapped the lactylome of proliferating tachyzoite cells and identified 1964 Kla sites on 955 proteins in the T.gondii RH strain.Lactylated proteins were distributed in multiple subcellular compartments and were closely related to a wide variety of biological processes,including mRNA splicing,glycolysis,aminoacyl-tRNA biosynthesis,RNA transport,and many signaling pathways.We also performed a chromatin immunoprecipitation sequencing(ChIP-seq)analysis using a lactylationspecific antibody and found that the histones H4K12la and H3K14la were enriched in the promoter and exon regions of T.gondii associated with microtubule-based movement and cell invasion.We further confirmed the delactylase activity of histone deacetylases TgHDAC2–4,and found that treatment with anti-histone acetyltransferase(TgMYST-A)antibodies profoundly reduced protein lactylation in T.gondii.This study offers the first dataset of the global lactylation proteome and provides a basis for further dissecting the functional biology of T.gondii.

Lactate metabolism in neurodegenerative diseases

Lactate,a byproduct of glycolysis,was thought to be a metabolic waste until the discovery of the Warburg effect.Lactate not only functions as a metabolic substrate to provide energy but can also function as a signaling molecule to modulate cellular functions under pathophysiological conditions.The Astrocyte-Neuron Lactate Shuttle has cla rified that lactate plays a pivotal role in the central nervous system.Moreover,protein lactylation highlights the novel role of lactate in regulating transcription,cellular functions,and disease development.This review summarizes the recent advances in lactate metabolism and its role in neurodegenerative diseases,thus providing optimal pers pectives for future research.

Histone lactylation driven by mROS-mediated glycolytic shift promotes hypoxic pulmonary hypertension

Increased mitochondrial reactive oxygen species(mROS)and glycolysis have been established in pulmonary hypertension(PH).However,the effect of elevated mROS on glycolytic shift and how increased glycolysis promotes hypoxic pulmonary artery smooth muscle cell(PASMC)proliferation and vascular remodeling remain elusive.Here,we reported that hypoxia-induced mROS inhibit HIF-1αhydroxylation and further trigger PASMC glycolytic switch through the upregulated HIF-1α/PDK1&PDK2/p-PDH-E1αaxis,which facilitates lactate accumulation and histone lactylation.Through H3K18la and HIF-1αChIP–seq analysis,we found that the enhanced histone lactylation of HIF-1αtargets,such as Bmp5,Trpc5,and Kit,promotes PASMC proliferation.Knockdown of Pdk1&2 blunts lactate production,histone lactylation marks,and PASMC proliferation.Moreover,pharmacological intervention with lactate dehydrogenase inhibitor diminishes histone lactylation and ameliorates PASMC proliferation and vascular remodeling in hypoxic PH rats.Taken together,this study provides proof of concept for anti-remodeling therapy through lactate manipulation.