NADPH Oxidase-driven Oxidative Profile in Adult Attention-deficit/Hyperactivity Disorder: NOX2/NOX4 Activation and...

Adult attention-deficit/hyperactivity disorder (ADHD) remains a clinically heterogeneous condition. Oxidative stress has been implicated, but biomarkers with clinical utility remain limited. NADPH oxidase (NOX) isoforms-particularly NOX2 and NOX4-generate reactive oxygen species and may drive lipid peroxidation, indexed by malondialdehyde (MDA).

Adults with ADHD (n = 79) and healthy controls (n = 63) were enrolled to the study. ADHD diagnosis was established with DIVA-2 and symptom severity assessed with ASRS. Plasma MDA and serum NOX2 (gp91^phox) and NOX4 levels were measured. Group comparisons, correlation, and ROC analyses were conducted.

ADHD patients showed higher MDA, NOX2, and NOX4 levels than controls (all p < 0.001). In ADHD, NOX2 correlated with MDA (r = 0.552) and NOX4 (r = 0.615; both p < 0.01), but not in controls. MDA and NOX2 showed excellent discrimination (AUC 0.942 and 0.915), and NOX4 good discrimination (AUC 0.824); MDA outperformed NOX4 by DeLong's test (p = 0.012). In adjusted models, MDA (aOR 2.84, 95% CI 1.92-4.12) and NOX2 (aOR 2.15, 95% CI 1.54-3.01) remained independently associated with ADHD (both p < 0.001).

Adult ADHD was associated with a NOX-linked oxidative profile, characterized by elevated NOX2/NOX4 and MDA levels. The NOX2-MDA association supports a pathway linking enzymatic ROS generation to lipid peroxidation. MDA and NOX2 showed strong discrimination and independent associations with ADHD, supporting their potential as adjunct biomarkers; however, given the transdiagnostic nature of oxidative stress, clinical utility requires external validation in independent, clinically representative samples.