Background <p>Langerhans cell histiocytosis (LCH) is an inflammatory and neoplastic disorder. The levels of metabolites in the plasma of children with LCH have not been studied and may be related to disease progression.</p> Objectives <p>We committed to find novel pre-diagnostic metabolites in the plasma of LCH children with posterior pituitary involvement (PI).</p> Methods <p>Non-targeted metabolomics sequencing was used to detect specific and pre-diagnostic metabolites in the plasma of children with LCH. Plasma samples from 56 children with LCH and 27 healthy volunteers were enrolled. Plasma samples of children with LCH were divided into three groups: children have no PI or central nervous system-risk (CNS-risk) bone lesions (NPC group), children with CNS-risk bone lesions but without PI (CNS-risk group), and children with PI (PI group).</p> Results <p>The N-acetylneuraminic acid, lipoamide, L-Glutathione oxidized and indole-3-propionic acids were potential pre-diagnostic metabolites for LCH children with PI in comparison with the healthy volunteers. Metabolites in the plasma of LCH children with PI enriched specific signaling pathways including arachidonic acid metabolism, ferroptosis, etc. Through targeted metabolomics sequencing, we verified that specific metabolites were existed in the stratified involvements of patients with LCH, such as N-acetylneuraminic acid and Vitamin A, which may be related with alteration of blood-brain barrier permeability and LCH disease progression. Through the joint multi-omics analyses, we discovered that the peripheral dendritic cells may have ferroptosis phenomena, which was regulated by osteopontin secreted in the plasma of patients with LCH.</p> Conclusion <p>Analyses and identification the differential metabolites in the plasma of children with LCH may significantly improve the early diagnosis and stratified treatment of children with pituitary invovlement.</p>