Effect of ozone therapy on oxidative stress indices in chronic inflammatory diseases: A systematic review and meta-analysis of randomized clinical trials

• Ozone (O 3 ) therapy is recognized as a promising complementary therapy for regulation of OS indicators • Ozone therapy could improve OS markers in individuals with CIDs, mostly by lowering AOPP and strengthening antioxidant defense systems • O 3 therapy appears to enhance the antioxidant system and modulate OS, contributing to improved therapeutic outcomes Chronic inflammatory diseases (CIDs) are defined by prolonged inflammation and oxidative stress (OS), both of which are associated with disease progression and consequences. Ozone (O 3 ) therapy is recognized as a promising complementary therapy for regulating OS indicators. The purpose of this systematic review and meta-analysis is to investigate the effect of O 3 therapy on OS parameters in patients with CID. A comprehensive literature search was conducted across multiple databases, including PubMed, Cochrane Library, Google Scholar, and Scopus, for randomized controlled trials (RCTs) published up to October 2024. Studies were selected if they investigated the effect of ozone therapy on OS parameters, including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), advanced oxidation protein products (AOPP), and protein peroxidation (PP) in CID patients. Fixed- or Random-effects models were used in the meta-analysis to determine weighted mean differences (WMD) and 95% confidence intervals (CIs). 12 RCTs with 846 participants included in the current study. Our findings showed that O 3 therapy had no significant difference in OS parameters when compared to control groups. According to subgroup analysis, O 3 therapy significantly increased SOD activity in patients with T2D (WMD = 7.59, 95% CI [2.98 to 12.19], I² = 97.75%, p = <0.001) and arthritis (WMD = 9.21, 95% CI [6.02 to 12.40], I² = 66.96%, p = 0.08). In addition, the rectal method showed a statistically significant effect on GPx activity (WMD = 20.00, 95% CI [0.55 to 39.45], I² = 92.42%, p = <0.001). O 3 therapy also significantly reduced AOPP levels at doses of ≤20 µg/ml and treatment durations of both ≥30 days (WMD = -5.15, 95% CI [-7.90 to -2.40], I² = 96.03%, p = <0.001) and <30 days (WMD = 7.44, 95% CI [5.00 to 9.88], I² = 89.27%, p = <0.001). Ozone therapy could improve OS markers in individuals with CIDs, mostly by lowering AOPP and strengthening antioxidant defense systems. More large-scale RCTs are required to validate these outcomes and better comprehend the fundamental mechanisms of action.