β-Nicotinamide mononucleotide prevents senescence and lipid accumulation in hepatic stellate cells by restoring SIRT1 function.

Aging is a chronic, destructive process characterized by the progressive breakdown of the body, leading to a loss of control over homeostasis. Glucose is the most important metabolite involved in metabolism and maintaining homeostasis in the human body. Glucose-based energy metabolism is fundamental to the activity and structural changes in the brain, which is the main regulator of life processes. Disturbances in energy metabolism and glucose-dependent metabolic processes have a decisive impact on the aging process. Age-related deficiency of the coenzyme NAD, which regulates glucose metabolism in neurons, leads to irreversible changes in the brain, culminating in senescence. Research on NAD precursors offers hope that although we cannot completely halt the aging process, NAD supplementation may enable healthy aging.

Acute kidney injury (AKI) is a critical public health concern with high morbidity and mortality. The chemotherapy agent cisplatin is widely used for various solid tumors; however, cisplatin-associated AKI (CIS-AKI) is a frequent complication in the clinic. Nicotinamide adenine dinucleotide (NAD+) is a coenzyme central to metabolism and redox reactions. β-Nicotinamide mononucleotide (NMN), a key precursor of NAD+, has shown protective effects in various disease models, but its role in CIS-AKI remains unclear. In this study, male mice subjected to CIS-AKI and cisplatin-treated HK-2 cells were employed as in vivo and in vitro models, respectively, to evaluate the renoprotective effects of NMN. Bulk RNA sequencing revealed marked inflammatory activation and disruption of NAD+ metabolism in cisplatin-treated mouse kidneys. NMN administration significantly ameliorated kidney dysfunction, as indicated by reduced plasma creatinine and blood urea nitrogen (BUN) levels, attenuated tubular injury, and decreased expression of kidney injury markers NGAL and KIM-1. It also markedly suppressed kidney inflammation, characterized by reduced IL-6 and IL-18 levels, diminished neutrophil infiltration and macrophage accumulation. Consistently, in vitro, NMN attenuated cisplatin-induced reactive oxygen species (ROS) generation and lactate dehydrogenase (LDH) release in HK-2 cells. Mechanistically, NMN elevated kidney NAD+ levels and enhanced SIRT1 expression. These findings demonstrate that NMN protects against CIS-AKI by activating the NAD+-SIRT1 pathway, thereby reducing oxidative stress and inflammation, and suggest its potential as a therapeutic strategy for CIS-AKI.

Nicotinamide mononucleotide rescues perinatal arsenic-induced autism-like behaviours via modulation of NAD+ metabolism in mice.

Primary open-angle glaucoma (POAG) is one of the leading ocular diseases leading to irreversible blindness and is often asymptomatic until advanced cases. While intraocular pressure reduction remains the cornerstone of treatment, neuroprotective strategies targeting retinal ganglion cell metabolism are actively investigated. Niacinamide (nicotinamide, vitamin B3), a precursor of NAD+, has shown neuroprotective potential in preclinical models. This exploratory study evaluated the short-term functional, structural, and electrophysiological effects of oral niacinamide supplementation in POAG. In this interventional study, patients with POAG received oral niacinamide 500 mg daily for six months. Visual field (VF) global and localized sensitivity (Mean Deviation [MD], Pattern Standard Deviation [PSD]), Optic Coherence Tomography (OCT)-derived peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC), and Visual evoked potentials (VEP) latency parameters (P2 1.4 Hz, P100 1°, and P100 15') were assessed at baseline and at six months. Because both eyes from some participants were included, primary longitudinal inference was based on clustered analyses using generalized estimating equations and linear mixed-effects models to account for inter-eye correlation. Eye-level paired analyses were used for exploratory comparison. Change-change relationships across modalities were explored using Spearman correlation. After accounting for inter-eye correlation, no statistically significant change in MD was detected (mean ΔMD +0.43 dB; GEE p = 0.099; LME p = 0.101), and PSD remained stable. RNFL thickness showed a small decrease (-1.26 µm; GEE p = 0.046), while GCC did not change significantly. VEP P100 latencies remained stable, whereas P2 latency showed a small increase (+3.9 ms; GEE p = 0.039). Correlation analysis revealed a moderate association between changes in GCC and MD (ρ = 0.44), suggesting concordance between macular structural stability and global visual field performance. When inter-eye correlation is appropriately accounted for, six months of niacinamide supplementation in POAG is associated with overall functional, structural, and electrophysiological stability, without evidence of clinically meaningful improvement or progression. These findings support short-term safety and highlight the importance of clustered analytical approaches and macular-centered biomarkers in future glaucoma neuroprotection trials.

