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
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
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
Metabolic dysfunction-associated steatohepatitis(MASH)and alcoholic steatohepatitis(ASH)are severe forms of chronic liver disease,characterized by inflammation,oxidative stress,lipid dysregulation,and fibrosis.Epigene...Metabolic dysfunction-associated steatohepatitis(MASH)and alcoholic steatohepatitis(ASH)are severe forms of chronic liver disease,characterized by inflammation,oxidative stress,lipid dysregulation,and fibrosis.Epigenetic changes,including acetylation,methylation,phosphorylation,ubiquitination,sumoylation,and lactylation of histones,dynamically regulate gene expression by altering the chromatin structure.Emerging evidence highlights histone modifications as chief contributors to the pathogenesis of chronic liver diseases.Lactylation which is a novel post-translational modification(PTM)of histone,has been observed as a crucial contributor to liver physiology as well as pathobiology.This modification,characterized by the addition of lactate to lysine residues on histones,influences gene expression and cellular metabolism in the liver.Intriguingly,elevated lactate levels in the liver,resulting from either chronic alcohol consumption or a highfat/fructose-rich diet,may promote histone lactylation,particularly at histone 3 at lysine 18(H3K18),which facilitates the transcription of pro-inflammatory and fibrogenic genes.This process not only intensifies hepatic inflammation and fibrosis but also disrupts normal metabolic pathways,resulting in further liver damage.This review aims to elucidate the role of histone lactylation in MASH.Although a direct demonstration of histone lactylation in ASH has not yet been reported,the altered lactate metabolism in ASH suggests that histone lactylation may significantly contribute to its pathogenesis.Finally,we explore novel strategies targeting histone lactylation to mitigate liver injury and improve disease management in MASH and ASH.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
Lactate is the end product of glycolysis,and extensive research has shown that lactate participates in various pathophysiological processes.Along with associated hydrogen ions,lactate typically functions as an immunos...Lactate is the end product of glycolysis,and extensive research has shown that lactate participates in various pathophysiological processes.Along with associated hydrogen ions,lactate typically functions as an immunosuppressive negative factor and plays a crucial role in tumor metabolic reprogramming.The recently discovered lactylation is a novel epigenetic modification that,similar to other epigenetic modifications,modifies histones to alter chromatin spatial configuration,thereby affecting DNA accessibility and regulating gene expression.More importantly,the degree of lactylation is closely related to local lactate concentrations,establishing a link between epigenetics and metabolic reprogramming.During cellular metabolism,lactate accumulation promotes histone lysine lactylation in cancer cells and immune cells such as macrophages and T cells,playing an essential role in tumor immune evasion and resistance to immunotherapy.This paper details the role of lactylation modifications in cancer immune evasion and resistance to immunotherapy,providing novel therapeutic directions and targets for cancer treatment.展开更多
The Warburg effect,characterized by excessive lactate production,and transcriptional dysregulation are two hallmarks of tumors.However,the precise influence of lactate on epigenetic modifications at a genome-wide leve...The Warburg effect,characterized by excessive lactate production,and transcriptional dysregulation are two hallmarks of tumors.However,the precise influence of lactate on epigenetic modifications at a genome-wide level and its impact on gene transcription in tumor cells remain unclear.In this study,we conducted genome-wide profiling of histone H3 lysine 18 lactylation(H3K18la)in T-cell acute lymphoblastic leukemia(T-ALL).We observed elevated lactate and H3K18la levels in T-ALL cells compared to normal T cells,with H3K18la levels positively associated with cell proliferation.Accordingly,we observed a significant shift in genome-wide H3K18la modifications from T cell immunity in normal T cells to leukemogenesis in T-ALL,correlated with altered gene transcription profiles.We showed that H3K18la primarily functions in active transcriptional regulation and observed clusters of H3K18la modifications resembling super-enhancers.Disrupting H3K18la modification revealed both synergistic and divergent changes between H3K18la and histone H3 lysine 27 acetylation(H3K27ac)modifications.Finally,we found that the high transcription of H3K18la target genes,IGFBP2 and IARS,is associated with inferior prognosis of T-ALL.These findings enhance our understanding of how metabolic disruptions contribute to transcription dysregulation through epigenetic changes in T-ALL,underscoring the interplay of histone modifications in maintaining oncogenic epigenetic stability.展开更多
