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

ABSTRACT 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.