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CircFOXP1 alleviates brain injury after acute ischemic stroke by regulating STAT3/apoptotic signaling
Jialei Yang1, Wanting He1, Lian Gu2
1School of Public Health, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, Guangxi, China.
Abstract:
According to previous studies, circular RNAs (circRNAs) are involved in multiple pathological processes of acute ischemic stroke (AIS). However, the relationship between circFOXP1 and IS has not yet been reported. Here, we found that circFOXP1 expression was significantly decreased in the peripheral blood of AIS patients compared to controls and was associated with the severity and prognosis of AIS. Functionally, knockdown and overexpression of circFOXP1 promoted and inhibited apoptotic signaling, respectively, following oxygen-glucose deprivation/reperfusion (OGD/R) treatment in vitro. Adeno-associated virus (AAV)-mediated circFOXP1 overexpression attenuated neurological deficits and improved functional recovery after transient middle cerebral artery occlusion (tMCAO) treatment in vivo. Mechanistically, decreased QKI expression inhibited circFOXP1 biogenesis under hypoxic conditions. Decreased circFOXP1 expression accelerated signal transducer and activator of transcription 3 (STAT3) protein degradation by binding to and increasing STAT3 protein ubiquitination, ultimately aggravating brain injury after cerebral ischemia by activating apoptotic signaling. In summary, our study is the first to reveal that circFOXP1 alleviates brain injury after cerebral ischemia by regulating STAT3/apoptotic signaling, which provides a potentially novel therapeutic target for AIS.
Insights
Circular RNA FOXP1 (circFOXP1) is decreased in acute ischemic stroke (AIS) patients. Restoring circFOXP1 levels may protect against brain injury by regulating STAT3 signaling and apoptosis.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Circular RNAs (circRNAs) play roles in acute ischemic stroke (AIS) pathology.
- The specific role of circFOXP1 in AIS remains uninvestigated.
Purpose of the Study:
- To investigate the expression and function of circFOXP1 in AIS.
- To elucidate the underlying molecular mechanisms of circFOXP1 in cerebral ischemia.
Main Methods:
- circFOXP1 expression analysis in AIS patients' blood.
- In vitro studies using oxygen-glucose deprivation/reperfusion (OGD/R) models.
- In vivo studies with adeno-associated virus (AAV)-mediated circFOXP1 overexpression in a transient middle cerebral artery occlusion (tMCAO) model.
- Mechanistic studies involving QKI, STAT3 ubiquitination, and apoptosis signaling.
Main Results:
- circFOXP1 expression was significantly reduced in AIS patients and correlated with disease severity and prognosis.
- circFOXP1 knockdown exacerbated OGD/R-induced apoptosis, while overexpression inhibited it.
- AAV-mediated circFOXP1 delivery improved neurological function and recovery in a mouse model of ischemic stroke.
- Hypoxia reduced circFOXP1 biogenesis via decreased QKI expression.
- circFOXP1 inhibited STAT3 degradation by reducing its ubiquitination, thereby alleviating ischemic brain injury.
Conclusions:
- circFOXP1 is downregulated in AIS and plays a protective role against cerebral ischemia.
- circFOXP1 alleviates brain injury by inhibiting STAT3 protein degradation and subsequent apoptotic signaling.
- circFOXP1 represents a potential therapeutic target for AIS.
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