What question did this study set out to answer?

This study aims to investigate whether NRG1 can reduce endothelial injury by inhibiting NLRP3 inflammasome activation and EndMT during cerebral ischemia-reperfusion injury.

March 1, 2026Open Access

NRG1 Suppresses NLRP3 Inflammasome Activation and Endothelial-Mesenchymal Transition in Cerebral Ischemia-Reperfusion Injury: Association with the AKT/NF-κB Pathway

Q: What does this research mean for the field?

NRG1 reduces cerebral infarct volume and alleviates neurological deficits by suppressing NLRP3 inflammasome activation and endothelial-mesenchymal transition in cerebral ischemia-reperfusion injury. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

Key Points

This study aims to investigate whether NRG1 can reduce endothelial injury by inhibiting NLRP3 inflammasome activation and EndMT during cerebral ischemia-reperfusion injury.
Established MCAO/R mouse models and OGD/R-treated human cerebral endothelial cells.
Applied NRG1 treatment to assess its effects on neurological function and cell viability.
Utilized mNSS, cerebral infarct volume quantification, cell viability assays, and Western blotting for analysis.
NRG1 significantly improved neurological function and reduced infarct volume in MCAO/R mice.
Increased cell viability and decreased cell death in OGD/R-treated endothelial cells after NRG1 treatment.
NRG1 enhanced AKT phosphorylation and inhibited NF-κB p65 phosphorylation, reducing NLRP3 and IL-1β levels.

Abstract

Background: Endothelial damage and NLRP3 inflammasome activation are key mechanisms underlying cerebral ischemia-reperfusion (I/R) injury. Neuregulin-1 (NRG1) alleviates endothelial damage, blood-brain barrier (BBB) disruption, and neurological deficits following acute ischemic stroke (AIS). This study investigates whether NRG1 attenuates endothelial-mesenchymal transition (EndMT) during endothelial injury by suppressing NLRP3 inflammasome activation, potentially through the AKT/NF-κB pathway, in cerebral I/R injury. Methods: Middle cerebral artery occlusion/reperfusion (MCAO/R) mouse models and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated immortalized human cerebral microvascular endothelial cells (hCMEC/D3) were established and treated with NRG1. Neurological deficits were assessed using the modified Neurological Severity Score (mNSS), while cerebral infarct volume and caspase-1 activity were quantified. Cell viability and death were evaluated by the Cell Counting Kit-8 (CCK-8), lactate dehydrogenase (LDH) assays, and TUNEL staining. Protein expression was analyzed using Western blotting and immunofluorescence staining. Results: NRG1 intervention significantly improved mNSS, reduced cerebral infarct volume, and decreased caspase-1 activity in MCAO/R mice. In OGD/R-treated hCMEC/D3, NRG1 enhanced cell viability while reducing cell death, as indicated by decreased LDH release and TUNEL-positive cells. Western blotting and immunofluorescence staining revealed that NRG1 enhanced AKT phosphorylation, inhibited NF-κB p65 phosphorylation, and downregulated NLRP3 and IL-1β expression. These effects were associated with the amelioration of occludin reduction and suppression of α-smooth muscle actin (α-SMA) increase during EndMT progression. Conclusion: The results demonstrate that NRG1 reduces cerebral infarct volume, alleviates neurological deficits, and suppresses NLRP3 inflammasome activation in association with modulation of the AKT/NF-κB pathway, thereby attenuating EndMT-associated proteins following cerebral I/R injury. Keywords: NRG1, ischemia/reperfusion injury, NLRP3 inflammasome, endothelial-mesenchymal transition

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