Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein ...Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications.Lactate,once considered merely a byproduct of anaerobic metabolism,has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system.Furthermore,recent studies have emphasized the significant role of lactate in numerous neurological diseases,including Alzheimer's disease,Parkinson's disease,acute cerebral ischemic stroke,multiple sclerosis,Huntington's disease,and myasthenia gravis.The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases,aiming to clarify their mechanisms of action and identify potential therapeutic targets.As such,this work provides an overview of the metabolic regulatory roles of lactate in various disorders,emphasizing its involvement in the regulation of brain function.Additionally,the specific mechanisms of brain lactate metabolism are discussed,suggesting the unique roles of lactate in modulating brain function.As a critical aspect of lactate function,lactylation modifications,including both histone and non-histone lactylation,are explored,with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications,such as lactylation writers and erasers.The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized,revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders.Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.展开更多
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
Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.How...Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.However,relatively few studies have explored the impact of post-translational modifications(PTM)on OC progression,which is essential for uncovering new therapeutic targets.This study aimed to systematically identify the key PTM types involved in OCprogression,and to explore and evaluate their translational potential as therapeutic targets.Methods:First,we utilized multiple general PTM antibodies to compare gross PTM levels between normal ovarian and OC tissues from clinical females.After identifying lactylation as the PTM with the most significant differences,we selected representative samples for label-free mass spectrometry to identify specific lactylation sites.Next,we transfected A2780(OC)cells with either wild-type(WT)or mutant(K192A[Q])poly(ADP-ribose)polymerase 1(PARP1)conjugated to enhanced green fluorescent protein(EGFP)with a StrepⅡpeptide tag and assessed various cellular indexes related to cell proliferation(clonogenicity assay),migration(scratch wound healing assay),and reactive oxygen species levels.Results:Pan-lactylation was significantly upregulated in clinical OC samples,with PARP1 lactylation at K192 being one of the most common modifications.The growth and migration of A2780 cells were markedly suppressed by overexpressing PARP1-WT but not mutant PARP1.Overexpressing PARP1 significantly downregulated the phosphorylation of extracellular signal-regulated kinases 1/2(ERK1/2).Conclusion:This study uncovered a novel PTM of PARP1 in OC,lactylation,and demonstrated that lactylation at K192 is crucial in regulating OC cell growth and migration via the ERK1/2 pathway.Further investigations are required to elucidate the broader functional implications of PARP1 lactylation and its therapeutic potential.展开更多
Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology i...Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology influenced by complex genetic and environmental risk factors such as maternal bacterial or virus infection.A prior case-control study revealed a surprisingly strong association between maternal periodontal disease and CP in offspring.However,the precise relationship remains unclear.In this study,the relationship between maternal oral pathogen and CP in offspring was studied by sonicated P.gingivalis injected intravenously and orally into pregnant mice.We investigated an obvious increasing CP(12.5%)in sonicated P.gingivalis group which had inhibited osteogenesis in mesenchyme and blocked efferocytosis in epithelium.Then glycolysis and H4K12 lactylation(H4K12la)were detected to elevate in both mouse embryonic palatal mesenchyme(MEPM)cells and macrophages under P.gingivalis exposure which further promoted the transcription of metallopeptidase domain17(ADAM17),subsequently mediated the shedding of transforming growth factor-beta receptor 1(TGFBR1)in MEPM cells and mer tyrosine kinase(MerTK)in macrophages and resulted in the suppression of efferocytosis and osteogenesis in palate,eventually caused abnormalities in palate fusion and ossification.The abnormal efferocytosis also led to a predominance of M1 macrophages,which indirectly inhibited palatal osteogenesis via extracellular vesicles.Furthermore,pharmacological ADAM17 inhibition could ameliorate the abnormality of P.gingivalis-induced abnormal palate development.Therefore,our study extends the knowledge of how maternal oral pathogen affects fetal palate development and provides a novel perspective to understand the pathogenesis of CP.展开更多
Breast cancer(BC)has the highest prevalence among cancers specific to women,and its incidence rates are increasing in many countries.Subtypes of BC,including HER2-positive or triple-negative BC,exhibit differing treat...Breast cancer(BC)has the highest prevalence among cancers specific to women,and its incidence rates are increasing in many countries.Subtypes of BC,including HER2-positive or triple-negative BC,exhibit differing treatment responses;consequently,demand for personalized therapy is increasing,and relevant precision medicine strategies are under development.Aerobic glycolysis in cancer cells can lead to excessive lactate production,which in turn promotes lactylation and influences tumor cell behavior.Epigenetic alterations and metabolic reprogramming are prominent characteristics of tumors.Because lactate and lactylation are important in cancer,further investigation of the mechanisms underlying lactate metabolism and lactylation,and the development of therapeutic strategies targeting these processes,are topics of increasing interest.This review describes current research on lactate metabolism and lactylation in BC,thus offering new perspectives for advancing treatment and management toward more precise and personalized approaches that will ultimately increase BC survival rates and patient quality of life.展开更多
