Unraveling the Role of PTGIR in Atrial Fibrillation: Insights From Single‐Cell Sequencing and Mendelian Randomization

ABSTRACT Atrial fibrillation (AF) is associated with atrial fibrosis, yet the underlying molecular mechanisms remain unclear. This study employed single‐cell RNA sequencing (scRNA‐seq) and Mendelian randomization (MR) to identify key genes and pathways involved in AF pathogenesis. We analyzed 47 565 cells from AF and control samples using scRNA‐seq and identified eight cell subtypes. Fibroblast‐specific genes were prioritized for MR analysis to assess their causal relationships with AF. Functional enrichment and protein validation analyses were subsequently performed. Fibroblasts demonstrated predominant intercellular communication. MR identified COL6A2 and PTGIR as protective factors, while SERPINE1 and VIM were identified as risk factors for AF. Notably, PTGIR expression was elevated in AF samples, with enrichment analyses suggesting its potential involvement in cardiac contraction and oxidative phosphorylation pathways. Validation in a rat model confirmed increased expression of PTGIR and fibrosis markers (α‐SMA, COL3A1) in AF. Fibroblast‐mediated mechanisms, particularly those involving PTGIR, may play significant roles in AF pathogenesis. Pathway analyses suggest potential links to cAMP/PKA signaling.