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Aging is associated with metabolic dysfunction and cardiovascular abnormalities. Defective nicotinamide adenine dinucleotide (NAD+) biosynthesis correlates with aging and aging‐associated complications. However, the precise molecular mechanisms linking aging‐associated NAD+ deficiency to cardiometabolic dysfunction remain unclear. Herein, we examined whether nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD+ biosynthesis, influences vascular endothelial function and whole‐body metabolic and hemodynamic homeostasis during aging. Vascular endothelial cell–specific Nampt knockout (VeNKO) mice fed a regular chow diet exhibited no cardiometabolic abnormalities, whereas male VeNKO mice fed a high‐fat diet exhibited reduced angiogenesis, resulting in impaired subcutaneous adipogenesis, impaired glucose metabolism, and hemodynamic disturbances. Mechanistically, NAMPT loss attenuated NAD+‐dependent deacetylase sirtuin‐1 (SIRT1) and endothelial nitric oxide synthase (eNOS) signaling, impairing angiogenesis. Aged mice exhibited endothelial NAD+ depletion driven by an imbalance between NAMPT‐mediated NAD+ biosynthesis and consumption, leading to impaired eNOS signaling and associated angiogenic and cardiometabolic dysfunction, similar to that observed in VeNKO mice. Nicotinamide mononucleotide administration replenished vascular endothelial NAD+ levels, improved angiogenesis, restored subcutaneous adipose tissue volume, and ameliorated aging‐associated cardiometabolic dysfunction. Collectively, our findings provide mechanistic and therapeutic insights into vascular endothelial NAMPT–NAD+–SIRT1–eNOS signaling related to aging‐associated cardiometabolic disorders. Using male vascular endothelial cell–specific Nampt knockout and naturally aged mice, we identified endothelial NAD+ deficiency as a central driver of age‐related angiogenic failure, impaired subcutaneous adipogenesis, and cardiometabolic dysfunction. NAD+ deficiency disrupts SIRT1‐dependent eNOS regulation by reducing Ser‐1177 phosphorylation and increasing acetylation, thereby attenuating angiogenesis. Restoring endothelial NAD+ levels with nicotinamide mononucleotide improves angiogenesis, subcutaneous adipose tissue volume, and cardiometabolic function, highlighting the NAMPT–NAD+–SIRT1–eNOS axis as a mechanistic and therapeutic target in aging‐associated cardiometabolic diseases.

Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD⁺). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD⁺ synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival. Pharmacological and genetic inhibition of NAMPT decreased NAD⁺ levels and GSC self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs. Regulatory network analysis of RNA sequencing data using GSCs treated with NAMPT inhibitor identified transcription factor E2F2 as the center of a transcriptional hub in the NAD⁺-dependent network. Accordingly, we demonstrate E2F2 is required for GSC selfrenewal. Downstream, E2F2 drives the transcription of members of the inhibitor of differentiation (ID) helix–loop–helix gene family. Finally, we find NAMPT mediates GSC radiation resistance. The identification of a NAMPT-E2F2-ID axis establishes a link between NAD+ metabolism and a self-renewal transcriptional program in glioblastoma, with therapeutic implications for this formidable cancer.

