JNK2 Is a Stress Integrator Driving Atrial Fibrillation Pathogenesis in Aging via Gut-Heart Crosstalk

BACKGROUND: dysfunction. However, the mechanisms by which cardiac JNK2 is activated during aging to promote AF remain unclear. Emerging evidence suggests that interorgan crosstalk contributes critically to the development of cardiovascular diseases. A hyperpermeable gastrointestinal epithelial barrier ("leaky gut"), commonly observed in aged individuals, is associated with elevated levels of proinflammatory cytokines and an increased risk of AF. Although proinflammatory cytokines have been proposed as predisposing factors for AF, clinical and experimental studies have yielded inconsistent results, underscoring the complexity of inflammation-associated AF pathogenesis. Here, we investigated whether cardiac JNK2 integrates diverse stress stimuli, including proinflammatory cytokines and lipopolysaccharide, to drive AF pathogenesis. METHODS: ) mice, and a well-established dextran sulfate sodium-induced leaky gut mouse model characterized by reduced gastrointestinal epithelial occludin expression. A series of physiological and molecular approaches was applied to assess cardiac and gastrointestinal responses. RESULTS: waves, and delayed afterdepolarizations. CONCLUSION: Activated JNK2 functions as a pathological nodal integrator of leaky gut-associated stress signals, mediating gut-to-heart crosstalk and driving inflammation-induced AF pathogenesis. Targeting JNK2 may represent a novel therapeutic strategy for AF.