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
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
Objective:Cisplatin-based chemotherapy is a cornerstone for bladder cancer treatment,but the development of resistance remains a major clinical challenge.Curcumol,a bioactive sesquiterpenoid derived from Curcumae Rhiz...Objective:Cisplatin-based chemotherapy is a cornerstone for bladder cancer treatment,but the development of resistance remains a major clinical challenge.Curcumol,a bioactive sesquiterpenoid derived from Curcumae Rhizoma,has shown anti-tumor potential.This study investigated the efficacy of curcumol in overcoming cisplatin resistance and elucidated its underlying molecular mechanisms in bladder cancer progression.Methods:Clinical correlation was assessed in patients receiving neoadjuvant chemotherapy with or without Curcumae Rhizoma.The anti-tumor effects of curcumol were evaluated in both cisplatin-sensitive and cisplatinresistant bladder cancer cells.Multi-omics approaches,including RNA sequencing,proteomics and metabolomics,were employed.Key mechanisms involving H3K9 lactylation(H3K9la)were explored via Western blotting,immunohistochemistry,and cleavage under targets and tagmentation(CUT&Tag)assays.The role of the identified target ORC6 was validated through genetic knockout and overexpression.Finally,ferroptosis was confirmed by measuring lipid peroxidation[malondialdehyde(MDA)],total iron levels,and ferroptosis-related protein markers in vitro.Results:Clinical data indicated that patients administered Curcumae Rhizoma exhibited enhanced responses to neoadjuvant chemotherapy.In addition,curcumol suppressed the proliferation,migration,and invasion of both bladder cancer cells and cisplatin-resistant cells.Mechanistically,proteomic analysis and non-targeted metabolomics revealed that curcumol suppresses glycolysis and lactate production.Subsequently,Western blotting analysis demonstrated a marked reduction in H3K9la levels in both T24 and 5637 cells following curcumol treatment.This decrease in H3K9la was also observed in patient tumor tissues via immunohistochemistry staining.CUT&Tag analysis identified that H3K9la is enriched with the highest number of reads at the ORC6 promoter region.Combined in vitro and in vivo experiments indicated that OCR6 exerted a tumor-promoting effect on bladder cancer.Its knockout induced G0/G1 phase arrest and enhanced apoptosis,while its expression contributed to cancer progression by enhancing invasive and migratory capabilities.Furthermore,ORC6 overexpression correlated with ferroptosis scores and ferroptosis-related genes.In vitro,OCR6 knockout promoted ferroptosis via DNA damage,characterized by elevated MDA content,decreased expression of core ferroptosis-related proteins(GPX4 and SLC7A11),increased percentage ofγH2AX-positive cells and longer DNA tails.Finally,we performed rescue experiments using a ferroptosis inhibitor in ORC6 knockout cells,which indicated that ferroptosis inhibitor could weaken the effect of ORC6 knockout on the invasive,migratory,and proliferative capacities.Conclusions:Our findings demonstrated that curcumol effectively counteracted cisplatin resistance and inhibited bladder cancer progression by targeting the glycolysis-H3K9la-ORC6 axis to induce ferroptosis.This study established a critical link between metabolic reprogramming,histone lactylation,and ferroptosis,providing a novel therapeutic avenue for treating chemoresistant bladder cancer.展开更多
Dear Editor,Lactate has long been recognized as a canonical end product of glycolysis and a hallmark metabolic byproduct of tumor cells(Vander Heiden et al.,2009).A seminal study identified histone lysine lactylation(...Dear Editor,Lactate has long been recognized as a canonical end product of glycolysis and a hallmark metabolic byproduct of tumor cells(Vander Heiden et al.,2009).A seminal study identified histone lysine lactylation(Kla)as a hitherto unrecognized epigenetic modification,demonstrating its direct role in activating chromatin-driven gene transcription(Zhang et al.,2019).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