The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metast...The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metastasis. This process is accompanied by the massive production and accumulation of lactate both intracellularly and extracellularly. The resulting acidic microenvironment impairs the normal physiological functions of immune cells and promotes tumor progression. An increasing number of studies indicate that lactate, a key metabolite in the tumor microenvironment (TME), acts as a pivotal immunosuppressive signaling molecule that modulates immune cell function. This review aims to comprehensively examine lactate’s role as an immunosuppressive molecule in TME. It focuses on mechanisms such as membrane receptor binding, functional reshaping of immune cells via lactate shuttle transport, epigenetic regulation of gene expression through histone lactylation, and modulation of protein structure and function through nonhistone lactylation, emphasizing lactate’s importance in immune regulation within the TME. Ultimately, this review offers novel insights into immunosuppressive therapies aimed at targeting lactate function.展开更多
The health benefits of physical exercise are well established and have been observed in both human studies and rodent models[1],improving overall health and stress resilience.However,the underlying molecular mechanism...The health benefits of physical exercise are well established and have been observed in both human studies and rodent models[1],improving overall health and stress resilience.However,the underlying molecular mechanisms have not been comprehensively investigated.Previous studies have focused extensively on its neuromodulatory effects and have also identified multiple exercise-associated molecular substrates and blood-borne metabolites,including neurotrophic factors,monoamine neurotransmitters,neuroinflammatory cytokines,kynurenine,N-lactoylphenylalanine,and the ketone bodyβ-hydroxybutyrate[2].Notably,lactate,a common energy source derived from cellular glycolysis in response to intensive exercise,has recently been reported to exert antidepressant activity[3].However,a detailed mechanistic explanation is lacking.展开更多
BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and ...BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and stem cell biotherapies are often used to facilitate this process.Histone lactylation modifications are involved in the regulation of various diseases.Lactate dehydrogenase A(LDHA)has been shown to play an important role in exosomes.AIM To explore the regulation of tendon-bone healing after ACLR by LDHA in exosomes derived from bone marrow mesenchymal stem cells(BMSC-Exos).METHODS BMSC-Exos and LDHA were characterized and analyzed by transmission electron microscopy,qNano,immunofluorescence and western blotting assay.The corresponding low expression cell lines were obtained using RNA interference transfection;LDHA expression in rat bone tissues after ACLR was analyzed by western blotting.The volume of newborn bone tissues was monitored by micro-computed tomography imaging.Tendon and fibrocartilage regeneration were further analyzed and calculated by histological analysis,including hematoxylin and eosin and Safranin O-Fast green staining,respectively;LDHA levels of chondrocyte stem cells(CSPCs)after co-incubation with BMSC-Exos were analyzed by western blotting.Extracellularly secreted lactic acid content was determined by lactate assay kit.Cell viability was assessed by cell counting kit 8 assay,and the proliferation and differentiation ability of cells was further examined by the expression of collagen II,SOX9 and aggrecan.Histone H3K18 lactylation modification was analyzed by western blotting.H3K18 La binding on bone morphogenetic protein 7(BMP7)promoter was analyzed by chromatin immunoprecipitation-quantitative polymerase chain reaction;BMP7 promoter activity was analyzed by dual luciferase reporter gene;BMP7 protein expression was analyzed using quantitative polymerase chain reaction and western blotting.Then,the proliferation of CSPCs promoted by BMSC-Exos LDHA was analyzed by protein expression levels of LDHA,BMP7,collagen II,SOX9,aggrecan,extracellular lactate content,and cell counting kit 8 assay.RESULTS The spherical nanosized BMSC-Exos could be uptaken by CSPCs.LDHA was highly expressed in BMSC-Exos,which could infiltrate into the bone tissue of ACLR rats and promoted the generation of new bone tissue,as well as significantly increased the regeneration of tendon and fibrocartilage.Co-incubation of CSPCs with high-expressing LDHA BMSC-Exos increased the secretion of lactate content from CSPCs,cell viability,and the expression of markers related to cell proliferation and differentiation,including collagen II,SOX9,and aggrecan;LDHA in BMSC-Exos upregulated BMP7 through histone H3K18 lactate modification;high LDHA expression reversed the knockdown of BMP7,further increasing the proliferation and differentiation of CSPCs,thereby inducing cartilage formation.CONCLUSION LDHA in BMSC-Exos promotes BMP7 expression via H3K18 lactylation modification,which further promotes tendon-bone healing after ACLR.展开更多
BACKGROUND Ferroptosis is a newly recognized form of regulated cell death characterized by iron-dependent accumulation of lipid reactive oxygen species.It has been extensively studied in various diseases,including can...BACKGROUND Ferroptosis is a newly recognized form of regulated cell death characterized by iron-dependent accumulation of lipid reactive oxygen species.It has been extensively studied in various diseases,including cancer,Parkinson’s disease,and stroke.However,its precise role and underlying mechanisms in ischemia/reperfusion injury,particularly in the intestinal ischemia-reperfusion(IIR),remain unclear.In current work,we aimed to investigate the participation of histone lactylation during IIR progression.AIM To investigate the role of mitochondrial alanyl-tRNA synthetase 2(AARS2)in ferroptosis and its epigenetic regulation of acyl-CoA synthetase long-chain family member 4(ACSL4)through histone lactylation during IIR injury.METHODS We established a mouse model to mimic IIR and conducted AARS2 knockdown as treatment.The expression of AARS2 in intestinal tissues was measured by western blot.The integrity of intestinal tissues was