Abstract：
Rheumatoid arthritis (RA) is a long-term autoimmune condition that causes joint and surrounding tissue inflammation. Lipid mediators are involved in inflammation and deterioration of the joints. Despite attempts to discover effective drug targets to intervene with lipid metabolism in the disease, progress has been limited. In this study, precise lipidomic technology was employed to quantify a broad range of serum ceramides and sphingomyelin (SM) in a large cohort, revealing an association between the accumulation of circulating ceramides and disturbed ceramide/SM cycles during the progression of RA. In our investigation, we discovered that eight ceramides exhibited a positive correlation with the activity of RA, thereby enhancing the accuracy of RA diagnosis, particularly in patients with serum antibody-negative RA. Furthermore, the enzyme SM phosphodiesterase 3 (SMPD3) was found to disrupt the circulating SM cycle and accelerate the progression of RA. The activity of SMPD3 can be inhibited by methotrexate, resulting in decreased metabolic conversion of SM to ceramide. These findings suggest that targeting the SM cycle may provide a new therapeutic option for RA.
摘要：
类风湿性关节炎(RA)是引起关节和周围组织炎症的长期自身免疫病症。脂质介质参与关节的炎症和恶化。尽管试图发现有效的药物靶点来干预疾病中的脂质代谢，进展有限。在这项研究中,精确的脂质组学技术被用来量化大量的血清神经酰胺和鞘磷脂（SM），揭示了在RA进展过程中循环神经酰胺的积累与神经酰胺/SM周期紊乱之间的关联。在我们的调查中,我们发现八种神经酰胺与RA的活性呈正相关，从而提高RA诊断的准确性，尤其是血清抗体阴性的RA患者。此外，发现酶SM磷酸二酯酶3（SMPD3）破坏循环SM循环并加速RA的进展。甲氨蝶呤可以抑制SMPD3的活性，导致SM向神经酰胺的代谢转化减少。这些发现表明，靶向SM周期可能为RA提供新的治疗选择。
