Plasma proteomics implicates NOX-driven redox imbalance in degenerative cervical myelopathy: findings from the Australian MYelopathy Natural History Registry [AO Spine RECODE-DCM research priority number 5]

<h4>Objectives</h4>To identify disease-relevant pathways and biomarkers in degenerative cervical myelopathy (DCM) patients from the MYelopathy Natural History Registry.<h4>Methods</h4>Shotgun bottom-up proteomics (DCM <i>n</i> = 20; controls <i>n</i> = 20) was performed using LC-MS/MS in DDA mode. Peptides were eluted over 90 min on an in-house manufactured C18 column. Differential proteins were validated using parallel reaction monitoring (PRM) on the same instrument over a 60-min gradient. Bioinformatics was conducted in Skyline and ELISA using Ella™.<h4>Results</h4>Discovery proteomics highlighted acute phase and cytokine signalling with STAT1/STAT3 involvement. Targeted assays showed higher IL-6 and IFN-γ in DCM, consistent with a pro-inflammatory state. PRM indicated upregulation of NADPH oxidase complex cytochrome b-245 α-chain (p22 phox or CYBA) and glutathione reductase, alongside downregulation of extracellular glutathione peroxidase, a pattern consistent with NOX-driven reactive oxygen species generation and impaired glutathione redox homeostasis. Together, this provides human plasma evidence of systemic redox imbalance in DCM and nominate a mechanistic framework linking cytokine signalling to oxidative stress via NOX activation and disrupted glutathione cycling.<h4>Conclusion</h4>Findings support the feasibility of a plasma 'liquid biopsy' to augment diagnosis and monitoring. The modest cohort size and potential confounding by age and adiposity, absolute quantification, multivariate adjustment, and external validation are warranted to establish specificity and clinical utility.