detected by hematoxylin and eosin staining,serum fatty acid-binding protein,protein levels of ZO-1 and occluding.An in vitro hypoxia-reperfusion(H/R)cell model was established,and cell viability was measured by CCK-8.The in vitro and in vivo ferroptosis was determined by the accumulation of Fe2+and malondialdehyde(MDA).The epigenetic regulation of ACSL4 by AARS2 was detected by chromatin immunoprecipitation(ChIP)assay and luciferase reporter assay.RESULTS We observed a notable elevated AARS2 level in intestinal tissue of mice in IIR model group,which was reversed by shAARS2 treatment.Knockdown of AARS2 repressed alleviated intestinal barrier disruption and repressed the accumulation of ferroptosis biomarker Fe2+and MDA during IIR.The in vitro results showed that shAARS2 alleviated impaired cell viability caused by H/R,as well as repressed ferroptosis.Knockdown of AARS2 notably downregulated the RNA and protein expression of ACSL4.Mechanistically,knockdown of AARS2 downregulated the enrichment of H3K18 La modification on AARS2,as well as suppressed its promoter activity.Overexpression of AARS2 could abolish the protective effects of shACSL4 in vitro.CONCLUSION The elevation of AARS2 during IIR led to cell ferroptosis via epigenetically upregulating the expression of ACSL4.Our findings presented AARS2 as a promising therapeutic target for IIR.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 Previous studies have shown that the vitrification of metaphaseⅡ(MⅡ)oocytes significantly represses their developmental potential.Abnormally increased oxidative stress is the probable factor;however,the u...Background Previous studies have shown that the vitrification of metaphaseⅡ(MⅡ)oocytes significantly represses their developmental potential.Abnormally increased oxidative stress is the probable factor;however,the underlying mechanism remains unclear.The walnut-derived peptide TW-7 was initially isolated and purified from walnut protein hydrolysate.Accumulating evidences implied thatTW-7 was a powerful antioxidant,while its prospective application in oocyte cryopreservation has not been reported.Result Here,we found that parthenogenetic activation(PA)zygotes derived from vitrified MⅡoocytes showed elevated ROS level and delayed progression of pronucleus formation.Addition of 25μmol/LTW-7 in warming,recovery,PA,and embryo culture medium could alleviate oxidative stress in PA zygotes from vitrified mouse MⅡoocytes,furtherly increase proteins related to histone lactylation such as LDHAe LDHB,and EP300 and finally improve histone lactylation in PA zygotes.The elevated histone lactylation facilitated the expression of minor zygotic genome activation(ZGA)genes and preimplantation embryo development.Conclusions Our findings revealed the mechanism of oxidative stress inducing repressed development of PA embryos from vitrified mouse MⅡoocytes and found a potent and easy-obtained short peptide that could significantly rescue the decreased developmental potential of vitrified oocytes,which would potentially contribute to reproductive medicine,animal protection,and breeding.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
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
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
Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings,particularly in intricate conditions such...Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings,particularly in intricate conditions such as cancer.Specifically,lactate has been demonstrated to be pivotal in molding the tumor microenvironment(TME)through its effects on different cell populations.Within tumor cells,lactate impacts cell signaling pathways,augments the lactate shuttle process,boosts resistance to oxidative stress,and contributes to lactylation.In various cellular populations,the interplay between lactate and immune cells governs processes such as cell differentiation,immune response,immune surveillance,and treatment effectiveness.Furthermore,communication between lactate and stromal/endothelial cells supports basal membrane(BM)remodeling,epithelial-mesenchymal transitions(EMT),metabolic reprogramming,angiogenesis,and drug resistance.Focusing on lactate production and transport,specifically through lactate dehydrogenase(LDH)and monocarboxylate transporters(MCT),has shown promise in the treatment of cancer.Inhibitors targeting LDH and MCT act as both tumor suppressors and enhancers of immunotherapy,leading to a synergistic therapeutic effect when combined with immunotherapy.The review underscores the importance of lactate in tumor progression and provides valuable perspectives on potential therapeutic approaches that target the vulnerability of lactate metabolism,highlighting the Heel of Achilles for cancer treatment.展开更多
Deactivation of the mitochondrial pyruvate dehydrogenase complex(PDC)is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis.Studies examining PDC activity regulati...Deactivation of the mitochondrial pyruvate dehydrogenase complex(PDC)is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis.Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase(E1),leaving other post-translational modifications largely unexplored.Here,we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X(PDHX)commonly occurs in hepatocellular carcinoma,disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression.PDHX,an E3-binding protein in the PDC,is acetylated by the p300 at Lys 488,impeding the interaction between PDHX and dihydrolipoyl transacetylase(E2),thereby disrupting PDC assembly to inhibit its activation.PDC disruption results in the conversion of most glucose to lactate,contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression,facilitating tumor progression.These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity,linking PDHX Lys 488 acetylation and histone lactylation during hepatocellular carcinoma progression and providing a potential biomarker and therapeutic target for further development.展开更多