Neuroblastoma(NB)is the most common extracranial solid tumor in children.Despite treatment advances,the survival rates of high-risk NB patients remain low.This highlights the urgent need for a deeper understanding of ...Neuroblastoma(NB)is the most common extracranial solid tumor in children.Despite treatment advances,the survival rates of high-risk NB patients remain low.This highlights the urgent need for a deeper understanding of the molecular mechanisms driving NB progression to support the development of new therapeutic strategies.In this study,we demonstrated that the reduced levels of DNAJC12,a protein involved in metabolic regulation,are associated with poor prognosis in NB patients.Our data indicate that low DNAJC12 expression activates glycolysis in NB cells,leading to increased lactic acid production and histone H4 lysine 5 lactylation(H4K5la).Elevated H4K5la upregulates the transcription of COL1A1,a gene implicated in cell metastasis.Immunohistochemistry staining of NB patient samples confirmed that high H4K5la levels correlate with poor clinical outcomes.Furthermore,we showed that inhibiting glycolysis,reducing H4K5la,or targeting COL1A1 can mitigate the invasive behavior of NB cells.These findings reveal a critical link between metabolic reprogramming and epigenetic modifications in the context of NB progression,suggesting that H4K5la could serve as a novel diagnostic and prognostic marker,and shed light on identifying new therapeutic targets within metabolic pathways for the treatment of this aggressive pediatric cancer.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.
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.
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 the Science and Engineering Research Board,No.CRG/2022/002149the Indian Council of Medical Research,No.ICMR/02/833/IGP-2024 and No.R.12016/12/2023-HR.
文摘Metabolic dysfunction-associated steatohepatitis(MASH)and alcoholic steatohepatitis(ASH)are severe forms of chronic liver disease,characterized by inflammation,oxidative stress,lipid dysregulation,and fibrosis.Epigenetic changes,including acetylation,methylation,phosphorylation,ubiquitination,sumoylation,and lactylation of histones,dynamically regulate gene expression by altering the chromatin structure.Emerging evidence highlights histone modifications as chief contributors to the pathogenesis of chronic liver diseases.Lactylation which is a novel post-translational modification(PTM)of histone,has been observed as a crucial contributor to liver physiology as well as pathobiology.This modification,characterized by the addition of lactate to lysine residues on histones,influences gene expression and cellular metabolism in the liver.Intriguingly,elevated lactate levels in the liver,resulting from either chronic alcohol consumption or a highfat/fructose-rich diet,may promote histone lactylation,particularly at histone 3 at lysine 18(H3K18),which facilitates the transcription of pro-inflammatory and fibrogenic genes.This process not only intensifies hepatic inflammation and fibrosis but also disrupts normal metabolic pathways,resulting in further liver damage.This review aims to elucidate the role of histone lactylation in MASH.Although a direct demonstration of histone lactylation in ASH has not yet been reported,the altered lactate metabolism in ASH suggests that histone lactylation may significantly contribute to its pathogenesis.Finally,we explore novel strategies targeting histone lactylation to mitigate liver injury and improve disease management in MASH and ASH.
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.
文摘Lactate is the end product of glycolysis,and extensive research has shown that lactate participates in various pathophysiological processes.Along with associated hydrogen ions,lactate typically functions as an immunosuppressive negative factor and plays a crucial role in tumor metabolic reprogramming.The recently discovered lactylation is a novel epigenetic modification that,similar to other epigenetic modifications,modifies histones to alter chromatin spatial configuration,thereby affecting DNA accessibility and regulating gene expression.More importantly,the degree of lactylation is closely related to local lactate concentrations,establishing a link between epigenetics and metabolic reprogramming.During cellular metabolism,lactate accumulation promotes histone lysine lactylation in cancer cells and immune cells such as macrophages and T cells,playing an essential role in tumor immune evasion and resistance to immunotherapy.This paper details the role of lactylation modifications in cancer immune evasion and resistance to immunotherapy,providing novel therapeutic directions and targets for cancer treatment.
