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 syst...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.展开更多
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 r...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.展开更多
Background:Protein lactylation is a new way for the“metabolic waste”lactic acid to perform novel functions.Nevertheless,our understanding of the contribution of protein lactylation to both tumor progression and ther...Background:Protein lactylation is a new way for the“metabolic waste”lactic acid to perform novel functions.Nevertheless,our understanding of the contribution of protein lactylation to both tumor progression and therapeutic interventions remains imited.The construction of a scoring system for lactylation to predict the prognosis of pancancer patients and to evaluate the tumor immune microenvironment(TIME)would improve our understanding of the clinical significance of lactylation.Methods:Consensus clustering analysis of lactylation-related genes was used to cluster 177 pancreatic adenocarcinoma(PAAD)patients.Subsequently,a scoring system was developed using the least absolute shrinkage and selection operator(LASSO)regression.Internal validation and external validation were both conducted to assess and confirm the predictive accuracy of the scoring system.Finally,leucine rich repeat containing 1(LRRC1),a newly discovered lactylation-related gene,was analyzed in PAAD in vitro.Results:Utilizing the profiles of 332 lactylation-related genes,a total of 177 patients with PAAD were segregated into two distinct groups.LacCluster^(high) patients had a poorer prognosis than LacCluster^(low) patients.Through the differential analysis between the LacCluster^(high) and LacCluster^(low) groups,we identified additional genes associated with lactylation.These genes were then integrated to construct the LacCluster-enhanced system,which enabled more accurate prognosis prediction for patients with PAAD.Then,a lactylation index containing three genes(LacI-3)was constructed using LASSO regression.This was done to enhance the usability of the LacCluster-enhanced system in the clinic.Compared to those in the LacI-3^(high) subgroup,patients in the LacI-3^(low) subgroup exhibited increased expression of immune checkpoint-related genes,more immune cell infiltration,lower tumor mutation burdens,and better prognoses,indicating a“hot tumor”phenotype.Moreover,knocking down the expression of LRRC1,the hub gene in the LacI-3 scoring system,inhibited PAAD cell invasion,migration,and proliferation in vitro.Ultimately,the significance of LacI-3 across cancers was confirmed.Conclusion:Our findings strongly imply that protein lactylation may represent a new approach to diagnosing and treating malignant tumors.展开更多
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 residue...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.展开更多
Endothelial-to-mesenchymal transition(EndMT)is a key driver of atherosclerosis.Aerobic glycolysis is increased in the endothelium of atheroprone areas,accompanied by elevated lactate levels.Histone lactylation,mediate...Endothelial-to-mesenchymal transition(EndMT)is a key driver of atherosclerosis.Aerobic glycolysis is increased in the endothelium of atheroprone areas,accompanied by elevated lactate levels.Histone lactylation,mediated by lactate,can regulate gene expression and participate in disease regulation.However,whether histone lactylation is involved in atherosclerosis remains unknown.Here,we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactatedependent histone H3 lysine 18 lactylation(H3K18la)in vitro and in vivo,as well as in atherosclerotic patients’arteries.Mechanistically,the histone chaperone ASF1A was first identified as a cofactor of P300,which precisely regulated the enrichment of H3K18la at the promoter of SNAI1,thereby activating SNAI1 transcription and promoting EndMT.We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction.Functional analysis based on Apoe^(KO)Asf1a^(ECKO) mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endotheliumspecific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development.Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la,SNAI1 transcription,and EndMT-induced atherosclerosis.This study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis,which provides emerging therapies for atherosclerosis.展开更多
In mammals,the neonatal heart can regenerate upon injury within a short time after birth,while adults lose this ability.Metabolic reprogramming has been demonstrated to be critical for cardiomyocyte proliferation in t...In mammals,the neonatal heart can regenerate upon injury within a short time after birth,while adults lose this ability.Metabolic reprogramming has been demonstrated to be critical for cardiomyocyte proliferation in the neonatal heart.Here,we reveal that cardiac metabolic reprogramming could be regulated by altering global protein lactylation.By performing 4D label-free proteomics and lysine lactylation(Kla)omics analyses in mouse hearts at postnatal days 1,5,and 7,2297 Kla sites from 980 proteins are identified,among which 1262 Kla sites from 409 proteins are quantified.Functional clustering analysis reveals that the proteins with altered Kla sites are mainly involved in metabolic processes.The expression and Kla levels of proteins in glycolysis show a positive correlation while a negative correlation in fatty acid oxidation.Furthermore,we verify the Kla levels of several differentially modified proteins,including ACAT1,ACADL,ACADVL,PFKM,PKM,and NPM1.Overall,our study reports a comprehensive Kla map in the neonatal mouse heart,which will help to understand the regulatory network of metabolic reprogramming and cardiac regeneration.展开更多
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 pre...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.展开更多
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 ...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.展开更多
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 signalin...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.展开更多
