Free Radicals in Health and Disease Original paper

What was reviewed?

This review, Free Radicals in Health and Disease, synthesizes contemporary redox biology with a focus on how reactive oxygen species (ROS) and reactive nitrogen species (RNS) act as both essential signaling molecules and potential drivers of tissue injury when dysregulated. The authors map endogenous radical generation to mitochondrial electron transport chain (ETC) “electron leak” (notably complexes I and III) and to pathological hyperglycemia via glycation and glucose autoxidation, emphasizing oxygen and transition metals (iron, copper, zinc) as key regulators of radical chemistry. They then integrate mechanistic “redox switch” concepts, detailing how reversible cysteine oxidation supports physiologic signaling, while excessive or insufficient radical flux produces oxidative stress or reductive stress, respectively. Finally, they evaluate redox-modulating interventions, arguing that many antioxidant approaches fail clinically due to imprecise dosing/targeting and proposing cold atmospheric plasma (CAP) as a tunable platform that can deliver calibrated reactive species to either restore redox balance in degenerative disorders or push proliferative disease cells past their oxidative tolerance threshold.

Who was reviewed?

Because this is a narrative review, there were no directly enrolled participants. Instead, the authors curated evidence spanning molecular and cellular experiments, animal models, and selected human clinical data across multiple disease domains, including cancers, inflammatory dermatologic disorders, neurodegeneration, joint degeneration, cardiovascular-metabolic disease, and diabetes complications. Notably, they highlight clinical trial evidence where antioxidant supplementation showed paradoxical harms (e.g., accelerated cognitive decline in some Alzheimer’s disease supplement regimens) and summarize early-phase clinical and randomized trials of CAP in settings such as metastatic/recurrent solid tumors and diabetic foot ulcers. The “who” in this review, therefore, consists of heterogeneous populations represented across the cited literature—ranging from patients with neurodegenerative disease to oncology cohorts—used to illustrate why redox interventions require context-specific precision.

Most important findings

The review’s central finding is that redox biology is fundamentally bidirectional: both excessive radicals (oxidative stress) and excessive reducing power (reductive stress) can be pathogenic, and clinical failures often arise from ignoring this spectrum. Mechanistically, mitochondrial ETC leak generates superoxide and hydrogen peroxide under normal physiology, while hyperglycemia amplifies radical production through AGE–RAGE signaling and transition-metal–catalyzed Fenton/Haber–Weiss chemistry. The authors place special emphasis on reductive stress (NADH/NADPH/GSH imbalance) as an underappreciated driver of disease onset and therapy resistance, especially via overactive antioxidant programs such as NRF2 and elevated glutathione supporting tumor survival and chemoresistance. Therapeutically, they frame CAP as uniquely flexible: at lower doses it can enhance endogenous antioxidant machinery and tissue repair (degenerative disease contexts), while at moderate doses it can selectively kill highly proliferative cells and sensitize tumors to chemo- and immunotherapies. From a microbiome-signature perspective, the paper is not microbiome-focused, but it repeatedly links redox imbalance to inflammatory barriers and metabolic disease states that commonly co-vary with microbial community shifts, making its mechanistic “redox-state” framing potentially useful as a host-context layer when interpreting microbiome associations.

Key implications

Clinically, this review argues that “more antioxidants” is not synonymous with benefit; both overcorrection and underdosing can worsen outcomes by shifting patients into reductive stress or leaving oxidative injury unaddressed. The practical implication is a precision-redox mindset: clinicians and translational teams should treat redox state as a dynamic, stage-specific phenotype, ideally guided by biomarkers (e.g., oxidative damage markers, glutathione redox ratios) and targeted delivery approaches. CAP is positioned as a promising tool because it can be dose-tuned and delivered in multiple formats (direct application, CAP-activated liquids, hydrogels) to modulate redox biology rather than blunt it. For clinicians working with microbiome-informed care pathways, the review supports a useful conceptual bridge: host redox tone—shaped by metabolism, inflammation, and tissue oxygenation—can plausibly influence which microbiome signals are causal, compensatory, or incidental, and may help stratify patients for interventions that otherwise show inconsistent microbiome-related responses.

Citation

Dai X, Huang Z, Lyu R. Free Radicals in Health and Disease. MedComm. 2025;6:e70396. doi:10.1002/mco2.70396