TANGO2 deficiency disorder (TDD) is a rare genetic disease caused by mutations in the TANGO2 gene, characterized by prominent neurological symptoms. However, the pathological mechanisms underlying TANGO2 loss-of-function in neurologic symptoms remain unknown. Here, we generated constitutive and cell-type-specific Tango2 knockout mouse models to examine TANGO2's role in the central nervous system (CNS). Behavioral analyses revealed that both constitutive and oligodendrocyte-specific deletion of Tango2 recapitulate the motor deficits associated with individuals with TDD. Morphological quantifications further showed that Tango2 deletion led to robust cerebellar myelin loss and an increase in synapse number in the cerebellar cortex. In addition, transcriptional analysis and lipidomic profiling demonstrated that Tango2 deletion downregulated key processes involved in phospholipid metabolism. Significantly, vitamin B5 supplementation alleviated motor deficits and cerebellar myelin defects in Tango2 knockout mice. Overall, our findings establish that TANGO2 is essential for maintaining normal motor behaviors by regulating lipid metabolism in oligodendroglia.

AIMS:Mitochondrial dysfunction is a critical driver of heart failure (HF). Syntabulin (SYBU), known for its role as a motor linker at the outer mitochondrial membrane in neuronal system, has recently been suggested as a HF-associated gene. However, the role of SYBU in regulating cardiac function remains unclear. METHODS AND RESULTS:Pressure overload-induced cardiac hypertrophy and HF was produced by transverse aortic constriction in mice and phenylephrine (PE) stimulation in neonatal rat ventricular myocytes. SYBU expression was significantly increased in hypertrophic mouse hearts and patient hearts with dilated cardiomyopathy. The cardiac-specific upregulating SYBU expression, achieved via recombinant adeno-associated virus driven by cardiac troponin T promoter, led to increased cardiomyocyte death and worsened HF under hypertrophic conditions. In contrast, SYBU knockdown mitigated PE-induced cardiomyocyte injury. Structured illumination microscopy and analysis of mitochondria-associated endoplasmic reticulum membrane fractions revealed that SYBU localizes to ER-mitochondria contact sites. SYBU enhances sarcoplasmic reticulum (SR)-mitochondria tethering through interactions with Ryanodine receptor 2 and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase, leading to mitochondrial Ca2+ overload and impaired mitochondrial respiratory capacity. Furthermore, excessive mitochondrial Ca2+ triggered ER stress and protein kinase A activation, inducing phosphorylation of dynamin-related protein 1 at Ser637, and ultimately disrupting mitochondrial fission and mitophagy. CONCLUSION:Our findings established a critical role of SYBU in promoting HF by inducing cardiomyocyte injury via increasing SR-mitochondria tethering and impairing mitochondrial fission and mitophagy. Therefore, targeting SYBU and its downstream signalling pathways could be a promising therapeutic strategy to restrain HF in pressure overload-induced cardiac hypertrophy.

Aerobic glycolysis, termed the Warburg effect, is one of the aberrant metabolic pathways in highly proliferating cells. Glycolysis provides glycolytic metabolites to support the generation of biomass, such as nucleotides, amino acids, and lipids. Research on the direct interactions between glycolysis and other metabolic pathways is an emerging field that has garnered significant interest. Phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) activates glycolysis by synthesizing fructose-2,6-bisphosphate (F2,6BP), which allosterically activates the rate-limiting enzyme 6-phosphofructo-1-kinase (PFK-1). In this study, we found that PFKFB3 directly interacts with and regulates the phosphorylation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), the enzyme catalyzing the first three steps of de novo pyrimidine synthesis. PFKFB3 inactivation reduced de novo pyrimidine synthesis, RNA and DNA production, and cell proliferation. Thus, the glycolytic activator PFKFB3 bridges glycolysis with pyrimidine synthesis, unites both glucose metabolism and nucleic acid metabolism, and contributes to cell proliferation under pathological conditions.

