CircFRRS1 drives neuroinflammation through the miR-27a-3p/TLR4 pathway after deep hypothermic circulatory arrest

TL;DR

This study shows that the circular RNA circFRRS1 worsens brain inflammation after a surgical procedure called deep hypothermic circulatory arrest by interacting with a specific pathway.

Contribution

The study identifies circFRRS1 as the first circRNA involved in DHCA-induced neuroinflammation.

Findings

circFRRS1 is upregulated in hippocampal tissue after DHCA and in hypoxic-ischemic PC-12 cells.

Silencing circFRRS1 reduces neuroinflammation and suppresses the TLR4/NF-κB/NLRP3 signaling pathway.

circFRRS1 functions as a molecular sponge for miR-27a-3p, which regulates TLR4 expression.

Abstract

Neurologic injury remains a critical complication of deep hypothermic circulatory arrest (DHCA) in aortic arch surgery, with neuroinflammation driven by multiple factors in its pathogenesis. While circular RNAs (circRNAs) are known to modulate inflammatory responses, their specific role in DHCA-associated brain injury has not been established. In this study, we demonstrated that circFRRS1 exacerbates hippocampal neuroinflammation via the miR-27a-3p/TLR4 axis through integrated in vivo and in vitro approaches. In a rat model of DHCA, machine learning-based motion sequencing (MoSeq) identified delirium-like behaviors, accompanied by hippocampal neuronal necrosis and activation of NLRP3 inflammasome. circFRRS1 was significantly upregulated in hippocampal tissue following DHCA and in hypoxic-ischemic PC-12 cells. Silencing circFRRS1 attenuated oxygen-glucose deprivation/reperfusion (OGD/R)-induced cytotoxicity and suppressed the TLR4/NF-κB/NLRP3 signaling pathway. Mechanistically, circFRRS1 acts as a molecular sponge for miR-27a-3p, thereby relieving its repression of TLR4; inhibition of miR-27a-3p abolished the observed neuroprotective effects. This study identifies circFRRS1 as the first reported circRNA to regulate DHCA-induced neuroinflammation, uncovering a novel epigenetic mechanism and suggesting the potential of circRNA-targeted therapies as adjuvants to conventional hypothermic strategies.

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