3.4.3 Ferroptosis induced by hyperglycemia plays an important role in the progression of diabetes and its complications
Pancreatic β-cell dysfunction and insulin resistance can lead to hyperglycemia(HG), which can increase MDA levels in cells, reduce GPX4 activity111, promote ferroptosis, and form a vicious cycle. This vicious cycle accelerates the process of diabetes and its complications. Previous studies have identified endothelial dysfunction as one of the most important factors in vascular complications of diabetes112. Hyperglycemia-induced oxidative stress and increased ROS production play an important role in the development of endothelial dysfunction. It has been proposed that HG induces ferroptosis in human umbilical vein endothelial cells (HUVECs), accompanied by a significant increase in p53 in HUVECs, and p53 siRNA and the use of ferroptosis inhibitors can attenuate HG-induced ferroptosis in HUVECs113. And studies show that in the condition of diabetes, endothelial p53 expression raised obviously, and endothelial-dependent vasodilation significant damage114. In an in vitro experiment mimicking diabetic brain ischemic injury, Meg3 expression was found to be increased, which could mediate p53 to cause ferroptosis by regulating GPX4 transcription and expression. Knockdown of p53 protected rat brain microvascular endothelial cells from ferroptosis induced by OGD + hyperglycemic reperfusion, whereas overexpression of p53 produced the opposite effect115. A recent study showed that HG intervention after MCAO aggravated neurological deficits, infarct size, oxidative stress, iron accumulation, and BBB damage in a hemorrhagic transformation model. Inhibition of P53 signaling attenuated ferroptosis in the endothelium and reduced HG-induced hemorrhagic transformation after MCAO116. In conclusion, p53 may mediate ferroptosis and play an important role in the progression of diabetes and its complications, and inhibition of the p53 signaling pathway may be a new therapeutic target for diabetes and its complications. Together, these findings suggest that ferroptosis plays an important role in the onset and progression of diabetes and its complications, and therefore, the treatment and prevention of ferroptosis is a very promising target for diabetes and its complications.