Antigenic heterogeneity and the tumor microenvironment remain major obstacles to effective chimeric antigen receptor T (CAR-T) therapy, but natural ligands engaging multiple antigens within tumors and their milieu offer a promising solution. Here, we present a multitarget switchable CAR-T (sCAR-T) strategy that integrates a universal receptor on T cells with an antibody-ligand motif, combining an anti-Her2 single-chain variable fragment (scFv) (4D5) and spliced VEGF-A (VEGF121) to target Her2, VEGFR1, and VEGFR2. Optimization of the switch and CAR hinge preserved the ligand’s native dimeric conformation, enhancing antigen recognition and promoting immunological synapse formation. In syngeneic and xenograft models, sCAR-T achieves superior tumor eradication and vasculature disruption compared with conventional CAR-T, overcoming immune escape driven by antigenic heterogeneity. We further extend the sCAR-T design to target receptor tyrosine kinase-like orphan receptor 1 (ROR1), demonstrating that the antibody-ligand motif-based strategy provides a versatile framework for complex antigen targeting, with potential to improve efficacy and safety and enable broader application in immunotherapies targeting complex antigenic combinations.

Membrane mechanics play a crucial role in cellular signaling and fate determination, yet their impact on angiogenesis remains poorly understood. Here, we identify Kindlin-2 as a key regulator of sprouting angiogenesis via regulating endothelial membrane tension through its interaction with Moesin, a crucial linker protein between the cell membrane and the actin cortex. Mechanistically, Kindlin-2 binds to the N62 residue of Moesin, limiting its overactivation and maintaining proper membrane tension to facilitate VEGFR2 endocytosis and downstream signaling. Using both developmental and pathological models, we demonstrate that the interaction of Kindlin-2 and Moesin is enhanced in high angiogenic conditions, and endothelial Kindlin-2 deletion reduces angiogenesis. Furthermore, mutation of Moesin at N62 phenocopies the effects of Kindlin-2 loss. Together, these findings uncover a previously unrecognized mechanism linking membrane tension regulation to angiogenesis and provide new insights into targeting the Kindlin-2 Moesin axis for therapeutic intervention in neovascular diseases.

Cardiovascular diseases are increasingly recognized as immune-inflammatory disorders in which adaptive immunity shapes tissue injury, repair, and long-term remodeling. T cells are central to these processes because they integrate antigen recognition, lineage-defining transcriptional programs, tissue trafficking, cytokine production, and immunological memory. In this Review, we synthesize current evidence on the Krüppel-like factor (KLF) family as a transcriptional framework linking T-cell biology to cardiovascular disease. KLF2 primarily regulates T-cell quiescence and trafficking, KLF10 supports regulatory T-cell suppressive function and immune-metabolic fitness, KLF4 contributes to inflammatory effector differentiation, and KLF13 regulates delayed inflammatory chemokine expression and, in thymocyte models, exerts a survival-restraining effect through apoptosis-related pathways. Across atherosclerosis, myocardial infarction, myocarditis, hypertension, and heart failure, these KLF-dependent programs may influence the balance between pathogenic effector responses and protective regulatory mechanisms. The strongest direct disease-specific evidence currently supports a role for KLF10 within the CD4+ T-cell lineage in experimental atherosclerosis, with complementary functional evidence implicating Treg–macrophage interactions, whereas the roles of KLF-dependent T-cell programs in other cardiovascular settings remain mechanistically compelling but less fully validated. Future progress will require disease-specific T-cell-restricted models, spatially resolved immune analyses, and cell-selective translational strategies to define the therapeutic relevance of the KLF–T-cell axis.

AIMS:Protein kinase D (PKD) is a family of serine/threonine kinases encoded by three genes-Prkd1, Prkd2, and Prkd3. PKD has been implicated in regulating cell proliferation, apoptosis, motility, and protein trafficking, but its physiological roles during embryonic development remain incompletely understood. In this study, we aimed to investigate the effects of PKD deletion on embryonic survival and development in mice. MATERIALS AND METHODS:Single knockout mice for each PKD isoform (Prkd1-/-, Prkd2-/-, and Prkd3-/-, referred to as D1KO, D2KO, and D3KO, respectively) were generated and bred with each other to produce compound double knockout (DKO) models. Genotypic and histological analysis were performed to determine embryonic viability and morphology. KEY FINDINGS:Single knockout mice of any PKD isoform exhibited normal embryonic development and postnatal survival with Mendelian inheritance patterns. However, deletion of both Prkd1 and Prkd2 (DKO1/2) or both Prkd1 and Prkd3 (DKO1/3) caused severe allantoic-placental defects, including reduced umbilical vessel size and decreased placental labyrinth depth. These defects led to growth retardation, pericardial edema, and embryonic lethality between embryonic day 10.5 (E10.5) and E11.5 with full penetrance. In contrast, deletion of Prkd2 and Prkd3 (DKO2/3) also caused embryonic lethality, but with partial penetrance and at a later stage. Although over 50 % of DKO2/3 embryos survived to E18.5, they exhibited marked growth retardation, as evidenced by reduced body weight and smaller organ size. SIGNIFICANCE:Our results demonstrate that PKD is essential for normal embryonic development and survival in mice, and that distinct PKD isoforms exhibit functional redundancy during this process.