Chemoresistance remains the major barrier to cancer treatment.Metabolic and epigenetic reprogramming are involved in this process;however,the precise roles and mechanisms are largely unknown.Here,we report that lactat...Chemoresistance remains the major barrier to cancer treatment.Metabolic and epigenetic reprogramming are involved in this process;however,the precise roles and mechanisms are largely unknown.Here,we report that lactate-induced lactylation promotes chemoresistance to anthracyclines by regulating homologous recombination(HR)repair.Using the global lactylome,we revealed the landscape of differentially lactylated sites and proteins in cancer cells isolated from resistant and nonresistant tumors.Specifically,BLM,a crucial helicase in the HR repair process,is highly lactylated at Lys24 by AARS1 in response to chemotherapy.展开更多
Since the debut of the Warburg effect,our understanding of lactate in cancer has evolved from a metabolic waste of"low-efficient"glucose metabolism,an acidification factor reshaping tumor microenvironments,t...Since the debut of the Warburg effect,our understanding of lactate in cancer has evolved from a metabolic waste of"low-efficient"glucose metabolism,an acidification factor reshaping tumor microenvironments,to key molecular signals modulating signaling pathways,thereby influencing cell fates.Recently,Zhang’s work introduced a novel post-translational modification(PTM),lactylation,revealing a previously unidentified identity of lactate.Further findings in Plantae and Bacteria have projected lactylation as a common PTM among biological kingdoms.展开更多
Background:Gastric cancer(GC)is a common malignancy characterized by the absence of reliable prognostic indicators and effective therapeutic targets.Claudin-9(CLDN9)has been demonstrated to be upregulated in various c...Background:Gastric cancer(GC)is a common malignancy characterized by the absence of reliable prognostic indicators and effective therapeutic targets.Claudin-9(CLDN9)has been demonstrated to be upregulated in various cancers.However,its prognostic value,biological function,and regulatory mechanisms in GC remain unclear.Therefore,this study aimed to elucidate the role of CLDN9 in GC progression and its underlying mechanisms.Methods:We utilized consensus cluster,random survival forest,and multivariate Cox regression analyses to identify CLDN9 in GC.Subsequently,we evaluated the mRNA and protein levels of CLDN9 in GC using quantitative real-time polymerase chain reaction(PCR)(qRT-PCR),Western blotting(WB),and immunohistochemistry(IHC).Furthermore,the role of CLDN9 in GC progression was investigated using a series of functional in vivo and in vitro experiments.Finally,we elucidated the molecular mechanisms of CLDN9 using bioinformatics,molecular biology,animal models,and patient tissue specimens.Results:Two GC subtypes with survival and functional differences were identified based on glycolytic metabolic genes in the Cancer Genome Atlas(TCGA)-Stomach adenocarcinoma(STAD)dataset.A prognostic risk score was calculated using seven genes to assess the overall survival(OS)in GC.Using random survival forest and multivariate Cox analyses,we identified CLDN9 as the key gene linked to the glycolytic subtype and prognosis of GC.CLDN9 expression was significantly upregulated in patients with GC as well as in GC cells.CLDN9 knockdown inhibited tumor proliferation,invasion,and metastasis both in vivo and in vitro.Mechanistically,CLDN9 was found to regulate lactate dehydrogenase A(LDHA)expression and promote glycolytic metabolism by activating the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/hypoxia-inducible factor 1-alpha(HIF1α)signaling pathway.Additionally,lactate,a glycolytic metabolite,enhanced programmed cell death ligand 1(PD-L1)lactylation and stability,which suppressed anti-tumor immunity in CD8t T cells,thereby contributing to GC progression.Conclusions:CLDN9 expression is associated with GC development and progression.Mechanistically,CLDN9 enhances the glycolysis pathway and facilitates PD-L1 lactylation through the PI3K/AKT/HIF1αsignaling pathway,thereby suppressing anti-tumor immunity in CD8t T cells.CLDN9 has the potential to serve as a novel prognostic marker and therapeutic target for GC.展开更多
The incidence of endometrial cancer(EC)is increasing,particularly in high-risk cases with poor prognosis.1 Reprogramming glucose metabolism is the main feature of energy metabolism in EC cells,resulting in substantial...The incidence of endometrial cancer(EC)is increasing,particularly in high-risk cases with poor prognosis.1 Reprogramming glucose metabolism is the main feature of energy metabolism in EC cells,resulting in substantial lactate accumulation.2 Recent research indicates that the accumulation of lactic acid during the metabolic process can serve as a substrate.3 The high concentration of lactate accumulated by metabolites can promote the malignant progression of tumor cells by modifying key proteins through lactylation.展开更多
基金supported by Applied Basic Research Joint Fund Project of Yunnan Province,No.202301AY070001-200Middle-aged Academic and Technical Training Project for High-Level Talents,No.202105AC160065+1 种基金Yunnan Clinical Medical Center for Neurological and Cardiovascular Diseases,No.YWLCYXZX2023300077Key Clinical Specialty of Neurology in Yunnan Province,No.300064(all to CL)。
文摘Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications.Lactate,once considered merely a byproduct of anaerobic metabolism,has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system.Furthermore,recent studies have emphasized the significant role of lactate in numerous neurological diseases,including Alzheimer's disease,Parkinson's disease,acute cerebral ischemic stroke,multiple sclerosis,Huntington's disease,and myasthenia gravis.The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases,aiming to clarify their mechanisms of action and identify potential therapeutic targets.As such,this work provides an overview of the metabolic regulatory roles of lactate in various disorders,emphasizing its involvement in the regulation of brain function.Additionally,the specific mechanisms of brain lactate metabolism are discussed,suggesting the unique roles of lactate in modulating brain function.As a critical aspect of lactate function,lactylation modifications,including both histone and non-histone lactylation,are explored,with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications,such as lactylation writers and erasers.The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized,revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders.Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.