Background Emerging research has reported that circular RNAs (circRNAs) play important roles in cardiac cell death after myocardial ischemia and reperfusion (I/R). Ferroptosis, a new form of cell death discovered in recent years, has been proven to participate in the regulation of myocardial I/R. This study used circRNA sequencing to explore the key circRNA in the regulation of cardiac ferroptosis after I/R and study the mechanisms of potential circRNA function. Methods We performed circRNA sequencing to explore circRNAs differentially expressed after myocardial I/R. We used quantitative polymerase chain reactions to determine the circRNA expression in different tissues and detect the circRNA subcellular localization in the cardiomyocyte. Gain- and loss-of-function experiments were aimed to examine the function of circRNAs in cardiomyocyte ferroptosis and cardiac tissue damage after myocardial I/R. RNA pull-down was applied to explore proteins interacting with circRNA. Results Here, we identified a ferroptosis-associated circRNA (FEACR) that has an underlying regulatory role in cardiomyocyte ferroptosis. FEACR overexpression suppressed I/R-induced myocardial infarction and ameliorated cardiac function. FEACR inhibition induces ferroptosis in cardiomyocytes and FEACR overexpression inhibits hypoxia and reoxygenation-induced ferroptosis. Mechanistically, FEACR directly bound to nicotinamide phosphoribosyltransferase (NAMPT) and enhanced the protein stability of NAMPT, which increased NAMPT-dependent Sirtuin1 (Sirt1) expression, which promoted the transcriptional activity of forkhead box protein O1 (FOXO1) by reducing FOXO1 acetylation levels. FOXO1 further upregulated the transcription of ferritin heavy chain 1 ( Fth1 ), a ferroptosis suppressor, which resulted in the inhibition of cardiomyocyte ferroptosis. Conclusions Our finding reveals that the circRNA FEACR-mediated NAMPT-Sirt1-FOXO1-FTH1 signaling axis participates in the regulation of cardiomyocyte ferroptosis and protects the heart function against I/R injury. Thus, FEACR and its downstream factors could be novel targets for alleviating ferroptosis-related myocardial injury in ischemic heart diseases.

Ulcerative colitis (UC), a chronic inflammatory bowel disease with rising global incidence, involves neutrophil-driven mucosal damage. The precise mechanisms remain elusive, hindering targeted therapies. Therefore, this study aims to integrate single-cell transcriptomics with in vivo experiments to reveal the key signaling axes driving pathogenic neutrophil activation in UC. Single-cell transcriptomics characterized UC inflammatory microenvironments, focusing on neutrophil functional states and intercellular interactions. Based on key findings from bioinformatics analysis, we hypothesize that the eNAMPT-integrin α5β1 signaling axis drives abnormal neutrophil-endothelial cell communication and functionally validate this hypothesis in in vivo models. Neutrophils exhibited aberrant activation and significant overexpression in UC. Extracellular eNAMPT functioned as a signaling molecule binding endothelial integrin α5β1, mediating pathological neutrophil-endothelial crosstalk. Pharmacological blockade of the eNAMPT/integrin α5β1 axis inhibited neutrophil mucosal infiltration, reducing inflammation and tissue damage in UC mouse models. The eNAMPT-integrin α5β1-mediated neutrophil-endothelial communication axis represents a novel pathogenic pathway in UC, providing a foundation for precision therapies targeting this mechanism.

Yongcheng Di,1,2,* Wenbin Ji,1,2,* Wenhao Xiong,1,2,* Wenbin Song,1,2 Guoshan Chen,1,2 Danzhou Li,1,2 Feng Qi1,2 1Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Feng Qi, Email fengqi01@tmu.edu.cnBackground: Ulcerative colitis (UC), a chronic inflammatory bowel disease with rising global incidence, involves neutrophil-driven mucosal damage. The precise mechanisms remain elusive, hindering targeted therapies. Therefore, this study aims to integrate single-cell transcriptomics with in vivo experiments to reveal the key signaling axes driving pathogenic neutrophil activation in UC.Methods: Single-cell transcriptomics characterized UC inflammatory microenvironments, focusing on neutrophil functional states and intercellular interactions. Based on key findings from bioinformatics analysis, we hypothesize that the eNAMPT-integrin α 5β 1 signaling axis drives abnormal neutrophil-endothelial cell communication and functionally validate this hypothesis in in vivo models.Results: Neutrophils exhibited aberrant activation and significant NAMPT overexpression in UC. Extracellular eNAMPT functioned as a signaling molecule binding endothelial integrin α 5β 1, mediating pathological neutrophil-endothelial crosstalk. Pharmacological blockade of the eNAMPT/integrin α 5β 1 axis inhibited neutrophil mucosal infiltration, reducing inflammation and tissue damage in UC mouse models.Conclusion: The eNAMPT-integrin α 5β 1-mediated neutrophil-endothelial communication axis represents a novel pathogenic pathway in UC, providing a foundation for precision therapies targeting this mechanism.Keywords: ulcerative colitis, neutrophils, endothelial cells, NAMPT, bioinformatics

Aging is associated with a loss of metabolic homeostasis, with cofactors such as nicotinamide adenine dinucleotide (NAD+) declining over time. The decrease in NAD+ production has been linked to the age‐related loss of circulating extracellular nicotinamide phosphoribosyltransferase (eNAMPT), the rate‐limiting enzyme in the NAD+ biosynthetic pathway. eNAMPT is found almost exclusively in extracellular vesicles (EVs), providing a mechanism for the distribution of the enzyme in different tissues. Currently, the physiological cause for the release of eNAMPT is unknown, and how it may be affected by age and physical exercise. Here, we show that release of small EVs into the bloodstream is stimulated following moderate intensity exercise in humans. Exercise also increased the eNAMPT content in EVs, most prominently in young individuals with higher aerobic fitness. Both mature fit and young unfit individuals exhibited a limited increase in EV‐eNAMPT release following exercise, indicating that this mechanism is related to both the age and physical fitness of a person. Notably, unfit mature individuals were unable to increase the release of eNAMPT in EVs after exercise, suggesting that lower fitness levels and aging attenuate this important signalling mechanism in the body. EVs isolated from exercising humans containing eNAMPT were able to alter the abundance of NAD+ and SIRT1 activity in recipient cells compared to pre‐exercise EVs, indicating a pathway for inter‐tissue signalling promoted through exercise. Our results suggest a mechanism to limit age‐related NAD+ decline, through the systemic delivery of eNAMPT via EVs released during exercise. Aging is associated with decreased NAD+ production, which is critical for maintaining tissue and metabolic homeostasis. Here, we identified that moderate intensity exercise in humans can result in the release of NAMPT in extracellular vesicles, that when delivered to recipient cells promotes NAD+ biosynthesis and SIRT1 activity. Our findings show an exercise‐based mechanism for the production of NAD+ that differs between age groups, moderated by the release of eNAMPT in EVs.

Nicotinamide phosphoribosyltransferase (NAMPT) has been implicated in neuroprotection against ischemic brain injury, but the mechanism underlying its protective effect remains largely unknown. To further examine the protective effect of NAMPT against ischemic stroke and its potential mechanism of action, we generated a novel neuron-specific NAMPT transgenic mouse line. Transgenic mice and wild-type littermates were subjected to transient occlusion of the middle cerebral artery (MCAO) for 60 minutes. Neuron-specific NAMPT overexpression significantly reduced infarct volume by 65% (P = 0.018) and improved long-term neurologic outcomes (P ≤ 0.05) compared with littermates. Interestingly, neuronal overexpression of NAMPT increased the area of myelinated fibers in the striatum and corpus callosum, indicating that NAMPT protects against white matter injury. The mechanism of protection appeared to be through extracellular release of NAMPT. First, NAMPT was secreted into the extracellular medium by primary cortical neurons exposed to ischemia-like oxygen–glucose deprivation (OGD) in vitro. Second, conditioned medium from NAMPT-overexpressing neurons exposed to OGD protected cultured oligodendrocytes from OGD. Third, the protective effects of conditioned medium were abolished by antibody-mediated NAMPT depletion, strongly suggesting that the protective effect is mediated by the extracellular NAMPT released into in the medium. These data suggest a novel neuroprotective role for secreted NAMPT in the protection of white matter after ischemic injury.