BACKGROUND:Neointimal hyperplasia is the major cause of significant vascular complications after arterial interventions. Despite the advancements in strategies such as drug-eluting stents to minimize neointimal hyperplasia, achieving consistently effective long-term outcomes remains a challenge. Protein-protein interactions mediated by PDZ (PSD-95, Discs-large, and ZO-1) domains are essential for numerous biological processes. However, little is known about the role of PDZ proteins in neointima formation. This study aims to explore the role of TAX1BP3 (Tax1 binding protein 3), a singular PDZ protein, in phenotypic switching of vascular smooth muscle cells (VSMCs) and its implication in neointimal hyperplasia. METHODS:Subcellular localization of TAX1BP3 was assessed in isolated VSMCs or arteries obtained from mice with neointima formation. TAX1BP3 mutants were constructed to study the role of SUMOylation on TAX1BP3 nucleocytoplasmic shuttling. VSMC-specific Tax1bp3 knockout mice were generated to determine the relevant phenotypes in a carotid artery wire injury model. RNA sequencing, assays for transposase-accessible chromatin using sequencing, computational prediction of complex structures, and coimmunoprecipitation were performed to elucidate the underlying molecular mechanisms. Adeno-associated virus-mediated Tax1bp3 gene delivery and nanoencapsulated-TAX1BP3 were employed to investigate the potential translational relevance. RESULTS:TAX1BP3 exhibited dynamic nucleocytoplasmic shuttling during phenotypic switching of VSMCs. TAX1BP3 is SUMOylated at K116, and its SUMOylation is essential for maintaining the nuclear localization of TAX1BP3. Deficiency of TAX1BP3 facilitated the transition from a contractile to a synthetic phenotype and aggravated neointima formation after vascular injury in mice. The integration of RNA sequencing and an assay for transposase-accessible chromatin using sequencing unveiled that TAX1BP3 primarily regulated the cell cycle progression and cell proliferation of VSMCs through YAP-TEAD transcription activity. The computational prediction of TAX1BP3/YAP1 complex structures and protein interaction-related experiments revealed that TAX1BP3 and TEAD1 compete for binding to YAP through its TEAD binding domain (BD) in a noncanonical PDZ manner. AAV-mediated Tax1bp3 gene delivery significantly attenuated postinjury neointima formation and the progression of atherosclerosis. Nanoencapsulated-TAX1BP3 administration effectively reduced VSMC phenotypic switching and neointimal hyperplasia. CONCLUSIONS:These results demonstrate that SUMOylation of TAX1BP3 at K116 enables its nucleocytoplasmic shuttling during phenotypic switching of VSMCs. TAX1BP3 competitively interacts with the YAP-TEAD complex in a noncanonical PDZ manner and exerts its protective role in vascular neointimal hyperplasia primarily through the regulation of cell proliferation.

Vascular calcification, a key risk factor for cardiovascular diseases, is driven by the phenotypic transition of vascular smooth muscle cells from a contractile to an osteogenic phenotype. NEXN, a protein highly associated with heart function, has also been implicated as a potential susceptibility factor in the development of coronary artery disease, but its role in the progression of vascular calcification remains unclear. In this study, multi-transcriptomics analysis and various animal models of male mice were used to explore the cell-specific roles and molecular mechanisms of NEXN in vascular calcification. Here, we show that vascular smooth muscle cell-specific NEXN knockout exacerbates calcification, while NEXN overexpression alleviates it. Mechanistically, NEXN interacts with SERCA2, enhancing its SUMOylation, stability, and function, thereby protecting against calcification. These findings suggest potential therapeutic strategies by targeting NEXN-SERCA2 interactions or enhancing SERCA2 SUMOylation to prevent vascular calcification and its complications.

