Spatial Modulation of Immune Cell Distribution and Pro- and Anti-Inflammatory Cytokines by Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) in a Preclinical Model of Ulcerative Colitis: A Desc

Langerhans cell histiocytosis (LCH), a rare inflammatory myeloid neoplasm characterized by the accumulation of pathological CD1a and CD207 cells in lesions, presents with highly variable clinical manifestations []. LCH can affect patients of all ages but predominantly occurs in children. Diagnosis relies on CD1a and CD207 staining of lesion tissues, and disease severity is clinically assessed based on lesion extent, ranging from isolated, indolent, to explosive multisystem involvement []. Children with LCH involving the liver, spleen, or bone marrow have a mortality risk of approximately 15%. Despite treatment advances, reactivation rates remain >30%, often leading to serious long-term neurological or endocrine complications that significantly impair quality of life []. The molecular characteristics of LCH have been partially elucidated and include variants (e.g., ) and and variants, which drive constitutive mitogen-activated protein kinase (MAPK) pathway activation [, ]. Currently, treatment decisions rely solely on clinical presentation because reliable molecular markers for risk stratification are lacking. Metabolic reprogramming is a fundamental characteristic of cancer cells and plays a crucial role in abnormal proliferation and carcinogenesis []. Metabolomic analysis is a powerful tool for monitoring disease status and unraveling the pathogenesis of various diseases []. Reprogrammed metabolic pathways have been widely investigated in the contexts of cancer development, progression, and treatment resistance [, ]. Advances in high-throughput metabolomics technologies have enabled comprehensive identification and quantification of endogenous low-molecular-weight metabolites, which reflect complex interplays among host factors, genetic influences, and environmental exposures []. The MAPK pathway, which is constitutively activated in LCH, is a master regulator of cellular metabolism, influencing glucose uptake, aerobic glycolysis, and biosynthetic processes essential for cell growth and proliferation [, ]. , a driver gene in LCH, has been implicated in metabolic reprogramming in numerous disorders [, ]. However, metabolic changes in LCH pathophysiology and treatment remain unclear. To address the above gaps, we profiled global metabolism in bone marrow aspirates (BMAs) from 34 patients with LCH of three subtypes: single-system disease (SS), multisystem disease without risk organ involvement (MS-RO), and multisystem disease with risk organ involvement (MS-RO). We mapped the metabolomic profiles of these subtypes and explored metabolic changes associated with treatment outcomes in high-risk LCH to improve molecular classification, treatment monitoring, and prognosis in affected children.