基金supported by the Major Scientific Research Program for Young and Middle-aged Health Professionals of Fujian Province(Grant No.2022ZQNZD011 to Yu Liu)the Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics(Grant No.20dz2260900 to Yu Liu)+3 种基金the National Natural Science Foundation of China(Grant No.31970627 to Yu Liu)the Foundation of National Research Center for Translational Medicine at Shanghai[Grant No.NRCTM(SH)-2019-04 to Shuhong Shen]the Shanghai Municipal Health Commission(Grant No.20234Z0003 to Meng Yin)the Shanghai Science and Technology Development Foundation(Grant No.23Y11907200 to Meng Yin),China.
文摘The Warburg effect,characterized by excessive lactate production,and transcriptional dysregulation are two hallmarks of tumors.However,the precise influence of lactate on epigenetic modifications at a genome-wide level and its impact on gene transcription in tumor cells remain unclear.In this study,we conducted genome-wide profiling of histone H3 lysine 18 lactylation(H3K18la)in T-cell acute lymphoblastic leukemia(T-ALL).We observed elevated lactate and H3K18la levels in T-ALL cells compared to normal T cells,with H3K18la levels positively associated with cell proliferation.Accordingly,we observed a significant shift in genome-wide H3K18la modifications from T cell immunity in normal T cells to leukemogenesis in T-ALL,correlated with altered gene transcription profiles.We showed that H3K18la primarily functions in active transcriptional regulation and observed clusters of H3K18la modifications resembling super-enhancers.Disrupting H3K18la modification revealed both synergistic and divergent changes between H3K18la and histone H3 lysine 27 acetylation(H3K27ac)modifications.Finally,we found that the high transcription of H3K18la target genes,IGFBP2 and IARS,is associated with inferior prognosis of T-ALL.These findings enhance our understanding of how metabolic disruptions contribute to transcription dysregulation through epigenetic changes in T-ALL,underscoring the interplay of histone modifications in maintaining oncogenic epigenetic stability.
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.
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supports of Science and Technology Plan Basic Project of Guizhou Province(No.ZK[2022]General 446)the Natural Science Fundation of Zhejiang Province(No.Q24H160134)+4 种基金Science and Technology Project of Zhejiang Health Commission(No.2024660542)Clinical Research Plan for TCM of Administration of Traditional Chinese Medicine of Zhejiang Province(No.2025075369)Bijie City Science and Technology Plan Project(No.[2025]No.60)National Health Commission of the People’s Republic of China-Zhejiang Province Jointly Constructed ProjectZhejiang Province Medical and Health Science and Technology Plan(No.WKJ-ZJ-2517)。
文摘Objective:Cisplatin-based chemotherapy is a cornerstone for bladder cancer treatment,but the development of resistance remains a major clinical challenge.Curcumol,a bioactive sesquiterpenoid derived from Curcumae Rhizoma,has shown anti-tumor potential.This study investigated the efficacy of curcumol in overcoming cisplatin resistance and elucidated its underlying molecular mechanisms in bladder cancer progression.Methods:Clinical correlation was assessed in patients receiving neoadjuvant chemotherapy with or without Curcumae Rhizoma.The anti-tumor effects of curcumol were evaluated in both cisplatin-sensitive and cisplatinresistant bladder cancer cells.Multi-omics approaches,including RNA sequencing,proteomics and metabolomics,were employed.Key mechanisms involving H3K9 lactylation(H3K9la)were explored via Western blotting,immunohistochemistry,and cleavage under targets and tagmentation(CUT&Tag)assays.The role of the identified target ORC6 was validated through genetic knockout and overexpression.Finally,ferroptosis was confirmed by measuring lipid peroxidation[malondialdehyde(MDA)],total iron levels,and ferroptosis-related protein markers in vitro.Results:Clinical data indicated that patients administered Curcumae Rhizoma exhibited enhanced responses to neoadjuvant chemotherapy.In