Background: Left ventricular non-compaction cardiomyopathy (LVNC) is a congenital heart disease characterized by abnormal prenatal development of the left ventricle that has an aberrantly thick trabecular layer and a thinner compacted myocardial layer. However, the underlying molecular mechanisms of LVNC regulated by mitochondrial phosphatase genes remain largely unresolved. Methods: We generated a mouse model with cardiac-specific deletion (CKO) of Ptpmt1, a type of mitochondrial phosphatase gene, using the αMHC-Cre, and investigated the effects of cardiac-specific Ptpmt1 deficiency on cardiac development. Morphological, histological, and immunofluorescent analyses were conducted in Ptpmt1 CKO and littermate controls. A transcriptional atlas was identified by RNA sequencing (RNA-seq) analysis. Results: We found that CKO mice were born at the Mendelian ratio with normal body weights. However, most of the CKO mice died within 24 h after birth, developing spontaneous ventricular tachycardia. Morphological and histological analysis further revealed that newborn CKO mice developed an LVNC phenotype, evidenced by a thicker trabecular layer and a thinner myocardium layer, when compared with the littermate control. We then examined the embryonic hearts and found that such an LVNC phenotype could also be observed in CKO hearts at E15.5 but not at E13.5. We also performed the EdU incorporation assay and demonstrated that cardiac cell proliferation in both myocardium and trabecular layers was significantly reduced in CKO hearts at E15.5, which is also consistent with the dysregulation of genes associated with heart development and cardiomyocyte proliferation in CKO hearts at the same stage, as revealed by both the transcriptome analysis and the quantitative real-time PCR. Deletion of Ptpmt1 in mouse cardiomyocytes also induced an increase in phosphorylated eIF2α and ATF4 levels, indicating a mitochondrial stress response in CKO hearts. Conclusions: Our results demonstrated that Ptpmt1 may play an essential role in regulating left ventricular compaction during mouse heart development.

Deubiquitinating enzymes play crucial roles in various cellular activities, yet their involvement in central nervous system (CNS) vascularization and barrier function remains elusive. Canonical Wnt signaling is essential for proper CNS vascularization and barrier maintenance. Using a loss-of-function screening for Wnt-signaling activity, we identified ubiquitin-specific peptidase 9 X-linked (USP9X) as a key regulator in brain endothelial cells (BECs). Endothelium-specific Usp9x knockout mice exhibit reduced Wnt-signaling activity, compromising CNS vascularization and barrier function during development. Activation of Wnt signaling rescues these defects. Mechanistically, we identified β-catenin as a direct substrate of USP9X, with USP9X catalyzing K48 polyubiquitin chains to stabilize β-catenin. In pathological mouse models of impaired CNS vascular barrier function, including intracerebral hemorrhage and an oxygen-induced retinopathy, loss of Usp9x intensifies barrier disruption, accentuating defects. This finding implicates USP9X as a critical regulator of CNS vascularization and barrier function through Wnt signaling, offering insights into CNS disease implications.

Astrocytic Ca2+ activity regulates activity-dependent synaptic plasticity, but its role in learning-related synaptic changes in the living brain remains unclear. We found that motor training induced synaptic potentiation on apical dendrites of layer 5 pyramidal neurons, as well as astrocytic Ca2+ rises in the mouse motor cortex. Reducing astrocytic Ca2+ led to synaptic depotentiation during motor training and subsequent impairment in performance improvement. Notably, synaptic depotentiation occurred on a fraction of dendrites with repetitive dendritic Ca2+ activity. On those dendrites, dendritic spines that were active before dendritic Ca2+ activity underwent CaMKII-dependent size reduction. In addition, the activation of adenosine receptors prevented repetitive dendritic Ca2+ activity and synaptic depotentiation caused by the reduction of astrocytic Ca2+, suggesting the involvement of ATP released from astrocytes and adenosine signaling in the processes. Together, these findings reveal the function of astrocytic Ca2+ in preventing synaptic depotentiation by limiting repetitive dendritic activity during learning.