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.
文摘Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.However,relatively few studies have explored the impact of post-translational modifications(PTM)on OC progression,which is essential for uncovering new therapeutic targets.This study aimed to systematically identify the key PTM types involved in OCprogression,and to explore and evaluate their translational potential as therapeutic targets.Methods:First,we utilized multiple general PTM antibodies to compare gross PTM levels between normal ovarian and OC tissues from clinical females.After identifying lactylation as the PTM with the most significant differences,we selected representative samples for label-free mass spectrometry to identify specific lactylation sites.Next,we transfected A2780(OC)cells with either wild-type(WT)or mutant(K192A[Q])poly(ADP-ribose)polymerase 1(PARP1)conjugated to enhanced green fluorescent protein(EGFP)with a StrepⅡpeptide tag and assessed various cellular indexes related to cell proliferation(clonogenicity assay),migration(scratch wound healing assay),and reactive oxygen species levels.Results:Pan-lactylation was significantly upregulated in clinical OC samples,with PARP1 lactylation at K192 being one of the most common modifications.The growth and migration of A2780 cells were markedly suppressed by overexpressing PARP1-WT but not mutant PARP1.Overexpressing PARP1 significantly downregulated the phosphorylation of extracellular signal-regulated kinases 1/2(ERK1/2).Conclusion:This study uncovered a novel PTM of PARP1 in OC,lactylation,and demonstrated that lactylation at K192 is crucial in regulating OC cell growth and migration via the ERK1/2 pathway.Further investigations are required to elucidate the broader functional implications of PARP1 lactylation and its therapeutic potential.
基金funded by grants from the National Natural Science Foundation of China(grant numbers 82170912 and 82370910)the Beijing Stomatological Hospital,Capital Medical University Young Scientist Program(No.YSP202404).
文摘Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology influenced by complex genetic and environmental risk factors such as maternal bacterial or virus infection.A prior case-control study revealed a surprisingly strong association between maternal periodontal disease and CP in offspring.However,the precise relationship remains unclear.In this study,the relationship between maternal oral pathogen and CP in offspring was studied by sonicated P.gingivalis injected intravenously and orally into pregnant mice.We investigated an obvious increasing CP(12.5%)in sonicated P.gingivalis group which had inhibited osteogenesis in mesenchyme and blocked efferocytosis in epithelium.Then glycolysis and H4K12 lactylation(H4K12la)were detected to elevate in both mouse embryonic palatal mesenchyme(MEPM)cells and macrophages under P.gingivalis exposure which further promoted the transcription of metallopeptidase domain17(ADAM17),subsequently mediated the shedding of transforming growth factor-beta receptor 1(TGFBR1)in MEPM cells and mer tyrosine kinase(MerTK)in macrophages and resulted in the suppression of efferocytosis and osteogenesis in palate,eventually caused abnormalities in palate fusion and ossification.The abnormal efferocytosis also led to a predominance of M1 macrophages,which indirectly inhibited palatal osteogenesis via extracellular vesicles.Furthermore,pharmacological ADAM17 inhibition could ameliorate the abnormality of P.gingivalis-induced abnormal palate development.Therefore,our study extends the knowledge of how maternal oral pathogen affects fetal palate development and provides a novel perspective to understand the pathogenesis of CP.
基金supported by grants from the National Natural Science Foundation of China(Grant No.82302626)Gusu Health Talent Project of Suzhou,China(Grant No.GSWS2022076)Suzhou Key Laboratory of Intelligent Critical Illness Biomarkers Translational Research Project(Grant No.SZS2024029)。
文摘Breast cancer(BC)has the highest prevalence among cancers specific to women,and its incidence rates are increasing in many countries.Subtypes of BC,including HER2-positive or triple-negative BC,exhibit differing treatment responses;consequently,demand for personalized therapy is increasing,and relevant precision medicine strategies are under development.Aerobic glycolysis in cancer cells can lead to excessive lactate production,which in turn promotes lactylation and influences tumor cell behavior.Epigenetic alterations and metabolic reprogramming are prominent characteristics of tumors.Because lactate and lactylation are important in cancer,further investigation of the mechanisms underlying lactate metabolism and lactylation,and the development of therapeutic strategies targeting these processes,are topics of increasing interest.This review describes current research on lactate metabolism and lactylation in BC,thus offering new perspectives for advancing treatment and management toward more precise and personalized approaches that will ultimately increase BC survival rates and patient quality of life.
基金supported by the National Natural Science Foundation of China(Nos.8227061256 and 871386269 to Peixiang Lan,No.82171760 to Song Chen)Startup Funding from Tongji Hospital(to Peixiang Lan).
