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.

中文翻译：

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关于活性氧的临床药理学。

活性氧（ROS）与几乎所有人类疾病都息息相关。然而，通过ROS的药理学调节来对这些假设进行临床开发的情况很少见。因此，ROS与疾病无关吗？否。ROS领域的一个主要误解是将其视为细胞代谢的有害代谢副产物，因此，将ROS消除至一定可耐受水平的任何方法都是有益的。现在，我们知道，无论浓度低或高，ROS均可发挥许多重要的信号传导和代谢功能。这可能解释了为什么全身性非特异性抗氧化剂在临床上失败了，常常导致中性甚至是有害的结果。最近，药物开发集中在 鉴定并选择性调节在特定星座引起疾病的ROS酶源，同时保持ROS的生理信号和代谢功能完整。作为来源，NADPH氧化酶家族是唯一专门致力于ROS形成的酶家族。选择性靶向与疾病相关的ROS相关蛋白已经相当先进，一些II / III期临床试验和首批通过注册的药物都证明了这一点。ROS领域不断扩大，包括目标酶，并且日趋成熟，类似于越来越现代的，大数据增强的药物发现和开发，包括网络药理学。通过基于独特的机制（在这种情况下是ROS失调）而不是症状或表型来定义疾病，