Vascular calcification (VC) is a major contributor to cardiovascular morbidity and mortality, particularly in patients with chronic kidney disease (CKD). Adenosine 2 A receptor (ADORA2A) is highly expressed in vascular cells and implicated in cardiovascular disease; however, its specific role in VC pathogenesis remains unclear. Here, we investigated the role of ADORA2A using in vitro (vascular smooth muscle cells; VSMCs), ex vivo (mouse aortic rings), and in vivo (5/6th nephrectomy with high phosphate and cholecalciferol) models of VC. The ADORA2A expression was significantly upregulated in calcified human and murine aortic tissues, as well as in VSMCs, under osteogenic conditions. Genetic deletion of Adora2a (global or VSMC-specific) or pharmacological antagonism of ADORA2A markedly attenuated aortic calcification and the expression of osteogenic markers in vivo. Consistent findings were observed in in vitro and ex vivo models. Conversely, ADORA2A overexpression exacerbated the osteogenic differentiation and calcification of VSMCs. Mechanistically, ADORA2A promoted VSMC osteogenic differentiation by facilitating cAMP-responsive element-binding protein 1 (CREB1) binding to the runt-related transcription factor 2 (RUNX2) promoter, thereby enhancing RUNX2 transcription and subsequent mineralization. Our findings reveal that ADORA2A drives VC through the cAMP/CREB1/RUNX2 signaling axis in VSMCs. Therefore, targeting ADORA2A represents a potential strategy for mitigating VC in CKD.

Investigations from the last four decades have correlated high O-linked N-acetylglucosamine (O-GlcNAc) levels with various cancer types, but it is not known how OGT responds to diverse nutrients to finetune cellular O-GlcNAcylation levels. Herein we identified a critical OGT phosphorylation site by unc-51 like autophagy activating kinase 1 (ULK1) under glucose depletion. First, we demonstrated that glucose levels modulate the interaction between OGT and ULK1 and cellular O-GlcNAcylation levels. Low glucose induces high O-GlcNAcylation, which could be reversed by ULK1 inhibition. Then, using mass spectrometry, we showed that ULK1 phosphorylates OGT at Ser576 and stabilizes OGT. Further biochemical experiments revealed that Ser576 phosphorylation inhibits Lys604 ubiquitination by stimulating OGT binding with BAP1, a de-ubiquitinase for OGT. Strikingly, using the OGTS576A knock-in cells, we found that in mouse xenograft models OGT-S576A completely abolishes the tumorigenicity of OGT, probably due to low O-GlcNAcylation. In sum, we found that ULK1 phosphorylates OGT at Ser-576 under glucose deprivation, which stabilizes OGT by promoting OGT-BAP1 association and is pivotal for O-GlcNAcylation levels and tumorigenesis. As low glucose is often associated with tumor progression, our work not only unearths a key mechanism of how OGT is regulated by glucose levels, but also offers new therapeutic opportunities targeting OGT.

Aim: Adipose tissue (AT) dysfunction that occurs in both obesity and lipodystrophy is associated with the development of cardiomyopathy. However, it is unclear how dysfunctional AT induces cardiomyopathy due to limited animal models available. We have identified vacuolar H+-ATPase subunit Vod1, encoded byAtp6v0d1, as a master regulator of adipogenesis, and adipose -specific deletion of Atp6v0d1 (Atp6v0d1(AKO)) in mice caused generalized lipodystrophy and spontaneous cardiomyopathy. Using this unique animal model, we explore the mechanism(s) underlying lipodystrophy-related cardiomyopathy. Methods and Results: Atp6v0d1(AKO) mice developed cardiac hypertrophy at 12 weeks, and progressed to heart failure at 28 weeks. The Atp6v0d1(AKO) mouse hearts exhibited excessive lipid accumulation and altered lipid and glucose metabolism, which are typical for obesity- and diabetes -related cardiomyopathy. The Atp6v0d1(AKO) mice developed cardiac insulin resistance evidenced by decreased IRS -1/2 expression in hearts. Meanwhile, the expression of forkhead box O1 (FoxO1), a transcription factor which plays critical roles in regulating cardiac lipid and glucose metabolism, was increased. RNA-seq data and molecular biological assays demonstrated reduced expression of myocardin, a transcription coactivator, in Atp6v0d1(AKO) mouse hearts. RNA interference (RNAi), luciferase reporter and ChIP-qPCR assays revealed the critical role of myocardin in regulating IRS -1 transcription through the CArG-like element in IRS -1 promoter. Reducing IRS -1 expression with RNAi increased FoxO1 expression, while increasing IRS -1 expression reversed myocardin downregulation-induced FoxO1 upregulation in cardiomyocytes. In vivo, restoring myocardin expression specifically in Atp6v0d1(AKO) cardiomyocytes increased IRS -1, but decreased FoxO1 expression. As a result, the abnormal expressions of metabolic genes in Atp6v0d1(AKO) hearts were reversed, and cardiac dysfunctions were ameliorated. Myocardin expression was also reduced in high fat diet -induced diabetic cardiomyopathy and palmitic acid -treated cardiomyocytes. Moreover, increasing systemic insulin resistance with rosiglitazone restored cardiac myocardin expression and improved cardiac functions in Atp6v0d1(AKO) mice. Conclusion: Atp6v0d1(AKO) mice are a novel animal model for studying lipodystrophy- or metabolic dysfunction -related cardiomyopathy. Moreover, myocardin serves as a key regulator of cardiac insulin sensitivity and metabolic homeostasis, highlighting myocardin as a potential therapeutic target for treating lipodystrophy- and diabetes -related cardiomyopathy.

