A Novel Mechanism of Chlorogenic Acid in Cardioprotection: Blocking NLRP3 Inflammasome via Ca 2+ /CaMKIIα Signaling in Sepsis‐Induced Cardiomyopathy

ABSTRACT Sepsis‐induced cardiomyopathy (SICM) is a severe complication of sepsis, characterized by myocardial inflammation, oxidative stress, and cardiac dysfunction. Chlorogenic acid (CGA), a natural polyphenol with known anti‐inflammatory and antioxidant properties, is abundant in many traditional medicinal plants used for cardiovascular and inflammatory disorders. However, its cardioprotective effects in SICM and the underlying mechanisms remain unclear. An in vivo cecal ligation and puncture (CLP) model was used to induce SICM in rats, followed by CGA treatment. Cardiac function and myocardial injury markers were assessed, while NLRP3 inflammasome activation and CaMKIIα involvement were investigated using molecular docking, gene overexpression, and site‐directed mutagenesis. H9c2 cardiomyocytes were treated with lipopolysaccharide (LPS) and hypoxia/reoxygenation (H/R) to establish an in vitro SICM model. Mitochondrial function and pyroptosis were evaluated using oxygen consumption rate (OCR), extracellular acidification rate (ECAR), scanning electron microscopy (SEM), and key protein expression analysis. CGA improved cardiac function, reduced myocardial injury markers, and alleviated inflammation and fibrosis in SICM rats. CGA (25 μM) improved H9c2 cell viability in LPS + H/R‐induced SICM by reducing LDH, CK‐MB, and cTnT levels and suppressing inflammation, oxidative stress, and pyroptosis. It preserved mitochondrial function and cristae structure. Molecular docking and functional studies confirmed CGA binds to CaMKIIα and NLRP3, inhibiting inflammasome activation via the Ca 2+ /CaMKIIα pathway. Mutation of the GLU60 binding site abolished CGA's protective effects both in vitro and in vivo. CGA ameliorates SICM by suppressing NLRP3 inflammasome activation and pyroptosis through the Ca 2+ /CaMKIIα pathway. These findings offer new insights into CGA's cardioprotective effects and highlight its potential as a therapeutic agent for SICM.