Nuclear factor I-C as a novel candidate regulator in postoperative atrial fibrillation: integrated omics and proof-of-concept validation.

Postoperative atrial fibrillation (POAF) is a frequent complication of cardiac surgery, yet the upstream transcriptional regulators driving the pro-arrhythmic substrate remain unexplored. We aimed to identify and validate key transcription factors associated with POAF susceptibility. We performed cross-cohort integration of two independent human atrial transcriptomic datasets and applied machine learning (LASSO and SVM-RFE) to prioritize candidate genes. Transcriptional targets were predicted using the TRRUST database and protein-protein interaction (PPI) network analysis. Cellular localization was resolved using murine atrial scRNA-seq data. In vivo functional validation and biochemical signaling assays were performed in a spontaneous POAF (sPOAF) mouse model using AAV9-mediated NFIC overexpression. Nuclear Factor I-C (NFIC) was identified as a robust candidate regulator, showing consistent downregulation in human POAF cohorts and sPOAF mice. By intersecting predicted NFIC targets with the PI3K/Akt pathway, hepatocyte growth factor (HGF) was nominated as a putative downstream effector. Single-cell profiling localized NFIC and HGF predominantly to the atrial fibroblast lineage, where both were significantly downregulated in POAF. In the sPOAF model, p-AKT/AKT ratios were significantly reduced during the acute postoperative phase. Critically, AAV9-mediated NFIC restoration significantly decreased POAF incidence by 50%. Our findings identify NFIC as a novel candidate transcriptional regulator associated with POAF. These data support a working model involving a fibroblast-centered NFIC-HGF-PI3K/AKT axis, providing a fresh framework for understanding the upstream control of the postoperative atrial microenvironment.