The FASEB Journal最新文献

{"title":"EDIL3 Deficiency Attenuates Liver Fibrosis Through Inhibiting Hepatic Stellate Cells Activation via the Integrin αvβ3-ERK1/2-RUNX2 Axis in MASH Mice","authors":"Cheng Wei,&nbsp;Dongwei Lu,&nbsp;Jianfang Liu,&nbsp;Juan-Juan Qin,&nbsp;Menglong Wang,&nbsp;Fang Lei","doi":"10.1096/fj.202403088R","DOIUrl":"https://doi.org/10.1096/fj.202403088R","url":null,"abstract":"<div>\u0000 \u0000 <p>Metabolic Dysfunction-Associated Steatohepatitis (MASH) emerges as an advanced stage of Metabolic Dysfunction-Associated Steatotic Liver Disease, marked by significant liver damage characterized by fat accumulation, inflammation, hepatocyte injury, and progressive fibrosis. Epidermal Growth Factor-like repeat and Discoidin I-like domain-containing protein 3 (EDIL3), a protein containing epidermal growth factor-like repeats and discoidin I-like domains, interacts with membrane integrins to modulate inflammation, fibrosis, and vascular remodeling. However, the potential role of EDIL3 in the progression of liver fibrosis in MASH remains unclear. Our study unveiled a significant correlation between plasma EDIL3 levels and liver fibrosis severity in a UK Biobank population. In choline-deficient, L-amino acid-defined high-fat diet-induced MASH mouse models, EDIL3 liver expression was markedly upregulated, whereas EDIL3 deficiency mitigated liver damage, lipid accumulation, and fibrosis. Transcriptomic analysis indicated that EDIL3 deficiency substantially impacts extracellular matrix-related processes and inhibits Hepatic Stellate Cells (HSCs) activation in MASH. Mechanistically, EDIL3 binds to integrin αvβ3, activating HSCs via the ERK1/2-RUNX2 pathway. In summary, our findings demonstrate that EDIL3 regulates HSC activation through the integrin αvβ3-ERK1/2-RUNX2 axis, influencing liver fibrosis in MASH, thus offering a potential therapeutic avenue for MASH and fibrotic liver diseases.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sirt1-Mediated Transcriptional Inhibition of Nr4a3 Alleviates Severe Acute Pancreatitis-Associated Acute Lung Injury","authors":"Xiaolin Dou,&nbsp;Zhongcheng Zhu,&nbsp;Qizhen Chen,&nbsp;Yebin Lu","doi":"10.1096/fj.202501210R","DOIUrl":"https://doi.org/10.1096/fj.202501210R","url":null,"abstract":"<div>\u0000 \u0000 <p>Acute lung injury (ALI) is closely associated with high mortality in severe acute pancreatitis (SAP). Nr4a3 is a nuclear receptor with proinflammatory effects. The role of Nr4a3 in SAP-associated ALI is unclear. Caerulein (CRE)-induced AP mice represented significant pancreatic and lung pathological injury, with high Nr4a3 expression in lung tissues. Nr4a3 expression in lung tissues of AP mice inhibited CD31 expression, suggesting lung microvascular injury. In vitro and in vivo experiments were performed to investigate the effect of Nr4a3 inhibition in mitigating SAP-associated ALI. Nr4a3 downregulation reduced permeability, increased trans-endothelial electrical resistance (TEER) and VE-cadherin expression in TNF-α-induced human pulmonary microvascular endothelial cells (hPMVECs), suggesting recovered endothelial barrier function. Nr4a3 knockdown attenuated lung injury in AP mice, as reflected by restored lung edema and endothelial barrier function. Reduced inflammatory cell counts and mediators indicated that Nr4a3 knockdown mitigated lung inflammation in AP mice. The up-regulation of Nr4a3 in TNF-α-induced hPMVECs was further elevated after Sirt1 (a deacetylase) inhibition. Mechanistically, Sirt1 deficiency increased the enrichment of CREB at the Nr4a3 promoter through acetylating H3K27, thereby promoting Nr4a3 expression. Rescue experiments in vivo demonstrated that Nr4a3 knockdown attenuated lung injury aggravated by Sirt1 inhibition. These results suggested that Sirt1 might prevent CREB enrichment by inhibiting histone acetylation in the Nr4a3 promoter, thereby suppressing Nr4a3 expression and ultimately attenuating ALI.