DISCUSSION
hemorrhage, high disability, hemorrhagic MMD
DISEASE, HEMORRHAGE, REGRESSION, OXIDATIVE STRESS, PATHOGENESIS
In this prospective study, we first compared the difference in clinical characteristics between MMD patients and HCs. We further explored the differences in ischemic and hemorrhagic MMD groups. It showed that the levels of four Met cycle‐related metabolites were significantly different in the MMD group and its subtypes from those in the HC group. The training set was used to construct the risk model by LASSO regression and analyze the role of Met cycle‐related risk score in MMD. We found that the risk score was independently associated with an increased risk of MMD and its subtypes. After adjusting for other risk factors, it showed an improvement in risk prediction. In this study, we provided a novel perspective on the role of metabolism dysregulation in the pathogenesis of MMD and suggested potential therapeutic targets.One of the Met cycle‐related metabolites, MetO, was produced from Met by reactive oxygen species (ROS) and had the potential to serve as a biomarker of oxidative stress.Hcy, a sulfur‐containing amino acid, was a key determinant of Met cycle. Folate and vitamin B12 were involved in the remethylation of Hcy back into Met.Choline has been an essential molecule involved in several key physiological processes, including the normal function of cell membranes, regulation of neurotransmitter function, transportation of lipids, and metabolism of one‐carbon units in body.The etiology of MMD remains unclear, which has been considered as a combined effect of immune, genetic, environmental, metabolic, and other factors. MMD has long been considered an irreversible condition with high disability and fatality rate, causing a huge burden to families and society. Direct and indirect revascularization procedures have been widely used in the treatment of MMD. However, the bypass surgery aimed to increase blood supply to the affected hemispheres, improve ischemic symptoms, and reduce the risk of recurrent hemorrhage, rather than reversing the progression of the disease. Therefore, it has been necessary to investigate novel risk factors associated with this disease, particularly modifiable risk factors, and explore potential therapeutic targets. Our study provided a new point of view in the exploration of metabolism dysregulation in the pathogenesis of MMD. In this study, we identified four different Met cycle‐related metabolites in MMD patients compared with HCs, including MetO, Hcy, choline, and betaine. We constructed a Met cycle‐related risk model with these metabolites and confirmed the correlation between the risk score and the risk of MMD. The Met cycle‐related risk score showed a favorable predictive ability in the risk of MMD and was validated by the testing set. However, there were still several limitations in our study. First, the sample size was relatively small due to the nature of a single‐center study. Therefore, the correlation between Met cycle dysregulation and the risk of MMD should be validated by large‐scale prospective studies. Second, the study only included adult patients with MMD, and it remained unclear whether the results could be extended to pediatric patients. Thirdly, dietary intake information was not collected, which might potentially impact the outcomes. Due to the limitation of the study design, we were unable to establish a causal link between Met cycle dysregulation and MMD, even after adjusting for potential confounding variables. Thus, further in vitro/in vivo experiments, as well as large‐scale prospective cohort studies with follow‐up outcomes, have been necessary to elucidate the effect and mechanism of Met cycle dysregulation on the pathogenesis of MMD.