Ozone Therapy Supports the Glutathione System as an Integrated Metabolic Network: From Physiological Regulation to Oncological Implications

Abstract

Ozone therapy has long been discussed within an "antioxidant" framework, yet this framing obscures how it actually engages the glutathione system. This review reframes ozone therapy not as a mere antioxidant intervention but as a qualitatively distinct redox intervention that supports the glutathione system as an integrated metabolic network, and examines its implications in settings — such as oncology — where exogenous glutathione (GSH) and ozone must be sharply distinguished. Low-grade, transient oxidative signals generated during ozone therapy — including lipid electrophiles such as 4-hydroxynonenal — modify Kelch-like ECH-associated protein 1 (Keap1) and promote nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, which in turn supports the GSH system at four coordinated levels: cystine import via the cystine/glutamate antiporter (xCT), de novo synthesis via glutamate–cysteine ligase, regeneration of reduced glutathione by glutathione reductase, and supply of nicotinamide adenine dinucleotide phosphate (NADPH) from the pentose phosphate pathway. This network-level perspective reorganizes the clinical meaning of glutathione across eight interlocking axes, spanning reactive oxygen and reactive nitrogen species handling, thiol switches (S-nitrosoglutathione [GSNO] and its reductase [GSNOR], and S-glutathionylation), immune and inflammatory modulation, infection defense, anti-glycation, xenobiotic detoxification, and mitochondrial integrity. In oncology, the same GSH system that protects the host can also support tumor survival through the xCT–GSH–glutathione peroxidase 4 (GPX4) axis and ferroptosis resistance. This dual nature requires that exogenous intravenous glutathione and ozone therapy — often grouped together as antioxidants — be sharply distinguished: intravenous glutathione produces supraphysiological plasma concentrations that raise conceptual concerns about reductive stress, whereas ozone therapy has been shown to elicit physiological, adaptive glutathione responses. Building on evidence that cluster of differentiation 8 (CD8⁺) T-cell-derived interferon-gamma (IFN-γ) suppresses xCT, this paper proposes that ozone therapy may act upstream of the IFN-γ–xCT axis through immune priming rather than direct tumoricidal activity. Within this framework, a clinical perspective on relatively high-concentration, low-total-dose ozone regimens in oncology, together with biomarker-guided titration, is outlined. Prospective clinical validation of this framework remains to be established