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 hyp...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.展开更多
Background:The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma(HCC)remains poor.Although serine-and arginine-rich splicing factor(SRSF)family members play crucial roles in tumo...Background:The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma(HCC)remains poor.Although serine-and arginine-rich splicing factor(SRSF)family members play crucial roles in tumors,their impact on tumor immunology remains unclear.This study aimed to elucidate the role of SRSF10 in HCC immunotherapy.Methods:To identify the key genes associated with immunotherapy resistance,we conducted single-nuclear RNA sequencing,multiplex immunofluorescence,and The Cancer Genome Atlas and Gene Expression Omnibus database analyses.We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems,flow cytometry,various tumor-bearing mouse models,and patient-derived organotypic tumor spheroids.Results:SRSF10 was upregulated in various tumors and associated with poor prognosis.Moreover,SRSF10 positively regulated lactate production,and SRSF10/glycolysis/histone H3 lysine 18 lactylation(H3K18la)formed a positive feedback loop in tumor cells.Increased lactate levels promoted M2 macrophage polarization,thereby inhibiting CD8^(+)T cell activity.Mechanistically,SRSF10 interacted with the 3′-untranslated region of MYB,enhancing MYB RNA stability,and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1(GLUT1),hexokinase 1(HK1),lactate dehydrogenase A(LDHA),resulting in elevated intracellular and extracellular lactate levels.Lactate accumulation induced histone lactylation,which further upregulated SRSF10 expression.Additionally,lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages,thereby activating transcription and enhancing pro-tumor macrophage activity.M2 macrophages,in turn,inhibited the enrichment of CD8^(+)T cells and the proportion of interferon-γ+CD8^(+)T cells in the tumor microenvironment(TME),thus creating an immunosuppressive TME.Clinically,SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors.Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1(PD-1)monoclonal antibodies(mAbs)in both murine and human preclinical models.Conclusions:The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance.Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.展开更多
文摘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.
基金Supported by National Natural Science Foundation of China,No.82172737Shanghai Science and Technology Development Funds(Shanghai Sailing Program),No.22YF1427600。
文摘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.
基金supported by the National Key Research and Development Program of China(Grant Number 2022YFA1205003)Major Research Projects of the National Natural Science Foundation of China(Grant Number 92059204)+1 种基金General Research Projects of the National Natural Science Foundation of China(Grant Number 82273419)Major Projects of Technological Innovation and Application Development Foundation in Chongqing(Grant Number CSTB2022TIAD-STX0012).
文摘Background:Protein lactylation is a new way for the“metabolic waste”lactic acid to perform novel functions.Nevertheless,our understanding of the contribution of protein lactylation to both tumor progression and therapeutic interventions remains imited.The construction of a scoring system for lactylation to predict the prognosis of pancancer patients and to evaluate the tumor immune microenvironment(TIME)would improve our understanding of the clinical significance of lactylation.Methods:Consensus clustering analysis of lactylation-related genes was used to cluster 177 pancreatic adenocarcinoma(PAAD)patients.Subsequently,a scoring system was developed using the least absolute shrinkage and selection operator(LASSO)regression.Internal validation and external validation were both conducted to assess and confirm the predictive accuracy of the scoring system.Finally,leucine rich repeat containing 1(LRRC1),a newly discovered lactylation-related gene,was analyzed in PAAD in vitro.Results:Utilizing the profiles of 332 lactylation-related genes,a total of 177 patients with PAAD were segregated into two distinct groups.LacCluster^(high) patients had a poorer prognosis than LacCluster^(low) patients.Through the differential analysis between the LacCluster^(high) and LacCluster^(low) groups,we identified additional genes associated with lactylation.These genes were then integrated to construct the LacCluster-enhanced system,which enabled more accurate prognosis prediction for patients with PAAD.Then,a lactylation index containing three genes(LacI-3)was constructed using LASSO regression.This was done to enhance the usability of the LacCluster-enhanced system in the clinic.Compared to those in the LacI-3^(high) subgroup,patients in the LacI-3^(low) subgroup exhibited increased expression of immune checkpoint-related genes,more immune cell infiltration,lower tumor mutation burdens,and better prognoses,indicating a“hot tumor”phenotype.Moreover,knocking down the expression of LRRC1,the hub gene in the LacI-3 scoring system,inhibited PAAD cell invasion,migration,and proliferation in vitro.Ultimately,the significance of LacI-3 across cancers was confirmed.Conclusion:Our findings strongly imply that protein lactylation may represent a new approach to diagnosing and treating malignant tumors.
文摘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.
基金supported by the National Natural Science Foundation of China(82270421,81970428,31771334,81800385,82270484,82370376,82121001,82030013,and 82241211)Major Research Plan of the National Natural Science Foundation of China(91649125)+3 种基金the National Key R&D Program of China(2019YFA0802704)The major project of Natural Science Foundation of the Jiangsu Higher Education Institution of China(21KJA310006)Jiangsu Provincial Social Development Project(BE2021749,China)Special Program for Top Innovative Talents(NJMUTY20230082,China).
