Cardiorespiratory Fitness as a Key Predictor of Metabolic, Inflammatory, and Oxidative Stress Biomarkers in Adults with Different Physical Activity Levels.

Sedentary lifestyles are associated with poor cardiorespiratory fitness (CRF) and predispose individuals to cardiometabolic diseases and increased all-cause mortality, events related to oxidative stress and inflammation. While regular exercise induces adaptations that improve metabolic homeostasis, its antioxidant effects are not fully characterised. This cross-sectional study compared antioxidant gene/protein expression in peripheral blood mononuclear cells (PBMCs) and metabolic, inflammatory, and oxidative stress biomarkers in sedentary and active individuals, and analysed potential associations with CRF. Fifty-one healthy adults (18-45 years) were recruited. Participants were classified as sedentary (SED), physically active (PA), or endurance athletes (EA) using the International Physical Activity Questionnaire (IPAQ; n = 17/group). Anthropometric, biochemical, metabolic, and inflammatory variables were assessed. Oxidative stress was measured via serum hydrogen peroxide (HO) and malondialdehyde (MDA). PBMC protein/mRNA expression of nuclear factor erythroid 2-related factor 2 (NRF2) and antioxidant enzymes [superoxide dismutase 1 (SOD1), glutathione reductase (GSR), glutathione peroxidase 1 (GPX1), catalase (CAT)] were evaluated. Metabolic flexibility was assessed at rest by indirect calorimetry, and CRF by maximal oxygen uptake (VOmax mL·kg·min) during a progressive maximal cardiopulmonary exercise test. The PA and EA groups showed greater metabolic flexibility and CRF than the SED group, which exhibited altered homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDL-C), elevated tumour necrosis factor alpha (TNFα), high-sensitivity C-reactive protein (hsCRP), oxidative stress (HO, MDA), and reduced antioxidant gene/protein expression. Higher VOmax correlated with healthier metabolic profiles, less inflammation, and higher antioxidant expression, while inversely correlating with HOMA-IR, MDA, and TNFα. Optimal or high CRF strongly protects against insulin resistance, oxidative stress, inflammation, and metabolic inflexibility, key hallmarks of sedentary behaviour. Regular physical exercise improves metabolic and redox profiles, enhancing antioxidant defences in PBMCs. A functional CRF threshold represents a practical target by which to reduce cardiometabolic risk.