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Exopolysaccharide, Highly Prevalent in Marine Spongiibacter, Triggers Pyroptosis to Exhibit Potent Anticancer Effects","authors":"Ge Liu,&nbsp;Yeqi Shan,&nbsp;Chaomin Sun","doi":"10.1096/fj.202500412R","DOIUrl":"https://doi.org/10.1096/fj.202500412R","url":null,"abstract":"<div>\u0000 \u0000 <p>Pyroptosis is an inflammatory programmed cell death. In recent years, the potential of pyroptosis in tumor treatment has received widespread attention and has become a promising anti-tumor therapeutic strategy. EPS3.9 is a novel deep-sea bacterial exopolysaccharide that we obtained and has potent anti-tumor activity. EPS3.9 consisted of mannose and glucose with a molar ratio of 1:0.42. The average molecular weight of EPS3.9 was 17.1 kDa. EPS3.9 can induce lytic cell death in tumor cells. Mechanism analysis has revealed that it can directly target 5 membrane phospholipids and exert tumor cytotoxic activity through triggering NLRP3 inflammasome-mediated pyroptosis in the human monocytic leukemia THP-1 cells. EPS3.9 also has significant anti-tumor effects in Huh7.5 tumor-bearing mice and can activate anti-tumor immune responses. Besides, this active exopolysaccharide is ubiquitous among the genus <i>Spongiibacter</i>. This study provides an important theoretical basis for EPS3.9 as a new type of marine carbohydrate anti-tumor drug candidate and also provides scientific evidence for the feasibility and potential of tumor treatment by triggering pyroptosis.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering Nanoparticles and Bioscaffolds for Targeted microRNA Delivery in Cardiovascular Regeneration—A Comprehensive Review","authors":"Jekhan Andimadam Madana Saravanan,&nbsp;Azam Ali,&nbsp;Rajesh Katare","doi":"10.1096/fj.202501226RR","DOIUrl":"https://doi.org/10.1096/fj.202501226RR","url":null,"abstract":"<p>Cardiovascular diseases, particularly myocardial infarction (MI), remain a leading cause of mortality worldwide, primarily due to the extensive loss of cardiomyocytes and the heart's limited regenerative capacity. MI, caused by obstructed blood flow, results in cardiac muscle damage, scar tissue formation, and ultimately, heart failure. While heart transplantation is the definitive treatment, its application is limited by donor shortages and the risk of immune rejection. This underscores the urgent need for regenerative strategies. MicroRNAs (miRNAs) play a crucial role in regulating myocardial healing post-ischemia, with specific miRNAs such as miR-92a, miR-126, and miR-145 shown to promote angiogenesis. However, the therapeutic application of miRNAs is hindered by delivery challenges at both extracellular and intracellular levels. This review explores the potential of nanoparticles (NPs) and engineered bioscaffolds to address these obstacles. We first examine the role of miRNAs in post-MI cardiovascular remodeling, followed by an overview of current challenges in miRNA-based therapy delivery. We then discuss the use of NPs and electrospun nanofibrous scaffolds in this context. Finally, we review existing cardiac bioscaffolds, their limitations, and future directions for developing optimized nanofibrous scaffolds for effective cardiac regeneration.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501226RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the Nicotinamide Adenine Dinucleotide Biosynthesis Pathway and Regulatory Mechanisms in Streptococcus mutans","authors":"Haojie Yu,&nbsp;Dandan Shao,&nbsp;Yuheng Zhao,&nbsp;Shuojie Lv,&nbsp;Ruoxi Tao,&nbsp;Yu Sang,&nbsp;Jie Ren,&nbsp;Paul R Cooper,&nbsp;Qingjing Wang","doi":"10.1096/fj.202500944R","DOIUrl":"https://doi.org/10.1096/fj.202500944R","url":null,"abstract":"<p>NAD⁺ and its derivatives, which act as redox coenzymes, are crucial for cellular metabolism and energy production. Nevertheless, the processes by which <i>Streptococcus mutans</i>, a bacterium known for causing dental caries, synthesizes NAD⁺ are not well elucidated. Through a genome-wide screen, we identified the nicotinic acid salvage pathway and the evolutionarily incomplete PnuC–NadR pathway involved in NAD⁺ biosynthesis in <i>S. mutans</i> UA159. The nicotinic acid pathway is regulated by <i>Sm</i>NiaR, a nicotinic acid-responsive transcription regulator featuring an N-terminal DNA-binding winged helix-turn-helix-like domain and a C-terminal 3-histidine domain. Notably, a single-site amino acid substitution at site K97 in <i>Sm</i>NiaR can reverse its DNA-binding ability, an effect mediated by acetylation at this site, which impacts the intracellular production of NAD⁺ and NADH. Additionally, the deletion of <i>niaR</i> in <i>S. mutans</i> UA159 impaired bacterial proliferation, reduced acid production, and altered biofilm formation, resulting in attenuated virulence in the rat caries model. Conclusively, the regulation of NAD⁺ homeostasis via <i>Sm</i>NiaR contributes significantly to the cariogenic virulence of <i>S. mutans</i>.