Esculin Alleviated NLRP3 Inflammasome Activation by Inducing PINK1/Parkin-Mediated Mitophagy in Cerebral Ischemia–Reperfusion Injury

Feb 11, 2026Molecular neurobiology

Esculin may reduce brain inflammation after stroke by boosting cell cleanup through PINK1/Parkin pathways

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Abstract

Esculin (ESCU) demonstrated robust neuroprotection in mice with cerebral ischemia/reperfusion injury, reducing infarct size and preserving neuronal structure.

ESCU improved neurological deficit scores and cerebral blood flow in a mouse model of ischemia/reperfusion injury.
The treatment significantly alleviated oxidative stress and restored mitochondrial function, indicated by reduced reactive oxygen species and improved mitochondrial morphology.
ESCU activated mitophagy by upregulating key proteins (LC3Ⅱ, PINK1, Parkin) and downregulating p62.
It inhibited the NLRP3 inflammasome pathway, evidenced by decreased levels of NLRP3, GSDMD-N, cleaved caspase-1, IL-1β, and IL-18.
The mitophagy inhibitor Mdivi-1 reversed ESCU's effects on the NLRP3 pathway, suggesting a direct relationship between mitophagy activation and inflammasome inhibition.

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Cerebral ischemia/reperfusion injury (CIRI) refers to the secondary brain injury that occurs when blood supply is restored to ischemic cerebral tissue, and represents one of the primary causes of adult disability and mortality. Current evidence indicates that aesculin exhibits antioxidative and anti-inflammatory activities; however, its therapeutic effects on CIRI remain to be elucidated. The objective of this study was to investigate the potential role of Esculin (ESCU) in protecting against CIRI and to elucidate its underlying mechanisms. Adult male mice were used to establish the middle cerebral artery occlusion/reperfusion (MCAO/R) model. The mice were administered varying doses of ESCU or a reference positive control drug. To evaluate the neuroprotective effects of ESCU, neurological deficit scores were assessed, and cerebral blood flow was measured. 2,3,5-triphenyltetrazolium chloride staining, H&E staining, and Nissl staining were used to determine neuronal damage. NLRP3-related markers and mitophagy-related markers were determined to investigate the mechanism of action of ESCU. ESCU afforded robust neuroprotection in mice, ameliorating functional deficits, reducing infarct size, and preserving neuronal structure. It potently alleviated oxidative stress and restored mitochondrial function (reduced ROS, improved cristae morphology, and increased mitochondrial membrane potential). Mechanistically, ESCU activated mitophagy (upregulating LC3Ⅱ, PINK1, and Parkin; downregulating p62) and inhibited the NLRP3 inflammasome (downregulating NLRP3, GSDMD-N, cleaved caspase-1, IL-1β, and IL-18). Notably, the mitophagy inhibitor Mdivi-1 abolished ESCU's inhibition of the NLRP3 pathway, establishing a causal relationship. Thus, ESCU mitigates cerebral ischemia-reperfusion injury by coordinately enhancing mitophagy and suppressing NLRP3 inflammasome activation. Our study demonstrates that ESCU attenuates CIRI mechanistically by promoting PINK1/Parkin-mediated mitophagy, thereby suppressing NLRP3 inflammasome activation. These findings not only elucidate a novel pathway underlying ESCU's neuroprotection but also position it as a promising therapeutic candidate for CIRI, warranting further investigation into its precise targets and clinical potential.

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Esculin Alleviated NLRP3 Inflammasome Activation by Inducing PINK1/Parkin-Mediated Mitophagy in Cerebral Ischemia–Reperfusion Injury

Abstract

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