Role of ROS in physiology and disease. ROS plays a crucial role in several physiologic mechanisms, i.e., angiogenesis, cell signaling, immune system, and memory formation. However, ROS have also been suggested to be part of several pathomechanisms because of a dysregulation of specific ROS sources that leads to unphysiological 1) regulation, 2) location, and 3) amount of ROS produced. Our approach is focused on inhibition of ROS formation through NOX, XO, MAO, NOS, and MPO. A parallel strategy focuses on the direct repair of ROS-induced damage through modulation of the cGMP-forming enzyme sGC using both activators [sGC activators (sGCas)] and stimulators (sGCs). ONOO⁻, peroxynitrite.

NADPH oxidase isoforms with clinical potential. NOX1 and 4 need a complete protein complex to be fully activated and generate superoxide (O₂⁻; in the case of NOX1) and H₂O₂ (in the case of NOX4). NOX5 stands out by being directly calcium-activated and also producing superoxide. Under several pathophysiological conditions, all NADPH oxidase isoforms can be directly induced. Pan-inhibitors, dual NOX1/4 inhibitors, and specific NOX4 and NOX5 inhibitors are shown based on their current status, i.e., under clinical testing or preclinical development.

Therapeutic targeting of NO-sGC signaling in physiology and disease. Under physiologic conditions, NO produced by NOS1 and 3 activates the sGC, which results in cGMP formation and cell signaling regulation. However, dysregulation of this mechanism leads to increase NO and superoxide production through NOS1 and NOS3, respectively, resulting in nitrative damage. In oxidative stress conditions, the sGC heme can be either oxidized or removed (apo-sGC) and, therefore, is no longer an active enzyme. NOS inhibitors, sGC stimulators, and activators are shown based on their current status, i.e., already marketed, under clinical testing, or under preclinical development. L-NAME, l-arginine methyl ester; L-NMMA, L-NG-monomethyl arginine; SMTC, S-methyl-L-thiocitrulline; un-NOS3, uncouple endothelial NO synthase.

XO as a therapeutic target. In normoxic conditions, ATP levels remain stable, whereas under hypoxia, ATP is catabolized, leading to accumulation of purines, i.e., inosine and hypoxanthine. XDH under oxidative conditions gets oxidized, leading to XO. Later, XO catabolizes purines to uric acid while generating ROS. Uric acid can directly activate inflammatory pathways, resulting in toll-like receptor–independent production of IL-1β and IL-18, activation of NACHT, LRR and PYD domains-containing protein 3 (NALP3) and, therefore, inflammation and oxidative stress coursing with the disease. XO inhibitors are shown based on their current status, i.e., already marketed or under preclinical development.

Clinical perspective of monoamine oxidase inhibitors. MAO-A and MAO-B catalyze the oxidative deamination of endogenous and exogenous amines including several neurotransmitters, i.e., serotonin, norepinephrine, and dopamine, leading to H₂O₂ and aldehyde production. Dysregulation of MAOs under certain pathologic conditions results in MAO activity and, therefore, elevated availability of MAO subproducts, i.e., H₂O₂. MAO inhibitors are shown based on their current status, i.e., already marketed or under clinical development.

Role of myeloperoxidase in physiology and disease. MPO generates through H₂O₂ several reactive chlorinating (Cl⁻), bromating (Br⁻), and radical (SCN⁻ NO₂) species, which are later transformed into more reactive hypohalous acids [hypobromous acid (HOBr), hypothiocyanous acid (HOSCN), hypochlorous acid (HOCl)] and reactive nitric species (NO^•/ONNO⁻). Thus, MPO actively contributes to nucleoside and lipid oxidation, together with protein (Tyr) nitration (NO₂Tyr) and chlorination (ClTyr). Dysregulation of MPO results in a broad oxidative environment that contributes to several pathologic conditions. MPO inhibitors are shown based on their current status, i.e., already marketed, under clinical testing, or under preclinical development. 8-oxoG, 8-oxo-guanosine.