Exercise-Induced Exerkines: Multi-Nodal Suppression of the NLRP3 Inflammasome and Translational Potential.

Chronic low-grade inflammation driven by persistent NLRP3 inflammasome activation is a unifying pathophysiological feature of most non-communicable diseases (NCDs). Whereas single-target pharmacological inhibitors exhibit limited breadth and durability, regular moderate-intensity exercise confers robust multi-system protection through a diverse network of exerkines. This narrative review synthesizes evidence that exercise-released myokines (irisin, Metrnl, context-reprogrammed IL-6), hepatokines/adipokines (FGF21, adropin, adiponectin), metabolites (lactate, β-hydroxybutyrate), microbiota-derived factors (SCFAs, betulinic acid), and extracellular vesicle (EV)-delivered non-coding RNAs converge on every regulatory node of the canonical NLRP3 inflammasome to achieve multi-nodal suppression that is currently unmatched by any single pharmacological approach based on available evidence. Acute high-intensity exercise transiently activates NLRP3 via canonical danger signals, whereas chronic moderate-intensity training (150-300 min·wk-1, 60%-75% HRmax) induces profound basal suppression through NF-κB attenuation, mitochondrial protection, direct interference with NEK7-NLRP3 interaction and ASC oligomerization, post-transcriptional silencing, and enhanced autophagic clearance. These mechanisms are supported by preclinical structural data and human biomarker studies across cardiovascular, metabolic, neurodegenerative, and musculoskeletal disorders. We propose a precision exercise medicine framework integrating exerkine/genetic/microbiome profiling to minimize non-responders, together with emerging mimetics, RNA therapeutics, and synergistic pharmacology, to deliver scalable systems-level modification of NLRP3-driven metaflammation.