Excessive binge alcohol intake is a well-recognized risk factor for atrial fibrillation (AF), the most common arrhythmia with a high morbidity and mortality, yet current therapies have suboptimal effectiveness. [While aging is an unavoidable AF risk factor, alcohol as a secondary stressor exacerbates AF risk in the aging population.] Clinical data suggest that one-third of all new-onset AF cases are related to alcohol intoxication and alcohol abuse brings a high AF risk even in people without co-existing cardiovascular diseases. It is a classic concept that enhanced inflammation contributes to alcohol-caused organ damage, which could also lead to AF. However, the ineffectiveness of the anti-inflammation therapies in AF patients has demonstrated the urgent need to understand the detailed underlying mechanisms of inflammation-associated AF and explore novel anti-AF therapeutic targets. The goal of this proposal is to fill this knowledge gap by establishing a previously unrecognized crosstalk between the pro-inflammatory signaling pathways and the stress kinase JNK2 in AF pathogenesis. In human donor atria, binge alcohol exposure increased pro-inflammatory TNFα and IL1β-NLRP3 signaling along with activated JNK2. And TNFα or IL1β significantly enhanced diastolic SR Ca2+ leak and triggered activities (Ca2+ waves and delayed after depolarizations), while either JNK2 or NLRP3 inhibition effectively alleviated those triggered activities, suggesting a crosstalk between JNK2 and pro-inflammatory signaling. However, we found that only TNFα, but not IL1β, activates cJNK2. Yet, TNFα is known to upregulate IL1β signaling, which could explain the involvement of NLRP3 in TNFα-induced triggered activities. But why JNK2 is not influenced by IL1β yet is critically involved in IL1β-NLRP3-mediated Ca2+ mishandling remains completely unknown. [This proposal is thus aimed to establish a novel and potentially paradigm-shifting and translationally important link between the JNK2-NLRP3 nexus