Exerkine-Mediated Regulation of the NLRP3 Inflammasome in Neuroprotection: Mechanistic Insights and the Role of Exercise.

Neurodegeneration is a leading cause of long-term disability and cognitive impairment, and the aberrant activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is closely implicated in its pathogenesis. The NLRP3 inflammasome, as a central mediator of inflammatory cascades, can, when excessively activated, promote neuroinflammation and glial polarization, induce neuronal death, disrupt the blood-brain barrier, suppress angiogenesis and neurogenesis, impair synaptic plasticity, and induce inflammaging, ultimately leading to neurodegeneration. Exerkines, including neurotrophic factors, adipokines, myokines, hepatokines, enzymes/coenzymes, metabolites, and miRNAs, can target the aberrant activation of the NLRP3 inflammasome, exerting neuroprotective effects. Exercise has attracted increasing attention for its benefits to brain health, as it can modulate the release and expression of numerous exerkines (such as BDNF, NGF, GDNF, APN, Chemerin, Apelin, Irisin, CX3CL1, HSP90, IGF-1, LCN2, SAA, SIRT1, lactate, and exosomal miRNAs), which, through the activation of specific kinases and downstream signaling pathways in the brain, precisely target the excessive activation of the NLRP3 inflammasome and thereby ameliorate neurodegeneration. This review summarizes and critically evaluates recent advances in the mechanistic roles of the NLRP3 inflammasome in the onset and progression of neurodegeneration, as well as in the molecular mechanisms by which exerkines regulate the NLRP3 inflammasome to ameliorate neurodegeneration, and in exercise interventions, providing a theoretical basis for the precise and targeted application of exercise in the prevention and treatment of neurodegeneration.