Serum Metabolomic Profiles Unveil Biomarkers and Core Metabolic Pathways in Multiple System Atrophy Patients

Abstract Background Multiple system atrophy (MSA) is an adult‐onset, fatal, neurodegenerative disease lacking mechanistic understanding, early diagnosis, and specific treatments. Metabolomics has been widely used in neurodegenerative diseases for biomarker identification and pathophysiology exploration; however its application in MSA is extremely limited. Objectives To investigate the metabolomic landscape, core metabolic pathways, and novel biomarkers for MSA. Methods Untargeted metabolomics (ultra‐high‐performance liquid chromatography‐Q‐Exactive HF mass spectrometry [UHPLC‐QE‐MS]) was performed on serum samples from 85 MSA patients and 85 healthy controls (HCs). Candidate metabolites were validated via targeted metabolomics in an internal cohort (37 MSA, 36 HCs) and an external cohort (44 MSA, 44 Parkinson's disease [PD], 42 HCs). In vitro validation was performed using MO3.13 cells and SH‐SY5Y cells overexpressing hSNCA . Results We identified 112 and 70 differential metabolites (DMs) in positive and negative modes, respectively. Pathway analysis revealed six significant pathways, including arginine and proline metabolism; pentose phosphate pathway; valine, leucine, and isoleucine biosynthesis; purine metabolism; arginine biosynthesis; and riboflavin metabolism. A riboflavin‐xanthine panel effectively distinguished MSA from HCs (internal validation: [area under the curve [AUC] = 0.876), and this performance was confirmed in the external cohort (AUC = 0.943). Reduced xanthine levels in MSA patients compared with HCs and PD patients slightly enhanced the diagnostic power of neurofilament light chain for MSA‐PD differentiation, boosting the AUC from 0.821 to 0.890. Both riboflavin and xanthine supplementation enhanced viability and reduced apoptosis in hSNCA ‐overexpressing MO3.13 cells, while only riboflavin exerted therapeutic effects in hSNCA ‐overexpressing SH‐SY5Y cells. Conclusions This study defined the serum metabolomic signature of MSA and highlighted novel biomarkers, pathological mechanisms, and therapeutic targets deserving further validation. © 2026 International Parkinson and Movement Disorder Society.