Previous observational studies have identified a link between obesity, adiposity distribution, type 1 Diabetes Mellitus (T1DM), type 2 Diabetes Mellitus (T2DM), and the risk of pressure ulcers (PUs). However, the definitive causality between obesity and PUs, and potential DM mediators remains unclear. Univariable, multivariable, and mediation Mendelian randomization (MR) analyses were conducted to explore the mediating role of T1DM or T2DM in the association between obesity, adiposity distribution, and PUs. Instrumental variables for obesity and adiposity distribution, including Body Mass Index (BMI), waist circumference, hip circumference, trunk fat mass, whole body fat mass, trunk fat percentage, and body fat percentage, were selected from two genome-wide association studies (GWAS). In univariable MR analysis, BMI, hip circumference, and obesity were associated with PUs using inverse variance weighted (IVW) regression. These findings were further corroborated by the replication cohorts and meta-analysis (BMI: OR = 1.537, 95

Background: NHHR (non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio) is a new lipid parameter used to assess the risk of cardiovascular disease. However, the association between NHHR and the risk of depression has not been studied before. Methods: We conducted a cross-sectional study using datasets from the National Health and Nutrition Examination Survey (NHANES) 2005-2016. The PHQ-9 questionnaire was used to evaluate depression. A weighted multivariable logistic regression model and a restricted cubic spline (RCS) model were applied to investigate the association between NHHR and depression risk. Additionally, subgroup and sensitivity analyses were conducted to test the robustness of the results. Results: In the total population, compared with the lowest reference group of NHHR, participants in the fourth quartile had a significantly increased risk of depression after full adjustments (OR: 1.61, 95%CI: 1.05-2.49). A linear dose-response relationship existed between NHHR and depression risk (P non-linearity = 0.264). The association remained significant in several subgroup analyses. Limitations: The cross-sectional design and use of self-reported scales. Conclusion: NHHR was significantly associated with a higher risk of depression in U.S. adults. Additional research on NHHR would help in depression prevention and treatment.

Aims Abdominal aortic aneurysm (AAA) is a common, serious vascular disease with no effective pharmacological treatment. The nucleoside adenosine plays an important role in modulating vascular homeostasis, which prompted us to determine whether adenosine kinase (ADK), an adenosine metabolizing enzyme, modulates AAA formation via control of the intracellular adenosine level, and to investigate the underlying mechanisms.Methods and results We used a combination of genetic and pharmacological approaches in murine models of AAA induced by calcium chloride (CaCl2) application or angiotensin II (Ang II) infusion to study the role of ADK in the development of AAA. In vitro functional assays were performed by knocking down ADK with adenovirus-short hairpin RNA in human vascular smooth muscle cells (VSMCs), and the molecular mechanisms underlying ADK function were investigated using RNA-sequencing, isotope tracing, and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The heterozygous deficiency of ADK protected mice from CaCl2- and Ang II-induced AAA formation. Moreover, specific knockout of ADK in VSMCs prevented Ang II-induced AAA formation, as evidenced by reduced aortic extracellular elastin fragmentation, neovascularization, and aortic inflammation. Mechanistically, ADK knockdown in VSMCs markedly suppressed the expression of inflammatory genes associated with AAA formation, and these effects were independent of adenosine receptors. The metabolic flux and ChIP-qPCR results showed that ADK knockdown in VSMCs decreased S-adenosylmethionine (SAM)-dependent transmethylation, thereby reducing H3K4me3 binding to the promoter regions of the genes that are associated with inflammation, angiogenesis, and extracellular elastin fragmentation. Furthermore, the ADK inhibitor ABT702 protected mice from CaCl2-induced aortic inflammation, extracellular elastin fragmentation, and AAA formation.Conclusion Our findings reveal a novel role for ADK inhibition in attenuating AAA via epigenetic modulation of key inflammatory genes linked to AAA pathogenesis. Graphical Abstract