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Oxidative stress is the result of an imbalance between pro-oxidant and antioxidant species at cellular level, also defined as a lack in redox signaling and control. Despite small amounts of reactive oxygen or nitrogen species (ROS and RNS) are essential to maintain cell homeostasis and redox signaling, currently, it is well understood that chronic oxidative stress conditions are responsible for several key biomolecule modifications, such as, DNA impairment, lipid peroxidation and protein carbonylation (Pisoschi et al., 2021). Ultimately, oxidative stress is tightly implicated in the pathophysiology of chronic disorders, such as diabetes, neurodegenerative and cardiovascular diseases, and cancer (Sharifi-Rad et al., 2020). Antioxidants are the first line of defense against the injurious effects of pro-oxidant species. By definition, an antioxidant is a molecule that prevents or retards the oxidation of a biomolecule both acting as radical scavengers (primary antioxidants) or modulating cellular mechanisms responsible for reactive species production (secondary antioxidants). They can be classified as enzymatic or nonenzymatic, or according to their mechanism of action, as preventive antioxidants, radical scavengers, repair antioxidants or antioxidants exploiting an adaptation mechanism. Finally, they can also be classified on the basis of their origin as endogenous, such as enzymes or small molecules produced by metabolic routes, and exogenous such as synthetic molecules and plant-derived secondary metabolites, normally not synthesized by human body whose intake is mainly due to diet or dietary supplements (Pisoschi et al., 2021). Literature describing the chemistry, absorption, and metabolism, mechanism of action and biological involvements of such antioxidants is very extensive, dating back to 1960 (Yeung et al., 2019). Nevertheless, the research on protective agents against oxidative stress never stopped growing, still resulting in a hot topic for the recent literature. The articles presented in this Research Topic further gathered scientific data and provided experimental evidence, therefore contributing to the potential development of new solutions for antioxidant implementation, development, and integration in therapeutic strategies. Recent discoveries assessing that oxidative stress is the main risk factor for several diseases without therapy, such as neurodegenerative diseases (NDs i.e., Alzheimer disease) and autoimmune disorders (i.e., multiple sclerosis, lupus, rheumatoid arthritis), opened new potential therapeutic approaches for their modulation. In addition, recent studies disclosing the involvement of oxidative stress in mitochondrial damage (Bobadilla et al., 2021; Mannucci et al., 2021), open new molecular pathways where antioxidants can play key roles. In this context, Costanzo et al., developed novel hydroxytyrosol-donepezil hybrids (Figure 1), and characterized their ROS scavenging, metal-chelating, and cytotoxic properties in vitro and in neuroblastoma cells. Among the donepezil hybrids, nitro hybrid HT2 and homovanillyl hybrid HT3a showed the most interesting antioxidant effects. The nitro Edited and reviewed by: Salvatore Salomone, University of Catania, Italy