Irisin targets the HK1-glycolysis-NLRP3 pyroptosis axis to prevent chronic kidney disease-associated vascular calcification.

Vascular calcification (VC) in chronic kidney disease (CKD) remains a critical clinical challenge with limited therapeutic options. This study investigates the regulatory role of HK1-mediated glycolysis in NLRP3 inflammasome-driven pyroptosis during chronic kidney disease (CKD)-associated vascular calcification (VC) and the protective effects of Irisin/FNDC5. Using β-glycerophosphate-treated vascular smooth muscle cells (VSMCs) and CKD mouse models, we employed transcriptomic analysis, FNDC5 genetic knockout, and overexpression strategies to dissect HK1's mechanistic contribution. Results revealed that HK1-dependent glycolysis amplifies NLRP3 inflammasome activation and pyroptosis in calcifying VSMCs, while Irisin suppressed HK1 expression and glycolytic flux, thereby inhibiting NLRP3-driven pyroptosis. Irisin precursor Fndc5 knockout exacerbated aortic calcification and upregulated HK1-NLRP3 signaling in CKD mice, whereas Irisin administration reversed these effects. This study demonstrates that HK1-driven glycolysis acts as a metabolic driver of NLRP3-mediated pyroptosis in CKD-associated vascular calcification. Irisin suppresses this HK1-glycolysis-inflammasome axis, thereby attenuating vascular smooth muscle cell pyroptosis and calcification. These findings reveal a previously unrecognized HK1-glycolysis-NLRP3 pathway as a metabolic-inflammatory target and suggest that Irisin/HK1 modulation may represent a novel therapeutic strategy for CKD-related vascular calcification.