The SIRT-1/Nrf-2/HO-1 antioxidant defense axis in adult attention-deficit/hyperactivity disorder.

Attention-Deficit/Hyperactivity Disorder (ADHD) frequently persists into adulthood and is associated with substantial functional impairment. Beyond classical neurotransmitter dysregulation, increasing evidence points to oxidative stress and impaired cellular defense mechanisms as key contributors to ADHD pathophysiology. However, data on upstream redox-regulatory pathways in adult ADHD remain limited. To evaluate serum tumor necrosis factor-alpha (TNF-α), heme oxygenase-1 (HO-1), nuclear factor erythroid 2–related factor 2 (Nrf-2), and sirtuin-1 (SIRT-1) levels in adults with ADHD and to examine their associations with symptom severity and clinical features. This cross-sectional study included 60 adults diagnosed with ADHD and 60 age- and sex-matched healthy controls. ADHD diagnosis was established using the Structured Clinical Interview for DSM-5 Clinician Version (SCID-5/CV) and the DIVA 2.0 diagnostic interview. Symptom severity was assessed using the Adult ADHD Self-Report Scale (ASRS). Serum TNF-α, HO-1, Nrf-2, and SIRT-1 levels, along with routine laboratory parameters, were measured and compared between groups. Associations between biomarkers and symptom severity were analyzed. Serum SIRT-1 (9.36 ± 9.62 vs. 18.52 ± 14.90, p < 0.001), Nrf-2 (11.18 ± 10.53 vs. 22.05 ± 17.44, p < 0.001), and HO-1 (0.86 ± 0.95 vs. 1.89 ± 1.65, p < 0.001) levels were significantly lower in adults with ADHD compared to controls, whereas TNF-α levels did not differ between groups (7.49 ± 2.15 vs. 7.78 ± 2.06, p = 0.439). CRP levels were modestly higher (3.50 ± 1.59 vs. 2.86 ± 1.68, p = 0.036), and ferritin levels were lower in the ADHD group (49.78 ± 46.68 vs. 71.54 ± 63.80, p = 0.035). SIRT-1 (r = − 0.430, p = 0.001), Nrf-2 (r = − 0.446, p < 0.001), and HO-1 (r = − 0.424, p = 0.001) levels were negatively correlated with ADHD symptom severity. ROC analysis demonstrated moderate discriminatory performance for HO-1 (AUC = 0.797), Nrf-2 (AUC = 0.756), and SIRT-1 (AUC = 0.753). Adult ADHD was associated with reduced serum SIRT-1, Nrf-2, and HO-1 levels, pointing to alterations in redox-regulatory mechanisms. TNF-α did not differ between groups; however, broader inflammatory pathways were not comprehensively assessed. These findings support further research on oxidative stress–related regulation and its potential value for biomarker-informed clinical strategies in adult ADHD.