Starlard-Davenport Athena, Palani Chithra D, Zhu Xingguo, Pace Betty S
Department of Genetics, Genomics and Informatics, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
Department of Pediatrics, Division of Hematology/Oncology, Augusta University, Augusta, GA 30912, USA.
Int J Mol Sci. 2025 Apr 28;26(9):4192. doi: 10.3390/ijms26094192.
Sickle cell disease (SCD) is a monogenic blood disorder characterized by abnormal hemoglobin S production, which polymerizes under hypoxia conditions to produce chronic red blood cell hemolysis, widespread organ damage, and vasculopathy. As a result of vaso-occlusion and ischemia-reperfusion injury, individuals with SCD have recurrent pain episodes, infection, pulmonary disease, and fall victim to early death. Oxidative stress due to chronic hemolysis and the release of hemoglobin and free heme is a key driver of the clinical manifestations of SCD. The net result is the generation of reactive oxygen species that consume nitric oxide and overwhelm the antioxidant system due to a reduction in enzymes such as superoxide dismutase and glutathione peroxidase. The primary mechanism for handling cellular oxidative stress is the activation of antioxidant proteins by the transcription factor NRF2, a promising target for treatment development, given the significant role of oxidative stress in the clinical severity of SCD. In this review, we discuss the role of oxidative stress in health and the clinical complications of SCD, and the potential of NRF2 as a treatment target, offering hope for developing effective therapies for SCD. This task requires our collective dedication and focus.
镰状细胞病（SCD）是一种单基因血液疾病，其特征是产生异常的血红蛋白S，该蛋白在缺氧条件下会聚合，导致慢性红细胞溶血、广泛的器官损伤和血管病变。由于血管阻塞和缺血再灌注损伤，SCD患者会反复出现疼痛发作、感染、肺部疾病，并过早死亡。慢性溶血以及血红蛋白和游离血红素的释放所导致的氧化应激是SCD临床表现的关键驱动因素。最终结果是产生活性氧物种，这些活性氧会消耗一氧化氮，并由于超氧化物歧化酶和谷胱甘肽过氧化物酶等酶的减少而使抗氧化系统不堪重负。处理细胞氧化应激的主要机制是转录因子NRF2对抗氧化蛋白的激活，鉴于氧化应激在SCD临床严重程度中的重要作用，NRF2是一个很有前景的治疗开发靶点。在这篇综述中，我们讨论了氧化应激在健康和SCD临床并发症中的作用，以及NRF2作为治疗靶点的潜力，为开发有效的SCD治疗方法带来了希望。这项任务需要我们共同的奉献和专注。