文摘The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metastasis. This process is accompanied by the massive production and accumulation of lactate both intracellularly and extracellularly. The resulting acidic microenvironment impairs the normal physiological functions of immune cells and promotes tumor progression. An increasing number of studies indicate that lactate, a key metabolite in the tumor microenvironment (TME), acts as a pivotal immunosuppressive signaling molecule that modulates immune cell function. This review aims to comprehensively examine lactate’s role as an immunosuppressive molecule in TME. It focuses on mechanisms such as membrane receptor binding, functional reshaping of immune cells via lactate shuttle transport, epigenetic regulation of gene expression through histone lactylation, and modulation of protein structure and function through nonhistone lactylation, emphasizing lactate’s importance in immune regulation within the TME. Ultimately, this review offers novel insights into immunosuppressive therapies aimed at targeting lactate function.
基金supported by grants from the National Natural Science Foundation of China(32271062 and 82305117)Science and Technology Program of Guangzhou,China(2023A04J0458)+1 种基金Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases(2023KT15524)the China Postdoctoral Science Foundation(2024M751343).
文摘The health benefits of physical exercise are well established and have been observed in both human studies and rodent models[1],improving overall health and stress resilience.However,the underlying molecular mechanisms have not been comprehensively investigated.Previous studies have focused extensively on its neuromodulatory effects and have also identified multiple exercise-associated molecular substrates and blood-borne metabolites,including neurotrophic factors,monoamine neurotransmitters,neuroinflammatory cytokines,kynurenine,N-lactoylphenylalanine,and the ketone bodyβ-hydroxybutyrate[2].Notably,lactate,a common energy source derived from cellular glycolysis in response to intensive exercise,has recently been reported to exert antidepressant activity[3].However,a detailed mechanistic explanation is lacking.
文摘BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and stem cell biotherapies are often used to facilitate this process.Histone lactylation modifications are involved in the regulation of various diseases.Lactate dehydrogenase A(LDHA)has been shown to play an important role in exosomes.AIM To explore the regulation of tendon-bone healing after ACLR by LDHA in exosomes derived from bone marrow mesenchymal stem cells(BMSC-Exos).METHODS BMSC-Exos and LDHA were characterized and analyzed by transmission electron microscopy,qNano,immunofluorescence and western blotting assay.The corresponding low expression cell lines were obtained using RNA interference transfection;LDHA expression in rat bone tissues after ACLR was analyzed by western blotting.The volume of newborn bone tissues was monitored by micro-computed tomography imaging.Tendon and fibrocartilage regeneration were further analyzed and calculated by histological analysis,including hematoxylin and eosin and Safranin O-Fast green staining,respectively;LDHA levels of chondrocyte stem cells(CSPCs)after co-incubation with BMSC-Exos were analyzed by western blotting.Extracellularly secreted lactic acid content was determined by lactate assay kit.Cell viability was assessed by cell counting kit 8 assay,and the proliferation and differentiation ability of cells was further examined by the expression of collagen II,SOX9 and aggrecan.Histone H3K18 lactylation modification was analyzed by western blotting.H3K18 La binding on bone morphogenetic protein 7(BMP7)promoter was analyzed by chromatin immunoprecipitation-quantitative polymerase chain reaction;BMP7 promoter activity was analyzed by dual luciferase reporter gene;BMP7 protein expression was analyzed using quantitative polymerase chain reaction and western blotting.Then,the proliferation of CSPCs promoted by BMSC-Exos LDHA was analyzed by protein expression levels of LDHA,BMP7,collagen II,SOX9,aggrecan,extracellular lactate content,and cell counting kit 8 assay.RESULTS The spherical nanosized BMSC-Exos could be uptaken by CSPCs.LDHA was highly expressed in BMSC-Exos,which could infiltrate into the bone tissue of ACLR rats and promoted the generation of new bone tissue,as well as significantly increased the regeneration of tendon and fibrocartilage.Co-incubation of CSPCs with high-expressing LDHA BMSC-Exos increased the secretion of lactate content from CSPCs,cell viability,and the expression of markers related to cell proliferation and differentiation,including collagen II,SOX9,and aggrecan;LDHA in BMSC-Exos upregulated BMP7 through histone H3K18 lactate modification;high LDHA expression reversed the knockdown of BMP7,further increasing the proliferation and differentiation of CSPCs,thereby inducing cartilage formation.CONCLUSION LDHA in BMSC-Exos promotes BMP7 expression via H3K18 lactylation modification,which further promotes tendon-bone healing after ACLR.
文摘BACKGROUND Ferroptosis is a newly recognized form of regulated cell death characterized by iron-dependent accumulation of lipid reactive oxygen species.It has been extensively studied in various diseases,including cancer,Parkinson’s disease,and stroke.However,its precise role and underlying mechanisms in ischemia/reperfusion injury,particularly in the intestinal ischemia-reperfusion(IIR),remain unclear.In current work,we aimed to investigate the participation of histone lactylation during IIR progression.AIM To investigate the role of mitochondrial alanyl-tRNA synthetase 2(AARS2)in ferroptosis and its epigenetic regulation of acyl-CoA synthetase long-chain family member 4(ACSL4)through histone lactylation during IIR injury.METHODS We established a mouse model to mimic IIR and conducted AARS2 knockdown as treatment.The expression of AARS2 in intestinal tissues was measured by western blot.The integrity of intestinal tissues was detected by hematoxylin and eosin staining,serum fatty acid-binding protein,protein levels of ZO-1 and occluding.An in vitro hypoxia-reperfusion(H/R)cell model was established,and cell viability was measured by CCK-8.The in vitro and in vivo ferroptosis was determined by the accumulation of Fe2+and malondialdehyde(MDA).The epigenetic regulation of ACSL4 by AARS2 was detected by chromatin immunoprecipitation(ChIP)assay and luciferase reporter assay.RESULTS We observed a notable elevated AARS2 level in intestinal tissue of mice in IIR model group,which was reversed by shAARS2 treatment.Knockdown of AARS2 repressed alleviated intestinal barrier disruption and repressed the accumulation of ferroptosis biomarker Fe2+and MDA during IIR.The in vitro results showed that shAARS2 alleviated impaired cell viability caused by H/R,as well as repressed ferroptosis.Knockdown of AARS2 notably downregulated the RNA and protein expression of ACSL4.Mechanistically,knockdown of AARS2 downregulated the enrichment of H3K18 La modification on AARS2,as well as suppressed its promoter activity.Overexpression of AARS2 could abolish the protective effects of shACSL4 in vitro.CONCLUSION The elevation of AARS2 during IIR led to cell ferroptosis via epigenetically upregulating the expression of ACSL4.Our findings presented AARS2 as a promising therapeutic target for IIR.
