Figure 1: Proposed therapeutic effects of O3 therapy for the treatment of COVID-19. Note: COVID-19 serves as an ACE2 receptor to enter into human respiratory epithelial cells through its Spike proteins. The transcription factor Nrf2 bound to Keep-1 activated by alkenals. The released Nrf2 translocates into the nucleus and, after binding to Maf, docks on ARE and activates several genes leading to the synthesis of antioxidant proteins. O3 can inhibit apoptosis and degradation of the cartilage matrix by inhibiting the activation of NF-κB resulting in cell survival. O3 has immunomodulatory effects by anti-inflammatory properties by modulating NLRP3, inhibition of cytokine storm (reduction of IL-1β, IL-6, TNF-α, IFN-γ, IL-18, IL-12, GM-CSF), O3 can stimulate cellular and humoral immunity through secondary messengers (H2O2) and NFAT/AP-1 signaling pathway. O3 is a multifunctional drug that can stimulate inflammatory cytokines (IL-1β, IL-6, IFN-γ, TNF-α), anti-inflammatory cytokines (IL-4, IL-10). Biological responses to Nrf2/ARE activation with mild OT oxidative stress increase the levels of direct antioxidants such as GSH, CO, and bilirubin through glutathione and thioredoxin reductase. O3 can reduce biomarkers such as CRP, ESR, and uric acid, which have been shown to reduce CRP in patients with COVID-19. O3 increases oxygenation to the blood and tissues prevents the formation of small thrombosis by secretion of some prostacyclins such as PGI2. O3 increases the expression of HO-1 in endothelial cells, stimulates 2–3 diphosphoglycerates, so more oxygen to the delivered tissues in COVID-19 patients. O3 or its mediators (ozonides [ROS, LOPs]) are capable of oxidizing cysteine and tryptophan residues on S-spike protein and preventing their binding to the ACE2. O2-O3 also affects NO and iNOS signaling pathways. NO, especially by inhibiting palmitoylation of S protein, reduces the viral replication of COVID-19, thus preventing the virus from binding to the ACE2 receptor. ACE2: Angiotensin-converting enzyme 2; AP-1: activating protein-1; ARE: antioxidant response element; CO: carbon monoxide; COVID-19: coronavirus disease 2019; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; GM-CSF: granulocyte-macrophage colony-stimulating factor; GSH: glutathione; H2O2: hydrogen peroxide; HO-1: heme oxygenase-1; IFN-γ: interferon-γ; IL: interleukin; iNOS: inducible nitric oxide synthase; Keep-1: Kelch like-ECH-associated protein 1; LOP: lipid ozonation product; Maf: musculoaponeurotic fibrosarcoma; NFAT: nuclear factor of activated T-cells; NF-κB: nuclear factor-κB; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3; NO: nitric oxide; Nrf2: nuclear factor erythroid 2-related factor 2; O2: oxygen; O3: ozone; OT: ozone therapy; PGI2: prostaglandin I2; ROS: reactive oxygen species; TNF-α: tomur necrosis factor-α.