Nitric oxide, NO°, is a gas and highly reactive molecule, long time considered as a noxious and harmful chemical until the mid-eighties when NO° was found to be a ubiquitous signalling molecule involved in many vital physiological processes. NO° became Science’s Breakthrough/Molecule of the Year 1992 and the 1998 Nobel Prize in Medicine was awarded for the discovery of NO° physiological role. Since then, NO° has been the topics of more than 170 000 scientific papers.

However as stated by Koshland in his editorial of the Science 1992 Molecule of the year issue, “it was a surprise to find such an unlikely agent, a labile and toxic gas, for such essential physiological roles”. Indeed, NO° is a redox and extremely reactive molecule. Redox (oxidoreduction) chemistry is a universal and extensive chemistry: upon biosynthesis, NO° will eventually get transformed in a large range of Reactive Nitrogen Species (RNSs) that will react with (almost) all biomolecules, from metabolites to lipids, DNA, proteins… Because of this large reactivity spectrum, NO° stands at the crossroad of many different (if not opposite) physiological activities, depending mostly on the physico-chemical properties of the milieu.

This is exemplified in mammals where NO° (and its derived RNSs) are involved in signalling processes (such as neural communication, vascular tone control, NANC signalling for the regulation of GI tract, cardiac or erectile processes) but also in the fine-tuning of the multifaceted endothelial homeostasis (antioxidant, platelet aggregation, neutrophil adhesion, vascular permeability, angiogenesis, proliferation…). However, NO° is also directly used as a cytotoxic agent in non-specific immune defence. In this context, NO° and RNS are among the most relevant molecules in oxidative stress related pathologies. When the oxidative activity of NO°/RNS become out of control, these ubiquitous redox molecules once engaged in signalling processes convert into self-harming compounds leading to major pathological conditions that account for inflammatory, neurodegenerative and cardiovascular diseases, but also directly related to cancer, asthma, diabetes…

This pleiotropic and unpredictable activity of a physiological molecule such as NO° was a kind of revolution in the field of chemical biology. This led the path to reassess the biological role of Redox active species (ROS, RSSs) such as H₂O₂, H₂S… In this context, others and we have proposed a new theoretical framework to address the multiple activities and functions of reactive species. We proposed the existence of a Reactive Species Interactome (RSI), a redox system that connects all (bio)chemical pathways generating reactive species with cellular intermediary metabolism, bioenergetics, and the extracellular environment. By interconnecting all redox active molecules, the RSI is shaping a Redox Landscape that synchronizes all redox-based processes and allows living entities to sense and to adapt to changes in the chemical composition of intra- and extracellular milieu[1].

Using philosophy of science and biosemiotics backgrounds, we have been investigating how redox chemistry has been fashioning biological communication system. Redox chemistry constitutes a universal molecular language, a lingua franca that bridges the inanimate and living realms, connecting major bio-geochemical cycles[2]. We proposed that redox processes have co-evolved with biological complexification, giving rise to a multi-layered system of increasingly complex redox architectures[3]. All redox-based structures, processes and functions that are taking place at different levels of biological organisation are integrated within what we defined as the ‘Redox Interactome’. This Redox Interactome is the communication system that enables self-regulation of each redox-based process along with the synchronisation of multiple physiological processes taking place in different tissues. This complex Redox Architecture provides the organism with an integrative, multi-scale Redox Regulation System that allows accommodation of different stresses within and across all levels of biological organisation.

This approach led us to revisit the concept of redox homeostasis that is increasingly utilized in the scientific literature but remains a catchall concept that is poorly defined with neither clear meaning nor relevant usage. We proposed that the molecular bases of homeostatic behaviours must be precisely characterised and considered within the frame of redox biochemical systems. The Redox Interactome framework seems therefore required to understand the integration of isolated redox processes within the context of any physio/pathological condition[4].

We also applied our Redox System’s approach to analyse the new COVID-19 disease, as an example of a stress response that challenges the integrity of redox balance at the whole-body level. We considered COVID-19 as a redox disease and explored its impact on stress signalling and adaptation in relation to the body’s ability to maintain homeostasis. Using our RSI framework, we highlighted the way acute and prolonged oxidative stresses lead to a progressive failure of the redox regulation systems, disturbing all redox-based signalling processes, and leading to catastrophic cascades of “oxidative storm”. This complete and profound redox system failure might help understanding the molecular foundations of long-Covid pathologies and fostering precise therapeutic interventions.