TY - JOUR T1 - On the Clinical Pharmacology of Reactive Oxygen Species JF - Pharmacological Reviews JO - Pharmacol Rev SP - 801 LP - 828 DO - 10.1124/pr.120.019422 VL - 72 IS - 4 AU - Ana I. Casas AU - Cristian Nogales AU - Hermann A. M. Mucke AU - Alexandra Petraina AU - Antonio Cuadrado AU - Ana I. Rojo AU - Pietro Ghezzi AU - Vincent Jaquet AU - Fiona Augsburger AU - Francois Dufrasne AU - Jalal Soubhye AU - Soni Deshwal AU - Moises Di Sante AU - Nina Kaludercic AU - Fabio Di Lisa AU - Harald H. H. W. Schmidt A2 - Touyz, Rhian M. Y1 - 2020/10/01 UR - http://pharmrev.aspetjournals.org/content/72/4/801.abstract N2 - Reactive oxygen species (ROS) have been correlated with almost every human disease. Yet clinical exploitation of these hypotheses by pharmacological modulation of ROS has been scarce to nonexistent. Are ROS, thus, irrelevant for disease? No. One key misconception in the ROS field has been its consideration as a rather detrimental metabolic by-product of cell metabolism, and thus, any approach eliminating ROS to a certain tolerable level would be beneficial. We now know, instead, that ROS at every concentration, low or high, can serve many essential signaling and metabolic functions. This likely explains why systemic, nonspecific antioxidants have failed in the clinic, often with neutral and sometimes even detrimental outcomes. Recently, drug development has focused, instead, on identifying and selectively modulating ROS enzymatic sources that in a given constellation cause disease while leaving ROS physiologic signaling and metabolic functions intact. As sources, the family of NADPH oxidases stands out as the only enzyme family solely dedicated to ROS formation. Selectively targeting disease-relevant ROS-related proteins is already quite advanced, as evidenced by several phase II/III clinical trials and the first drugs having passed registration. The ROS field is expanding by including target enzymes and maturing to resemble more and more modern, big data–enhanced drug discovery and development, including network pharmacology. By defining a disease based on a distinct mechanism, in this case ROS dysregulation, and not by a symptom or phenotype anymore, ROS pharmacology is leaping forward from a clinical underperformer to a proof of concept within the new era of mechanism-based precision medicine.Significance Statement Despite being correlated to almost every human disease, nearly no ROS modulator has been translated to the clinics yet. Here, we move far beyond the old-fashioned misconception of ROS as detrimental metabolic by-products and suggest 1) novel pharmacological targeting focused on selective modulation of ROS enzymatic sources, 2) mechanism-based redefinition of diseases, and 3) network pharmacology within the ROS field, altogether toward the new era of ROS pharmacology in precision medicine. ER -