BackgroundRunt-related transcription factor 2 (Runx2), a transcription factor of the RUNX family, is involved in various inflammatory diseases. However, the role of Runx2 was unclear in chronic obstructive pulmonary disease (COPD).MethodsPulmonary Runx2 level was compared in COPD patients and control subjects via a case-control study. Runx2 expression was detected in lung tissues of COPD mice and human bronchial epithelial (BEAS-2B) cells simulated with cigarette smoke extracts (CSE).ResultsPulmonary Runx2 expression was upregulated, and inversely associated with pulmonary function and positively correlated with inflammatory cytokines in COPD patients. Mechanistically, Runx2 activation facilitated the transcription of CDK8, a co-regulator of nuclear factor-κB (NF-κB), and inflammatory cytokines production. Luciferase report gene assay confirmed that CDK8 was the downstream target gene of Runx2. Further analysis found that CSE inhibited Runx2 ubiquitination and proteasomal degradation. Besides, CSE elevated nicotinamide adenine dinucleotide (NAD+) consumes and Sirtuin 3 (Sirt3) depletion. Additionally, Runx2 acetylation was increased in CSE-exposed BEAS-2B cells, lungs tissues from COPD mice and patients. Interestingly, Sirt3 overexpression or supplementation with Nicotinamide Riboside (NR), the precursor of NAD+, abolished CSE-induced Runx2 acetylation and Runx2-CDK8 axis activation. In vivo experiment further confirmed NR supplementation evidently mitigated cigarette smoke-induced a COPD-like phenotype in mice.ConclusionsThese results indicated that Sirt3 depletion-induced Runx2 acetylation contributes to CDK8 activation and pulmonary inflammation in the progression of COPD.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12931-025-03475-4.

Abstract Background and aims This project aims to investigate CD38, a multifunctional ectoenzyme regulating NAD metabolism, as a novel therapeutic target to prevent intestinal fibrosis in Crohn’s disease (CD). We hypothesize that CD38 promotes profibrotic activation of intestinal fibroblasts through NAD depletion and that its inhibition can mitigate fibrosis progression in CD. Supporting this, our preliminary data show increased CD38 expression in fibrotic regions of human CD surgical specimens and murine ileitis models. Spatial transcriptomics and pseudo time analysis indicate CD38 involvement in mesenchymal differentiation, and prior studies have shown antifibrotic effects of CD38 inhibition in other organs and diseases that share similarities with CD. Methods To test this hypothesis, we envision two specific aims: Aim 1 will evaluate whether CD38 drives fibroblast activation via NAD depletion. Human intestinal fibroblasts (CCD-18Co) will be stimulated with TNF or TGFβ, treated with an inhibitor of CD38 (78c) and the NAD precursor nicotinamide riboside, and assessed for fibrosis markers (COL1A1, ACTA2) and sirtuin activation. Aim 2 will determine the efficacy and mechanisms of CD38 inhibition in vivo using two Crohn’s-like ileitis and intestinal fibrosis models (SAMP1/YitFc and TnfΔARE/+ mice). Sub-aims include generating CD38-/- x TnfΔARE/+ mice to evaluate susceptibility to fibrosis, treating mice with 78c from 6 to 20 weeks of age to assess fibrosis prevention, and performing ileal transcriptomics to identify molecular pathways altered by CD38 inhibition. Anticipated impact This work is expected to demonstrate that CD38 inhibition reduces fibroblast activation and intestinal fibrosis in vitro and in vivo. Considering that drugs that target CD38 are already in use in other conditions, our findings may accelerate the development of antifibrotic therapies for CD resulting in reduced need for surgery and improved quality of life in CD patients.

Nicotinamide mononucleotide supplement combined with prolonging maturation time improves the quality of oocytes cultured in vitro.

Multifunctional nanocomposite chitosan-based hydrogel promotes healing of infected wounds through sustained release of Zn2+ and nicotinamide mononucleotide.