Background Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis, is up-regulated in several cancers, including metastatic melanoma (MM). The BRAF oncogene is mutated in different cancer types, among which MM and thyroid carcinoma (THCA) are prominent. Drugs targeting mutant BRAF are effective, especially in MM patients, even though resistance rapidly develops. Previous data have linked NAMPT over-expression to the acquisition of BRAF resistance, paving the way for therapeutic strategies targeting the two pathways. Methods Exploiting the TCGA database and a collection of MM and THCA tissue microarrays we studied the association between BRAF mutations and NAMPT expression. BRAF wild-type (wt) cell lines were genetically engineered to over-express the BRAF V600E construct to demonstrate a direct relationship between over-activation of the BRAF pathway and NAMPT expression. Responses of different cell line models to NAMPT (i)nhibitors were studied using dose–response proliferation assays. Analysis of NAMPT copy number variation was performed in the TCGA dataset. Lastly, growth and colony forming assays were used to study the tumorigenic functions of NAMPT itself. Results The first finding of this work is that tumor samples carrying BRAF -mutations over-express NAMPT, as demonstrated by analyzing the TCGA dataset, and MM and THC tissue microarrays. Importantly, BRAF wt MM and THCA cell lines modified to over-express the BRAF V600E construct up-regulated NAMPT, confirming a transcriptional regulation of NAMPT following BRAF oncogenic signaling activation. Treatment of BRAF -mutated cell lines with two different NAMPTi was followed by significant reduction of tumor growth, indicating NAMPT addiction in these cells. Lastly, we found that several tumors over-expressing the enzyme, display NAMPT gene amplification. Over-expression of NAMPT in BRAF wt MM cell line and in fibroblasts resulted in increased growth capacity, arguing in favor of oncogenic properties of NAMPT. Conclusions Overall, the association between BRAF mutations and NAMPT expression identifies a subset of tumors more sensitive to NAMPT inhibition opening the way for novel combination therapies including NAMPTi with BRAFi/MEKi, to postpone and/or overcome drug resistance. Lastly, the over-expression of NAMPT in several tumors could be a key and broad event in tumorigenesis, substantiated by the finding of NAMPT gene amplification.

Nicotinamide (NAM), a form of vitamin B 3 , plays essential roles in cell physiology through facilitating NAD + redox homeostasis and providing NAD + as a substrate to a class of enzymes that catalyze non-redox reactions. These non-redox enzymes include the sirtuin family proteins which deacetylate target proteins while cleaving NAD + to yield NAM. Since the finding that NAM exerts feedback inhibition to the sirtuin reactions, NAM has been widely used as an inhibitor in the studies where SIRT1, a key member of sirtuins, may have a role in certain cell physiology. However, once administered to cells, NAM is rapidly converted to NAD + and, therefore, the cellular concentration of NAM decreases rapidly while that of NAD + increases. The result would be an inhibition of SIRT1 for a limited duration, followed by an increase in the activity. This possibility raises a concern on the validity of the interpretation of the results in the studies that use NAM as a SIRT1 inhibitor. To understand better the effects of cellular administration of NAM, we reviewed published literature in which treatment with NAM was used to inhibit SIRT1 and found that the expected inhibitory effect of NAM was either unreliable or muted in many cases. In addition, studies demonstrated NAM administration stimulates SIRT1 activity and improves the functions of cells and organs. To determine if NAM administration can generate conditions in cells and tissues that are stimulatory to SIRT1, the changes in the cellular levels of NAM and NAD + reported in the literature were examined and the factors that are involved in the availability of NAD + to SIRT1 were evaluated. We conclude that NAM treatment can hypothetically be stimulatory to SIRT1.

Visfatin/NAMPT (nicotinamide phosphoribosyltransferase) is an adipocytokine with several intriguing properties. It was first identified as pre-B-cell colony-enhancing factor but turned out to possess enzymatic functions in nicotinamide adenine dinucleotide biosynthesis, with ubiquitous expression in skeletal muscles, liver, cardiomyocytes, and brain cells. Visfatin exists in an intracellular (iNAMPT) and extracellular (eNAMPT) form. Intracellularly, visfatin/iNAMPT plays a regulatory role in NAD+ biosynthesis and thereby affects many NAD-dependent proteins such as sirtuins, PARPs, MARTs and CD38/157. Extracellularly, visfatin is associated with many hormone-like signaling pathways and activates some intracellular signaling cascades. Importantly, eNAMPT has been associated with several metabolic disorders including obesity and type 1 and 2 diabetes. In this review, a brief overview about visfatin is presented with special emphasis on its relevance to metabolic diseases. Visfatin/NAMPT appears to be a unique molecule with clinical significance with a prospective promising diagnostic, prognostic, and therapeutic applications in many cardiovasculo-metabolic disorders.