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500944R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144672631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Type III Secretion Effector SsPH2 of Salmonella enterica Targets LMO4 for Ubiquitination and Degradation","authors":"Chenmei He,&nbsp;Jiayu Cong,&nbsp;Ting Wang,&nbsp;Chuan Xia","doi":"10.1096/fj.202500636R","DOIUrl":"https://doi.org/10.1096/fj.202500636R","url":null,"abstract":"<div>\u0000 \u0000 <p>The type III secretion systems (T3SSs) of <i>Salmonella enterica</i> are encoded by genes located in the <i>Salmonella</i> pathogenicity islands 1 and 2 (SPI-1 and SPI-2), which are essential for virulence. T3SSs mediate the translocation of effectors into the eukaryotic host cells, where the effectors alter cell signaling and manipulate cell functions. However, how these effectors interact with host cells is incompletely understood. Identification of the cellular binding partners could help us investigate the roles of the effectors. Here, using <i>Salmonella</i> SPI-2 T3SS effector SsPH2 as a bait, we performed a yeast two-hybrid screen and identified a LIM domain family protein LMO4 as a binding partner for SsPH2. This interaction was further confirmed by GST pull-down, coimmunoprecipitation, and immunofluorescence microscopy analysis. Interestingly, we determined that the expression of SsPH2 alters the subcellular localization of LMO4. Further, we revealed that the leucine-rich repeat (LRR) domain of SsPH2 and the two LIM domains of LMO4 are critical for the interaction. We demonstrated that SsPH2 mediates the Lysine 48 (K48)-linked poly-ubiquitination of LMO4 in vivo and in vitro. The Lysine 29 and Lysine 67 within the LIM domains were proven to be the major ubiquitination sites of LMO4. Furthermore, we determined that SsPH2 downregulates the levels of LMO4 by inducing the ubiquitination and proteasome-dependent degradation of LMO4. Importantly, the expression of SsPH2 destabilizes the IL-6 receptor component gp130, inhibiting the STAT3 activation. SsPH2 was also found to suppress cell migration while enhancing apoptosis. Overall, this work identifies LMO4 as a novel cellular target and ubiquitination substrate for <i>Salmonella enterica</i> effector SsPH2 and reveals new insights into the interplay between bacteria and the host cells.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144672888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2-Induced Phosphorylation of HSPA9 at Ser627: Potential Implications for Mitochondrial Function, Cell Cycle Regulation, and Immune Evasion","authors":"Zi-Xiang Guo,&nbsp;Can Xie,&nbsp;Xian-Xin Lai,&nbsp;Yu-Qing Zhang,&nbsp;Yi Gao,&nbsp;Ruo-Chen Wang,&nbsp;Ze-Cong Zeng,&nbsp;Zhong-Wei Zhou","doi":"10.1096/fj.202501244R","DOIUrl":"https://doi.org/10.1096/fj.202501244R","url":null,"abstract":"<div>\u0000 \u0000 <p>Heat shock proteins (HSPs), particularly those in the HSP70 family, play essential roles in maintaining cellular homeostasis and orchestrating stress responses, including those triggered by viral infections. Based on data mining of published datasets and experimental characterization, this study identified HSPA9 phosphorylation at serine 627 (S627) as a potential regulatory site associated with SARS-CoV-2 infection. Our findings demonstrate that phospho-S627 HSPA9 enhances mitochondrial function and mass, potentially meeting the elevated energy demands of viral replication. Concurrently, phosphorylation at S627 suppresses host cell proliferation, potentially delaying immune activation and facilitating viral spread. Moreover, phosphorylation at both the S627 and S378 sites markedly reduces the expression of the proinflammatory cytokines IL-6 and IL-8, which may further weaken the immune response during SARS-CoV-2 infection. These data suggest that SARS-CoV-2 may exploit HSPA9 phosphorylation to bolster its replication and evade host defenses. Notably, MAPKAPK2 has emerged as a latent kinase that regulates this phosphorylation, making it a promising therapeutic target for the treatment of these conditions. Overall, our results shed light on a novel mechanism of SARS-CoV-2 pathogenesis, suggesting that HSPA9 phosphorylation may be a potential therapeutic target.