Rsity, State Important Lab of Genetic Engineering, College of Life Sciences, and Department of Supplies Science, Fudan University, Shanghai 200438, China 3Department of Anatomy and Neuroscience Analysis Institute, College of Simple Healthcare Sciences, Zhengzhou University, Zhengzhou 450001, China 4Urogenital Development Research Center, Division of Urology, Shanghai Children’s Hospital College of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China 5Department of Anesthesiology, Common Hospital of Southern Theatre Command of People’s Liberation Army, Guangzhou 510030, China 6International Human Phenome Institutes (Shanghai), Shanghai 200433, China 7These authors contributed equally 8Lead contact *Correspondence: husq04@163 (X.-Y.Z.), caojing73@126 (J.C.), [email protected] (K.S.), [email protected] (J.-Y.Z.) https://doi.org/10.1016/j.xcrm.2023.SUMMARYDysregulated maternal fatty acid metabolism increases the threat of congenital heart disease (CHD) in offspring with an unknown mechanism, and the impact of folic acid fortification in stopping CHD is controversial. Employing gas chromatography coupled to either a flame ionization detector or mass spectrometer (GC-FID/MS) evaluation, we obtain that the palmitic acid (PA) concentration increases significantly in serum samples of pregnant girls bearing young children with CHD. Feeding pregnant mice with PA enhanced CHD danger in offspring and can’t be rescued by folic acid supplementation. We additional find that PA promotes methionyl-tRNA synthetase (MARS) expression and protein lysine homocysteinylation (K-Hcy) of GATA4 and results in GATA4 inhibition and abnormal heart improvement. Targeting K-Hcy modification by either genetic ablation of Mars or applying N-acetyl-L-cysteine (NAC) decreases CHD onset in high-PA-diet-fed mice. In summary, our work links maternal malnutrition and MARS/K-Hcy with the onset of CHD and delivers a possible method in stopping CHD by targeting K-Hcy apart from folic acid supplementation.increasing the risk of CHD.7 Additionally, increased proteasome activity-mediated folate transmembrane transport decreases the risk of CHD by lowering homocysteine levels.10 With regards towards the mechanisms underlying the teratogenic effects of homocysteine, we identified that improved homocysteine levels might be sensed by methionyl-tRNA synthetase (MARS), major towards the lysine homocysteinylation (K-Hcy) modification of proteins and generation of K-Hcy signals.11 Elevated K-Hcy levels inhibit developmental signals and lead to birth defects. In human genetic studies, we observed improved copy numbers of MARS and/or MARS2 in patients with CHD, validating the pathological effects of K-Hcy.12 These findings suggest that teratogenic K-Hcy levels are determined by each the substrate homocysteine and enzyme MARS.Fmoc-Asn(Trt)-OH 13 Although K-Hcy might be alleviated by lowering homocysteine levels working with folic acid supplementation, that is performed globally, the incidence of CHD has increased substantially in current years on account of unknown reasons.Baricitinib 1,INTRODUCTION Congenital heart illness (CHD), one of the most frequent congenital human birth defect, affects 9.PMID:24065671 1 per 1,000 reside births worldwide.1 CHD onset is influenced by each genetic and nutritional elements.2 The periconceptional administration of folic acid, which can be a synthetic kind of folate, is the most productive process for CHD prevention. Epidemiological research have shown that folic acid fortification reduces the threat of CHD in newborns,3 whereas exposure to folic acid antagonist.