From Multi-Omics to Mechanism: Nucleocapsid–RCHY1–JUNB Axis Underlies SARS-CoV-2 Related Atrial Fibrillation Vulnerability

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BACKGROUND AND AIMS: SARS-CoV-2 exposure has been linked to cardiovascular complications, including atrial fibrillation (AF), but the host pathways coupling viral factors to atrial remodeling and AF vulnerability remain incompletely understood. METHODS: We integrated multi-cohort human transcriptomes from SARS-CoV-2-infected cardiac models and AF tissues, applied WGCNA and machine-learning-based feature selection, and profiled immune infiltration. To approximate a sustained low-grade inflammatory milieu relevant to prolonged COVID-19-related cardiovascular sequelae, mice with cardiac SARS-CoV-2 N expression underwent repeated low-dose LPS administration. JUNB loss-of-function was evaluated by rAAV9-mediated cardiac knockdown, with echocardiographic, electrophysiological, histological, and molecular phenotyping. Mechanistic studies were performed in modified cardiomyocytes. RESULTS: Integrated transcriptomic analyses identified JUNB as a shared hub associated with SARS-CoV-2-related cardiac signaling and AF, with enrichment of inflammatory pathways relevant to atrial remodeling. In the chronic inflammatory model, cardiac N expression exacerbated atrial enlargement, inflammatory-fibrotic remodeling, AF inducibility and duration, and AERP shortening, whereas cardiac JUNB knockdown attenuated these changes. Mechanistically, co-immunoprecipitation and in-cell ubiquitination assays showed that SARS-CoV-2 N enhanced the JUNB-RCHY1 interaction, promoting K63-linked ubiquitination and stabilizing JUNB. Site-mapping and functional assays identified K36 as the dominant ubiquitination site required for N-driven JUNB stabilization, TNF-α/NF-κB activation, and downstream inflammatory and fibrotic gene programs. CONCLUSION: Cardiac SARS-CoV-2 N protein promotes atrial inflammatory-fibrotic remodeling and AF vulnerability under chronic inflammatory conditions relevant to post-acute or prolonged COVID-19-related cardiovascular sequelae through RCHY1-dependent ubiquitination and stabilization of JUNB, identifying the N-RCHY1-JUNB axis as a mechanistically defined pathway for future therapeutic investigation.

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