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(No.2021YFD1200403)the National Natural Science Foundation of China(No.32072735)Xigaze City regional Science and technology Collaborative innovation project-Genetic resources of rescue protection for Zhangmu goat(No.QYXTZX-RKZ2023-06)。
文摘Background Previous studies have shown that the vitrification of metaphaseⅡ(MⅡ)oocytes significantly represses their developmental potential.Abnormally increased oxidative stress is the probable factor;however,the underlying mechanism remains unclear.The walnut-derived peptide TW-7 was initially isolated and purified from walnut protein hydrolysate.Accumulating evidences implied thatTW-7 was a powerful antioxidant,while its prospective application in oocyte cryopreservation has not been reported.Result Here,we found that parthenogenetic activation(PA)zygotes derived from vitrified MⅡoocytes showed elevated ROS level and delayed progression of pronucleus formation.Addition of 25μmol/LTW-7 in warming,recovery,PA,and embryo culture medium could alleviate oxidative stress in PA zygotes from vitrified mouse MⅡoocytes,furtherly increase proteins related to histone lactylation such as LDHAe LDHB,and EP300 and finally improve histone lactylation in PA zygotes.The elevated histone lactylation facilitated the expression of minor zygotic genome activation(ZGA)genes and preimplantation embryo development.Conclusions Our findings revealed the mechanism of oxidative stress inducing repressed development of PA embryos from vitrified mouse MⅡoocytes and found a potent and easy-obtained short peptide that could significantly rescue the decreased developmental potential of vitrified oocytes,which would potentially contribute to reproductive medicine,animal protection,and breeding.
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.
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 grants from the Science and Technology Commission of Shanghai(22Y31900700)Program of Innovative Research Team of High‑Level Local Universities in Shanghai(SHSMU‑ZDCX20210902)+1 种基金Shanghai Municipal Health Commission(2022YQ01)“New Star of Medical College”Young Medical Talents Training Program in Shanghai in 2020.
文摘Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings,particularly in intricate conditions such as cancer.Specifically,lactate has been demonstrated to be pivotal in molding the tumor microenvironment(TME)through its effects on different cell populations.Within tumor cells,lactate impacts cell signaling pathways,augments the lactate shuttle process,boosts resistance to oxidative stress,and contributes to lactylation.In various cellular populations,the interplay between lactate and immune cells governs processes such as cell differentiation,immune response,immune surveillance,and treatment effectiveness.Furthermore,communication between lactate and stromal/endothelial cells supports basal membrane(BM)remodeling,epithelial-mesenchymal transitions(EMT),metabolic reprogramming,angiogenesis,and drug resistance.Focusing on lactate production and transport,specifically through lactate dehydrogenase(LDH)and monocarboxylate transporters(MCT),has shown promise in the treatment of cancer.Inhibitors targeting LDH and MCT act as both tumor suppressors and enhancers of immunotherapy,leading to a synergistic therapeutic effect when combined with immunotherapy.The review underscores the importance of lactate in tumor progression and provides valuable perspectives on potential therapeutic approaches that target the vulnerability of lactate metabolism,highlighting the Heel of Achilles for cancer treatment.
基金supported in part by National Natural Science Foundation of China(Grant Nos.81930083,82192893,81821001,and 82303217)National Key R&D Program of China(2022YFA1304504)+2 种基金the Chinese Academy of Sciences(XDB39000000)the Global Select Project(DJK-LX-2022001)of the Institute of Health and Medicine,Hefei Comprehensive National Science Centerthe Fundamental Research Funds for the Central Universities(WK9100000051).
文摘Deactivation of the mitochondrial pyruvate dehydrogenase complex(PDC)is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis.Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase(E1),leaving other post-translational modifications largely unexplored.Here,we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X(PDHX)commonly occurs in hepatocellular carcinoma,disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression.PDHX,an E3-binding protein in the PDC,is acetylated by the p300 at Lys 488,impeding the interaction between PDHX and dihydrolipoyl transacetylase(E2),thereby disrupting PDC assembly to inhibit its activation.PDC disruption results in the conversion of most glucose to lactate,contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression,facilitating tumor progression.These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity,linking PDHX Lys 488 acetylation and histone lactylation during hepatocellular carcinoma progression and providing a potential biomarker and therapeutic target for further development.