Introduction Radiation-induced intestinal injury (IR) is a common complication in patients with colorectal cancer (CRC) after radiotherapy. Currently, the search for effective treatments has become an urgent priority. Nicotinamide riboside (NR), the precursor of vitamin B3 derivative and NAD (+), was enriched in IR after treatment with commensal Bacteroides fragilis, suggesting that NR may perform a protective role. However, the specific role of NR in IR remains unclear. In this study, we investigated the therapeutic effects of NR on IR.Methods C57BL/6J, GsdmeΔIEC (lacking GSDME in intestinal epithelial cells, IECs), and wild-type littermates were treated with NR after abdominal radiation exposure at 10 Gy. The small intestinal crypt-derived organoids and cell lines FHC, NCM460, and IEC-6 were irradiated with or without administration of the SIRT1 inhibitor EX527 under NR stimulation. A series of assays were subsequently carried out to explore the therapeutic effects, the degree of IECs repair, and the underlying mechanism.Results NR significantly ameliorated IR in mice, as evidenced by reduced weight loss, shortened small intestinal and colonic length, improved histological associated index, and restored the intestinal flora, which increased the relative abundance of the commensal Muribaculaceae, and decreased the relative abundance of Escherichia_coli. Additionally, NR increased goblet cell density, increased crypt length, promoted Ki-67 and ZO-1 expression, reduced reactive oxygen species (ROS) levels, and maintained mitochondrial morphology in IECs. Mechanistically, NR activated SIRT1 and inhibited gasdermin E (GSDME)-induced pyroptosis. Further investigations using an experimental GsdmeΔIEC mouse model (lacking GSDME in IECs) and a SIRT1 inhibitor revealed that NR promoted intestinal barrier repair through GSDME inhibition in a SIRT1-dependent manner. Compared with those in healthy controls, the GSDME level in radiation-injured colorectal mucosa from CRC patients after radiotherapy increased with the downregulation of SIRT1, Ki-67, and ZO-1.Conclusion Our study demonstrated that NR mitigates IR by inhibiting GSDME-mediated pyroptosis and restoring IECs homeostasis. These findings suggest that NR could serve as a promising therapeutic strategy for IR following radiotherapy.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12967-025-07012-1.

Alcoholism is a significant contributor to the development of alcoholic liver disease, for which no universally accepted and effective treatment currently exists. A precursor of NAD+, β-Nicotinamide mononucleotide (NMN), has revealed potential therapeutic benefits. However, its effectiveness in preventing ethanol-induced liver damage remains uncertain. The objective of this study was to assess the protective effects of NMN and elucidate its potential mechanisms using a mouse model subjected to chronic and binge ethanol feeding. Eight-week-old C57BL/6J mice were randomly assigned to one of four groups (n = 10 per group): control (CTRL), ethanol (EtOH), ethanol with low-dose NMN (EtOH + NMN(L)), and ethanol with high-dose NMN (EtOH + NMN(H)). Following the completion of the experimental protocol, the mice were euthanized at designated time points, and blood, liver, and ileum tissues were collected for analysis of relevant biomarkers. Compared to the CTRL group, the EtOH group demonstrated increased liver specific gravity and elevated blood ALT levels. Administration of NMN improved histopathological changes in the liver and ileum of the mice. NMN significantly counteracted the ethanol-induced elevation in liver MDA levels and restored the diminished glutathione (GSH) and superoxide dismutase (SOD) activity levels caused by ethanol exposure. Additionally, NMN inhibited the ethanol-induced expression of cytochrome P450 2E1 (CYP2E1). It also reduced the release of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, which were triggered by ethanol exposure, improved energy homeostasis in the ileum, and reversed the downregulation of mRNA and protein expression of key tight junction proteins in the ileum, specifically ZO-1, Claudin-1, and Occludin, thereby restoring their functional integrity. Furthermore, NMN activated the NAD+/ SIRT1 signaling pathway, leading to the upregulation of all target genes. NMN supplementation provides protection against alcoholic liver injury in a mouse model, potentially through the upregulation of the cellular NAD+/ SIRT1 pathway. This upregulation enhances antioxidant and anti-inflammatory activities and improves intestinal permeability.