addition,curcumol suppressed the proliferation,migration,and invasion of both bladder cancer cells and cisplatin-resistant cells.Mechanistically,proteomic analysis and non-targeted metabolomics revealed that curcumol suppresses glycolysis and lactate production.Subsequently,Western blotting analysis demonstrated a marked reduction in H3K9la levels in both T24 and 5637 cells following curcumol treatment.This decrease in H3K9la was also observed in patient tumor tissues via immunohistochemistry staining.CUT&Tag analysis identified that H3K9la is enriched with the highest number of reads at the ORC6 promoter region.Combined in vitro and in vivo experiments indicated that OCR6 exerted a tumor-promoting effect on bladder cancer.Its knockout induced G0/G1 phase arrest and enhanced apoptosis,while its expression contributed to cancer progression by enhancing invasive and migratory capabilities.Furthermore,ORC6 overexpression correlated with ferroptosis scores and ferroptosis-related genes.In vitro,OCR6 knockout promoted ferroptosis via DNA damage,characterized by elevated MDA content,decreased expression of core ferroptosis-related proteins(GPX4 and SLC7A11),increased percentage ofγH2AX-positive cells and longer DNA tails.Finally,we performed rescue experiments using a ferroptosis inhibitor in ORC6 knockout cells,which indicated that ferroptosis inhibitor could weaken the effect of ORC6 knockout on the invasive,migratory,and proliferative capacities.Conclusions:Our findings demonstrated that curcumol effectively counteracted cisplatin resistance and inhibited bladder cancer progression by targeting the glycolysis-H3K9la-ORC6 axis to induce ferroptosis.This study established a critical link between metabolic reprogramming,histone lactylation,and ferroptosis,providing a novel therapeutic avenue for treating chemoresistant bladder cancer.
基金supported by the National Natural Science Foundation of China(82472705,32422082)。
文摘Dear Editor,Lactate has long been recognized as a canonical end product of glycolysis and a hallmark metabolic byproduct of tumor cells(Vander Heiden et al.,2009).A seminal study identified histone lysine lactylation(Kla)as a hitherto unrecognized epigenetic modification,demonstrating its direct role in activating chromatin-driven gene transcription(Zhang et al.,2019).
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.
基金supported by grants from the Fun-damental Research Funds for the Central Universities(YG2022ZD021)the Natural Science Foundation of Shanghai(22ZR1440200 and 23410760900)+1 种基金the Science and Technology Development Fund of Shanghai Pudong New Area(PKJ2022-Y01 and PKJ2022-Y03)the Science and Technology Commission of Shanghai Municipality(202140143).
文摘Neuroblastoma(NB)is the most common extracranial solid tumor in children.Despite treatment advances,the survival rates of high-risk NB patients remain low.This highlights the urgent need for a deeper understanding of the molecular mechanisms driving NB progression to support the development of new therapeutic strategies.In this study,we demonstrated that the reduced levels of DNAJC12,a protein involved in metabolic regulation,are associated with poor prognosis in NB patients.Our data indicate that low DNAJC12 expression activates glycolysis in NB cells,leading to increased lactic acid production and histone H4 lysine 5 lactylation(H4K5la).Elevated H4K5la upregulates the transcription of COL1A1,a gene implicated in cell metastasis.Immunohistochemistry staining of NB patient samples confirmed that high H4K5la levels correlate with poor clinical outcomes.Furthermore,we showed that inhibiting glycolysis,reducing H4K5la,or targeting COL1A1 can mitigate the invasive behavior of NB cells.These findings reveal a critical link between metabolic reprogramming and epigenetic modifications in the context of NB progression,suggesting that H4K5la could serve as a novel diagnostic and prognostic marker,and shed light on identifying new therapeutic targets within metabolic pathways for the treatment of this aggressive pediatric cancer.
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.
