The Hormetic Adaptative Capacity and Resilience to Oxidative Stress Is Strengthened by Exposome Enrichment with Air Cold Atmospheric Plasma: A Metabolome Targeted Follow-Up Approach

<b>Background/Objectives</b>: The exposome, encompassing all environmental influences on health, plays a pivotal role in oxidative stress-related diseases. Negative air ions (NAIs), generated via cold atmospheric plasma (CAP), have been proposed as potential modulators of oxidative resilience. This study aims to investigate the metabolic adaptations induced by prolonged exposure to an NAI-enriched environment in mice, focusing on its effects in oxidative stress markers and energy metabolism in liver and blood. <b>Methods</b>: Twenty male C57BL/6J mice were divided into four groups: two experimental groups exposed to NAI-enriched air generated by an Air Cold Atmospheric Plasma-Nanoparticle Removal (aCAP-NR) device for either 18 days (short-term, ST) or 28 days (long-term, LT), and two control groups without exposure. Targeted metabolomics was performed in whole blood and liver using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). Statistical and pathway analyses were conducted to assess metabolic alterations. <b>Results</b>: Metabolic profiling revealed significant shifts in oxidative stress-related pathways, including enhanced glutathione metabolism, reduced lipid peroxidation, and modulation of purine metabolism. Short-term exposure led to increased mitochondrial efficiency and energy homeostasis, while long-term exposure induced adaptive metabolic reprogramming, with higher inosine levels suggesting enhanced antioxidant and anti-inflammatory responses. No adverse effects on systemic or hepatic health markers were observed. <b>Conclusions</b>: NAI exposure via aCAP-NR elicits a hormetic response, enhancing metabolic efficiency and resilience to oxidative stress. These findings suggest that controlled environmental enrichment with NAIs may serve as a novel non-invasive strategy for mitigating oxidative damage and improving metabolic health, as hormetic adaptative capacity and resilience to oxidative stress, warranting further translational research.