Metabolic Pathway Dysregulation in Diffuse Axonal Injury: A Multimodal Biomarker Approach for Early Diagnosis and Mechanistic Insights

Weiliang Chen¹Shengwen Li²Taotao Zhang²Kaijie Sun²Chunyu Yao²Wen Su²Lisheng Xu²Guanjun Wang²Chunfei Xu^2*

• ¹Department of Neurosurgery, Haining People's Hospital, Zhejiang, China
• ²Haining People's Hospital, Haining, China

Background Diffuse axonal injury (DAI), a severe subtype of traumatic brain injury (TBI), lacks reliable early diagnostic biomarkers, contributing to poor clinical outcomes. Systemic metabolic pathway dysregulation in DAI remains poorly characterized, limiting targeted therapeutic strategies. Objectives Identify DAI-specific metabolic network disruptions and evaluate their diagnostic and prognostic utility. Methods In this prospective cohort study, serum metabolomics profiling, pathway enrichment analysis, and machine learning were integrated with clinical assessments in 64 adults with acute TBI (30 DAI, 34 non-DAI). Untargeted metabolomics via UPLC-LTQ-Orbitrap MS identified differential metabolites, which were mapped to biological pathways using MetaboAnalyst 5.0. Diagnostic and prognostic performance of pathway-based models was assessed using ROC analysis. Results DAI patients exhibited distinct metabolic perturbations, with significant dysregulation in mitochondrial fatty acid oxidation (FAO) and phospholipid metabolism. Key discriminative metabolites included carnitine C8:1 (VIP=3.26) and lysophosphatidylcholine 22:3 sn-2, which correlated with Marshall CT scores (ρ=0.62, p<0.001) and pupillary reflex loss. A multi-parameter model integrating FAO and phospholipid degradation markers achieved superior diagnostic accuracy (AUC=0.927, 95% CI: 0.86–0.98) compared to clinical models (AUC=0.744). Pathway disruptions further predicted 3-month functional outcomes (GOSE AUC=0.912). Conclusions DAI involves systemic metabolic network dysfunction centered on mitochondrial energetics and lipid metabolism. Pathway-centric biomarkers enhance diagnostic precision and prognostication, offering a novel framework for biomarker-driven management of TBI. These findings highlight mitochondrial FAO and phospholipid homeostasis as potential therapeutic targets, addressing a critical gap in DAI care.