Age-related declines in neuronal bioenergetic levels may limit vesicular trafficking and autophagic clearance of damaged organelles and proteins. Age-related ATP depletion would impact cognition dependent on ionic homeostasis, but limits on proteostasis powered by GTP are less clear. We used neurons isolated from aged 3xTg-AD Alzheimer's model mice and a novel genetically encoded fluorescent GTP sensor (GEVAL) to evaluate live GTP levels in situ. We report an age-dependent reduction in ratiometric measurements of free/bound GTP levels in living hippocampal neurons. Free GTP colocalized in the mitochondria decreased with age accompanied by the accumulation of free GTP-labeled vesicular structures. The energy dependence of autophagy was demonstrated by depletion of GTP with rapamycin stimulation, while bafilomycin inhibition of autophagy raised GTP levels. Twenty-four-hour supplementation of aged neurons with the NAD precursor nicotinamide and the Nrf2 redox modulator EGCG restored GTP levels to youthful levels and mobilized endocytosis and lysosomal consumption for autophagy via the respective GTPases Rab7 and Arl8b. This vesicular mobilization promoted the clearance of intraneuronal Aβ aggregates, improved viability, and lowered protein oxidative nitration in AD model neurons. Our results reveal age- and AD-related neuronal GTP energy deficits that impair autophagy and endocytosis. GTP deficits were remediated by an external NAD precursor together with a Nrf2 redox modulator which suggests a translational path.

Administration of β-Nicotinamide Mononucleotide Attenuates Myocardial Dysfunction in Tail-Suspended Mice.

ABSTRACTNicotinamide adenine dinucleotide (NAD) is an essential cofactor in hundreds of cellular processes. Genetic disruption of NAD de novo synthesis causes congenital NAD deficiency disorder (CNDD), characterized by multiple congenital malformations or death in utero. Patient outcomes are highly variable, likely due to differences in the availability of maternal NAD precursors vitamin B3 and tryptophan to the embryo and its extraembryonic tissues. Here, maternal plasma and yolk sac NAD metabolomes, embryonic NAD levels, and pregnancy outcomes were quantified in a CNDD mouse model to determine how maternal circulatory NAD precursor provision affects pregnancy outcome and to identify metabolic markers of CNDD risk. Maternal levels of nicotinamide positively correlated with embryonic NAD levels, highlighting its central role for embryonic NAD metabolism. Levels of nicotinamide‐derived excretion metabolites were the best predictors of adverse pregnancy outcome. NAD metabolomic analysis of pregnant women confirmed the relationship between dietary NAD precursor intake and circulatory nicotinamide and derived excretion product levels seen in mice, as women taking vitamin B3 supplements had elevated levels. Furthermore, mouse embryos with genetic disruption of NAD de novo synthesis (Haao−/−) were more susceptible to CNDD when maternal circulatory nicotinamide was limited, as their yolk sacs cannot generate NAD de novo from tryptophan. Metabolites originating from Haao−/− embryos were detectable in maternal plasma, showing that embryonic NAD metabolism also affects maternal circulation. Together, our findings elucidate the complex interplay between NAD metabolism of mother and conceptus and identify metabolic markers in maternal circulation that predict risk of NAD deficiency‐related adverse pregnancy outcomes.

β-nicotinamide mononucleotide (NMN), a precursor of NAD+, holds promise as a functional food ingredient for mitigating age-related decline. This study enhanced NMN biosynthesis in probiotic Lactiplantibacillus plantarum. A putative niacin transporter, lp2514, was identified via molecular docking and validated by CRISPR/Cas9. A dual-copy expression strategy was also employed to increase NMN production. In parallel, RNA-seq was used to analyze genome-wide transcriptional changes associated with enhanced NMN biosynthesis. Overexpression of lp2514 increased NMN production by 62.3%, and a dual-copy strategy raised NMN titers to 203 μmol L-1-269% increase compared to empty-vector control without NAM and the highest yield reported in lactic acid bacteria. Transcriptomic analysis revealed 598 differentially expressed genes, including upregulated ribosomal proteins (rpsJ, rplE) and NAD+ salvage enzymes (aspA), indicating enhanced translation and precursor flux. Deleting cinA, encoding a metabolic constraint, further boosted NMN levels, confirming transcriptomic predictions. This combined transporter engineering and transcriptome-guided strategy establishes a food-grade L. plantarum platform for efficient NMN production in functional fermented foods.

Nicotinamide riboside promoted cardiac energetics and alleviated doxorubicin-induced cardiotoxicity via SIRT1/ERRα signal in human pluripotent stem cells-derived cardiomyocytes.

