The Role of Cold-Inducible RNA-Binding Protein (CIRP) in Neurological Disorders

Feb 27, 2026Brain sciences

The Role of Cold-Activated RNA-Binding Protein in Brain Disorders

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Abstract

Cold-inducible RNA-binding protein (CIRP) plays critical roles in the central nervous system, with extracellular CIRP (eCIRP) being associated with neuroinflammation and brain injury.

Intracellular CIRP (iCIRP) helps maintain circadian rhythms by regulating core clock gene mRNA stability.
During mild hypothermia, iCIRP protects the blood-brain barrier and inhibits cell death.
eCIRP acts as a damage-associated signal that promotes neuroinflammation and contributes to brain injury in various conditions.
In ischemic stroke, eCIRP enhances the formation of neutrophil extracellular traps and activates microglia through the Toll-like receptor 4 pathway.
In cerebral ischemia-reperfusion injury, eCIRP triggers oxidative stress and activates the NLRP3 inflammasome, worsening mitochondrial damage.
eCIRP is linked to increased inflammation in intracerebral hemorrhage and activates pathways that intensify cell death in traumatic brain injury.

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Cold-inducible RNA-binding protein (CIRP) is a critical molecule in the central nervous system (CNS) with functions that depend on its subcellular localization, exhibiting biphasic regulatory roles in both physiological and pathological processes. Under physiological conditions, intracellular cold-inducible RNA-binding protein (iCIRP) contributes to the maintenance of circadian rhythms by regulating the stability of core clock gene mRNAs and exerts neuroprotective effects during mild hypothermia by preserving the blood-brain barrier and inhibiting apoptosis. Pathologically, extracellular cold-inducible RNA-binding protein (eCIRP) functions as a damage-associated molecular pattern (DAMP) that drives neuroinflammation and brain injury. In ischemic stroke (IS), eCIRP promotes neutrophil extracellular trap (NET) formation and increases microglial activity via the Toll-like receptor 4 (TLR4) pathway. In cerebral ischemia-reperfusion (I/R) injury, eCIRP activates oxidative stress and the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome through the TLR4 axis, exacerbating mitochondrial damage. In intracerebral hemorrhage (ICH), eCIRP further amplifies inflammation via the interleukin-6 receptor (IL-6R)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. In traumatic brain injury (TBI), eCIRP activates the endoplasmic reticulum stress pathway, intensifying apoptosis. In Alzheimer's disease (AD), eCIRP regulates tau phosphorylation and β-amyloid (Aβ) metabolism and may mediate the link between alcohol exposure and AD pathology. Preclinical studies indicate that serum eCIRP levels correlate with IS and ICH severity, highlighting its potential as a biomarker. This systematic review elucidates the mechanisms of CIRP in CNS diseases, providing insights for understanding and preventing conditions such as IS, cerebral I/R injury, ICH, TBI, and AD.

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The Role of Cold-Inducible RNA-Binding Protein (CIRP) in Neurological Disorders

Abstract

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