# The JNK2-NLRP3 nexus in atrial fibrillation and its anti-AF therapeutic potentials

> **NIH AA R01** · OHIO STATE UNIVERSITY · 2026 · $591,477

## Abstract

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

## Key facts

- **NIH application ID:** 11332640
- **Project number:** 5R01AA031056-03
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Xun  Ai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** AA
- **Fiscal year:** 2026
- **Award amount:** $591,477
- **Award type:** 5
- **Project period:** 2024-06-01T00:00:00 → 2029-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11332640

## Citation

> US National Institutes of Health, RePORTER application 11332640, The JNK2-NLRP3 nexus in atrial fibrillation and its anti-AF therapeutic potentials (5R01AA031056-03). Retrieved via AI Analytics 2026-06-26 from https://api.ai-analytics.org/grant/nih/11332640. Licensed CC0.

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