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.