基金supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project(2024ZD0525700 to T.L.)the National Natural Science Foundation of China(82403698 to X.L.)+5 种基金the Postdoctoral Fellowship Program of CPSF grant(GZC20233348 to X.L.)the National Natural Science Foundation of China grant(82472779 to X.G.)the National Natural Science Foundation of China grant(82372881 to W.H.)the Chongqing Natural Science Foundation(CSTB2024NSCQ-MSX1030 to X.L.)the Chongqing Medical Youth Top Talent Project(YXQN202431 to X.L.)the Qiande Excellent Young Talent Project(2025QDYQ-06 to X.L.).
文摘Chemoresistance remains the major barrier to cancer treatment.Metabolic and epigenetic reprogramming are involved in this process;however,the precise roles and mechanisms are largely unknown.Here,we report that lactate-induced lactylation promotes chemoresistance to anthracyclines by regulating homologous recombination(HR)repair.Using the global lactylome,we revealed the landscape of differentially lactylated sites and proteins in cancer cells isolated from resistant and nonresistant tumors.Specifically,BLM,a crucial helicase in the HR repair process,is highly lactylated at Lys24 by AARS1 in response to chemotherapy.
基金supported by the National Natural Science Foundation of China(NSFC)(T2225006,T2488301,and 82272948 to M.L.)the Beijing Municipal Natural Science Foundation(Key Program Z220011 to M.L.).
文摘Since the debut of the Warburg effect,our understanding of lactate in cancer has evolved from a metabolic waste of"low-efficient"glucose metabolism,an acidification factor reshaping tumor microenvironments,to key molecular signals modulating signaling pathways,thereby influencing cell fates.Recently,Zhang’s work introduced a novel post-translational modification(PTM),lactylation,revealing a previously unidentified identity of lactate.Further findings in Plantae and Bacteria have projected lactylation as a common PTM among biological kingdoms.
基金supported by grants from the National Natural Science Foundation of China(Nos.82273204 and 81972471)the Guangdong Medical Science and Technology Program(No.A2023077)+1 种基金Guangdong Basic and Applied Basic Research Foundation(No.2023A1515110952)the China Postdoctoral Science Foundation(Nos.2023M744024 and 2023M734015).
文摘Background:Gastric cancer(GC)is a common malignancy characterized by the absence of reliable prognostic indicators and effective therapeutic targets.Claudin-9(CLDN9)has been demonstrated to be upregulated in various cancers.However,its prognostic value,biological function,and regulatory mechanisms in GC remain unclear.Therefore,this study aimed to elucidate the role of CLDN9 in GC progression and its underlying mechanisms.Methods:We utilized consensus cluster,random survival forest,and multivariate Cox regression analyses to identify CLDN9 in GC.Subsequently,we evaluated the mRNA and protein levels of CLDN9 in GC using quantitative real-time polymerase chain reaction(PCR)(qRT-PCR),Western blotting(WB),and immunohistochemistry(IHC).Furthermore,the role of CLDN9 in GC progression was investigated using a series of functional in vivo and in vitro experiments.Finally,we elucidated the molecular mechanisms of CLDN9 using bioinformatics,molecular biology,animal models,and patient tissue specimens.Results:Two GC subtypes with survival and functional differences were identified based on glycolytic metabolic genes in the Cancer Genome Atlas(TCGA)-Stomach adenocarcinoma(STAD)dataset.A prognostic risk score was calculated using seven genes to assess the overall survival(OS)in GC.Using random survival forest and multivariate Cox analyses,we identified CLDN9 as the key gene linked to the glycolytic subtype and prognosis of GC.CLDN9 expression was significantly upregulated in patients with GC as well as in GC cells.CLDN9 knockdown inhibited tumor proliferation,invasion,and metastasis both in vivo and in vitro.Mechanistically,CLDN9 was found to regulate lactate dehydrogenase A(LDHA)expression and promote glycolytic metabolism by activating the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/hypoxia-inducible factor 1-alpha(HIF1α)signaling pathway.Additionally,lactate,a glycolytic metabolite,enhanced programmed cell death ligand 1(PD-L1)lactylation and stability,which suppressed anti-tumor immunity in CD8t T cells,thereby contributing to GC progression.Conclusions:CLDN9 expression is associated with GC development and progression.Mechanistically,CLDN9 enhances the glycolysis pathway and facilitates PD-L1 lactylation through the PI3K/AKT/HIF1αsignaling pathway,thereby suppressing anti-tumor immunity in CD8t T cells.CLDN9 has the potential to serve as a novel prognostic marker and therapeutic target for GC.
基金supported by the National Natural Science Foundation of China(No.82203469)the Liaoning Province Joint Fund General Project(China)(No.2023-MSLH-166).
文摘The incidence of endometrial cancer(EC)is increasing,particularly in high-risk cases with poor prognosis.1 Reprogramming glucose metabolism is the main feature of energy metabolism in EC cells,resulting in substantial lactate accumulation.2 Recent research indicates that the accumulation of lactic acid during the metabolic process can serve as a substrate.3 The high concentration of lactate accumulated by metabolites can promote the malignant progression of tumor cells by modifying key proteins through lactylation.