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144672699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia-Induced Suppression of FAM99A and FAM99B Contributes to the Development and Glucose Metabolic Reprogramming of Hepatocellular Carcinoma","authors":"Cang-sang Song,&nbsp;Guo-hui Wang,&nbsp;Pan-pan Mao,&nbsp;Han-shu Zhang,&nbsp;Lu Liu,&nbsp;Xue-jiao Ma,&nbsp;Xing-de Li,&nbsp;Yang Zhang","doi":"10.1096/fj.202501058R","DOIUrl":"https://doi.org/10.1096/fj.202501058R","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) is a highly aggressive and highly malignant cancer. Glucose metabolic reprogramming provides sufficient ATP to support HCC's rapid proliferation and invasion. Consequently, this study intends to investigate the effects of FAM99A and FAM99B on glucose metabolic reprogramming, and provide new insights for HCC treatment. Changes in malignant phenotypes and glycolysis-related indices of HCC cells (HCCLM3 and HEPG2) were assessed after exogenous regulation of FAM99A and FAM99B under hypoxic conditions. Oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and glycolytic proton efflux rate (glycoPER) were measured using the Seahorse XF Glycolysis Rate Assay Kit (103344-100, Agilent). HCCLM3 cells were subjected to transcriptome and smallRNA sequencing to identify differentially expressed genes (DEGs) and miRNAs (DE-miRNAs) associated with FAM99A and FAM99B. Under hypoxic conditions, the expression of FAM99A and FAM99B was significantly downregulated in HCC cells. Overexpression of FAM99A or FAM99B significantly inhibited HCC cell proliferation, wound healing, and invasion. Moreover, they effectively decreased intracellular glucose, extracellular lactate, ATP, glycolysis-related enzymes, ECAR, and glycoPER, and increased pH, extracellular glucose, and mitoOCR/glycoPER. A total of 31 DEGs and 15 DE-miRNAs were present in HCCLM3 cells overexpressing FAM99A, and 375 DEGs and 68 DE-miRNAs were identified in HCCLM3 cells overexpressing FAM99B. These DEGs and DE-miRNA targets were involved in cell cycle, apoptosis, metastasis, extracellular matrix remodeling, and metabolic reprogramming. The FAM99B-associated ceRNA network contained one DE-miRNA and 10 DEGs, and their expression differences were consistent with the sequencing results. Hypoxia-induced suppression of FAM99A and FAM99B facilitates proliferation, metastasis, and glucose metabolic reprogramming of HCC.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501058R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Collagen Matrix in the Development and Progression of Heterotopic Ossification in Tendon and Its Biological Mechanisms","authors":"Chenxi Ren,&nbsp;Fa Liu,&nbsp;Shuyang Zhang,&nbsp;Huiyun Xu,&nbsp;Pengfei Yang","doi":"10.1096/fj.202501170RR","DOIUrl":"https://doi.org/10.1096/fj.202501170RR","url":null,"abstract":"<div>\u0000 \u0000 <p>As the primary force-transmitting structure in the musculoskeletal system, tendons are susceptible to collagen fiber disorganization and microenvironmental alterations following mechanical overload or traumatic injury. The aberrant mineralization cascade ultimately culminates in heterotopic ossification (HO), wherein heterotopic bone forms through dysregulated osteogenic processes. Current therapeutic paradigms for tendon HO remain palliative rather than curative, underscoring critical knowledge gaps in its etiopathogenesis. Therefore, the present review paper systematically examines emerging evidence on the synergistic interplay between damaged collagen architecture and ionic/protein microenvironment changes in driving HO progression, with particular emphasis on how collagen ultrastructural defects serve as mineralization templates through stereochemical nucleation, and microenvironmental ionic/protein alterations that amplify osteochondrogenic differentiation. The mechanistic framework of HO elucidated in the present paper would further contribute to novel strategies development for the prevention and treatment of pathological mineralization in tendon.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501170RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal Circulatory NAD Precursor Levels and the Yolk Sac Determine NAD Deficiency-Driven Congenital Malformation Risk","authors":"Kayleigh Bozon,&nbsp;Hartmut Cuny,&nbsp;Delicia Z. Sheng,&nbsp;Alena Sipka,&nbsp;Antonia W. Shand,&nbsp;Natasha Nassar,&nbsp;Sally L. Dunwoodie","doi":"10.1096/fj.202500708RR","DOIUrl":"https://doi.org/10.1096/fj.202500708RR","url":null,"abstract":"<p>Nicotinamide adenine dinucleotide (NAD) is an essential cofactor in hundreds of cellular processes. Genetic disruption of NAD <i>de novo</i> 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 <i>de novo</i> synthesis (<i>Haao</i>^−/−) were more susceptible to CNDD when maternal circulatory nicotinamide was limited, as their yolk sacs cannot generate NAD <i>de novo</i> from tryptophan. Metabolites originating from <i>Haao</i>^−/− 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.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500708RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}