Effects of NAD+ supplementation with oral nicotinamide riboside on vascular health and cognitive function in older adults with peripheral artery disease: Results from a pilot 4-week open-label clinical trial.

NAD is an important metabolite that functions as a cofactor in various metabolic reactions, and its biosynthesis is known to be upregulated during malignant transformation. The NAD salvage, in which NAMPT is a rate-limiting enzyme, is a predominant pathway for NAD synthesis in most tissues including cancer. However, less is known about how cancer sensitivity against NAMPT inhibition (NAMPTi) is dictated. Here we report that lung and prostate neuroendocrine carcinomas (NECs) are extremely vulnerable to NAMPTi and that the therapeutic effect of NAMPTi is markedly enhanced by dietary restriction of the NAD precursor, niacin. We found that de novo NAD synthesis is inactivated during neuroendocrine differentiation of tumor cells, leading to a high dependence of NEC cells on NAD salvage. Further investigations in mouse transplantation models showed that lowering blood levels of nicotinic acid riboside (NAR), one of the non-classical niacin, dramatically increases the therapeutic effect of NAMPTi on NEC. Metabolic studies showed that dietary nicotinic acid is converted to NAR and then released into the circulation, and NAD synthesis using NAR substrates can compensate for the effects of NAMPTi in tumor cells. These findings reveal that niacin restriction with NAMPTi is synthetic lethal to NECs.

Diabetes is a prevalent metabolic disorder, and its associated microvascular dysfunction plays a key role in the pathogenesis of complications such as retinopathy, nephropathy, and peripheral vascular disease. However, the mechanism governing metabolic regulation and functional heterogeneity of endothelial dysfunction remains incompletely understood. This study investigates the role of metabolic stress‐induced activation of choline kinase α (CHKA) in endothelial cell (EC) subpopulations, contributing to diabetes‐induced microvascular dysfunction. Using single‐cell RNA sequencing (scRNA‐seq), three distinct EC subclusters are identified within retinal vessels. Among them, one subcluster characterized by elevated CHKA expression is associated with enhanced angiogenic activity. CHKA silencing in ECs inhibited angiogenic effects and reduced retinal vascular dysfunction in diabetic murine models. CHKA silencing also disrupted NAD+ metabolism, causing reduced NAD+ levels. Supplementation with nicotinamide mononucleotide (NMN), a precursor of NAD+, partially reversed the anti‐angiogenic effects induced by CHKA silencing. Mechanistically, CHKA regulated endothelial dysfunction through the NAD+‐SIRT1‐Notch signaling. Clinical sample analysis and Mendelian randomization studies provided strong evidence linking increased CHKA expression with diabetic microvascular complications. Collectively, this study advances the understanding of endothelial heterogeneity and identifies CHKA as a critical regulator of pathological angiogenesis, highlighting its potential as a therapeutic target for diabetic vascular complications.

Age-related declines in neuronal bioenergetic levels may limit vesicular trafficking and autophagic clearance of damaged organelles and proteins. Age-related ATP depletion would impact cognition dependent on ionic homeostasis, but limits on proteostasis powered by GTP are less clear. We used neurons isolated from aged 3xTg-AD Alzheimer's model mice and a novel genetically encoded fluorescent GTP sensor (GEVAL) to evaluate live GTP levels in situ. We report an age-dependent reduction in ratiometric measurements of free/bound GTP levels in living hippocampal neurons. Free-GTP co-localized in the mitochondria decreased with age accompanied by the accumulation of free-GTP labeled vesicular structures. The energy dependence of autophagy was demonstrated by depletion of GTP with rapamycin stimulation, while bafilomycin inhibition of autophagy raised GTP levels. 24 hr. supplementation of aged neurons with the NAD precursor nicotinamide and the Nrf2 redox modulator EGCG restored GTP levels to youthful levels and mobilized endocytosis and lysosomal consumption for autophagy via the respective GTPases Rab7 and Arl8b. This vesicular mobilization promoted the clearance of intraneuronal Aβ aggregates and lowered protein oxidative nitration in AD model neurons. Our results reveal age- and AD-related neuronal GTP energy deficits that impair autophagy and endocytosis. GTP deficits were remediated by an external NAD precursor together with a Nrf2 redox modulator which suggests a translational path.