文摘Endothelial-to-mesenchymal transition(EndMT)is a key driver of atherosclerosis.Aerobic glycolysis is increased in the endothelium of atheroprone areas,accompanied by elevated lactate levels.Histone lactylation,mediated by lactate,can regulate gene expression and participate in disease regulation.However,whether histone lactylation is involved in atherosclerosis remains unknown.Here,we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactatedependent histone H3 lysine 18 lactylation(H3K18la)in vitro and in vivo,as well as in atherosclerotic patients’arteries.Mechanistically,the histone chaperone ASF1A was first identified as a cofactor of P300,which precisely regulated the enrichment of H3K18la at the promoter of SNAI1,thereby activating SNAI1 transcription and promoting EndMT.We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction.Functional analysis based on Apoe^(KO)Asf1a^(ECKO) mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endotheliumspecific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development.Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la,SNAI1 transcription,and EndMT-induced atherosclerosis.This study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis,which provides emerging therapies for atherosclerosis.
文摘In mammals,the neonatal heart can regenerate upon injury within a short time after birth,while adults lose this ability.Metabolic reprogramming has been demonstrated to be critical for cardiomyocyte proliferation in the neonatal heart.Here,we reveal that cardiac metabolic reprogramming could be regulated by altering global protein lactylation.By performing 4D label-free proteomics and lysine lactylation(Kla)omics analyses in mouse hearts at postnatal days 1,5,and 7,2297 Kla sites from 980 proteins are identified,among which 1262 Kla sites from 409 proteins are quantified.Functional clustering analysis reveals that the proteins with altered Kla sites are mainly involved in metabolic processes.The expression and Kla levels of proteins in glycolysis show a positive correlation while a negative correlation in fatty acid oxidation.Furthermore,we verify the Kla levels of several differentially modified proteins,including ACAT1,ACADL,ACADVL,PFKM,PKM,and NPM1.Overall,our study reports a comprehensive Kla map in the neonatal mouse heart,which will help to understand the regulatory network of metabolic reprogramming and cardiac regeneration.
基金supported by the National Natural Science Foundation of China(No.82060042)Guangxi Natural ScienceFoundation(China)(No.2020GXNSFBA297082)+1 种基金Guangxi Science and Technology Program Project(China)(No.AD19245005)The Basic Ability Enhancement Program for Young and Middle-aged Teachers of Guangxi(China)(No.2020KY12017).
文摘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.
基金supported by grants from the National Key R&D Program of China(Grant Nos.2017YFD0500400 and 2017YFD0501200)the National Natural Science Foundation of China(Grant Nos.31972702 and 81772219)the CAMS Innovation Fund for Medical Sciences(CIFMS)(Grant No.2019-I2M-5-042).
文摘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.
基金supported by the National Natural Science Foundation of China,Nos.82230042 and 81930029(to ZY),U2004201(to FG and RYP)the China Postdoctoral Science Foundation,No.2020M683748(to RYP)。
文摘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.
基金supported by the National Natural Science Foundation of China(82070054,31671186,81970076,and 81800046)the Achievement Cultivation Project of Tangdu Hospital(2020CGPY001).
文摘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.
基金supported by the National Natural Science Foundation of China(No.82372946 and No.82072670)the 12 Leading Project of the Science and Technology Committee of Shanghai Municipality(No.21Y21900100)the Project of Shanghai Municipal Health Commission(No.202140269).
文摘Background:The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma(HCC)remains poor.Although serine-and arginine-rich splicing factor(SRSF)family members play crucial roles in tumors,their impact on tumor immunology remains unclear.This study aimed to elucidate the role of SRSF10 in HCC immunotherapy.Methods:To identify the key genes associated with immunotherapy resistance,we conducted single-nuclear RNA sequencing,multiplex immunofluorescence,and The Cancer Genome Atlas and Gene Expression Omnibus database analyses.We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems,flow cytometry,various tumor-bearing mouse models,and patient-derived organotypic tumor spheroids.Results:SRSF10 was upregulated in various tumors and associated with poor prognosis.Moreover,SRSF10 positively regulated lactate production,and SRSF10/glycolysis/histone H3 lysine 18 lactylation(H3K18la)formed a positive feedback loop in tumor cells.Increased lactate levels promoted M2 macrophage polarization,thereby inhibiting CD8^(+)T cell activity.Mechanistically,SRSF10 interacted with the 3′-untranslated region of MYB,enhancing MYB RNA stability,and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1(GLUT1),hexokinase 1(HK1),lactate dehydrogenase A(LDHA),resulting in elevated intracellular and extracellular lactate levels.Lactate accumulation induced histone lactylation,which further upregulated SRSF10 expression.Additionally,lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages,thereby activating transcription and enhancing pro-tumor macrophage activity.M2 macrophages,in turn,inhibited the enrichment of CD8^(+)T cells and the proportion of interferon-γ+CD8^(+)T cells in the tumor microenvironment(TME),thus creating an immunosuppressive TME.Clinically,SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors.Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1(PD-1)monoclonal antibodies(mAbs)in both murine and human preclinical models.Conclusions:The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance.Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.
