Recently, SEU Prof. Zhu Xinjian’s research team published a paper titledCircular RNA PTPN4 Contributes to Blood-Brain Barrier Disruption during Early Epileptogenesis in 

Advanced Science, a a leading international journal. This study provides the first systematic elucidation of a novel molecular mechanism in which a circular RNA called 

CircPTPN4 is critically involved in disrupting the blood-brain barrier (BBB) during the early stages of epilepsy. The findings offer a promising new target and biomarker for 

the diagnosis and intervention of epilepsy-related neurological damage.

The blood-brain barrier (BBB) is a crucial structure that protects the central nervous system by maintaining a stable internal environment. Its integrity is essential for brain 

health. Following epileptic seizures, the BBB’s integrity is usually damaged, which is considered a key factor in worsening the disease. The breakdown of the barrier allows 

harmful peripheral substances and inflammatory cells to invade the brain tissue, triggering more severe neuroinflammation, which further lowers the threshold for seizures 

and results in more frequent and severe episodes. However, the exact mechanisms behind how epilepsy “breaches” this critical protective barrier have remained unclear, 

and this has become a major obstacle in the clinical prevention of secondary neurological damage.

This study directly addresses this critical question. The research team used high-throughput circular RNA sequencing technology to discover that the expression of 

CircPTPN4 was significantly elevated in the cortical tissue of epileptic model mice. Subsequent cellular and in vivo experiments confirmed that this molecule was specifically 

upregulated in the brain microvascular endothelial cells under epileptic conditions, acting as a molecular “switch” for BBB disruption. Functional experiments showed that 

overexpression of CircPTPN4 directly increased the permeability of endothelial cells in the brain, damaging the BBB, whereas knocking down its expression alleviated barrier 

damage and significantly reduced the frequency of spontaneous seizures in chronic-stage mice.

At the mechanistic level, the research team outlined a clear and complete molecular pathway: CircPTPN4 acts as a “molecular sponge” within cells, competitively binding and 

inhibiting the protective microRNA miR-145a-5p. This binding leads to an increase in the expression of one of miR-145a-5p’s target genes, endothelin-converting enzyme 1 

(ECE-1). Elevated ECE-1 catalyzes the production of more endothelin-1 (ET-1), which has potent vasoconstrictive and pro-inflammatory effects. ET-1 further activates the 

p38 mitogen-activated protein kinase (p38/MAPK) signaling pathway within endothelial cells, ultimately leading to downregulation of tight junction proteins such as ZO-1 and 

Occludin, which are critical for maintaining cell-cell junction integrity. This cascade from CircPTPN4 to p38/MAPK forms the core mechanism responsible for increased BBB 

permeability during the early stages of epilepsy.

The study also found that the plasma levels of CircPTPN4 in epileptic mice correlated positively with the severity of BBB damage, and confirmed that this RNA originated from 

the endothelial cells in the brain. This discovery suggests that CircPTPN4 in plasma could potentially serve as a convenient and non-invasive liquid biopsy marker for early 

warning and dynamic monitoring of BBB status in epilepsy patients. In terms of treatment, the study identified the CircPTPN4/miR-145a-5p/ECE-1 axis as a novel therapeutic 

target. In the future, drugs or gene therapies designed to specifically inhibit CircPTPN4 could potentially prevent BBB disruption caused by epilepsy at its source, thereby i

nterrupting the pathological chain of events that exacerbate neurological damage and opening up new avenues for the development of neuroprotective treatments for epilepsy.

The first author of this paper is Yang Jiurong, a PhD student from SEU, with Associate Professor Zhu Xinjian being the corresponding author and SEU being the first 

corresponding institution. This research was funded by the National Natural Science Foundation of China, the Jiangsu Provincial Natural Science Foundation, and the Special 

Fundamental Research Funds for the Central Universities, among other sources.

Paper’s link: