Anacardic acid mitigates post‑MI cardiac fibrosis via suppressing p38/JNK-GATA3 pathway and H3K9ac‑dependent epigenetic regulation.

Myocardial fibrosis (MF), a hallmark of cardiovascular diseases (CVDs) such as myocardial infarction (MI), drives progressive cardiac dysfunction and adverse remodeling. Histone acetylation is a critical epigenetic regulator in cardiovascular pathology. Anacardic acid (AA), a histone acetyltransferase inhibitor (HATi) with pleiotropic bioactivities, has been studied in various disease contexts; however, its antifibrotic efficacy and mechanisms in MF remain unclear. In vivo, a mouse model of post-infarction MF was established by permanent left anterior descending (LAD) ligation. Using pirfenidone (PFD, an antifibrotic by inhibiting TGF-β) as a positive control, AA's effects were assessed by cardiac function, histopathology, and quantification of fibrotic burden. In vitro, primary cardiac fibroblasts (CFs) stimulated with TGF-β1 were used to delineate mechanisms, focusing on proliferation, migration, myofibroblast differentiation, and transcription of fibrosis-related genes. In vivo, AA and PFD comparably attenuated cardiac fibrosis and collagen deposition, downregulated fibrosis-related gene expression, and improved heart failure biomarkers in MI mice. Transcriptomic profiling indicated that MAPK pathway and GATA3 expression were reduced in AA-treated MI mouse hearts but increased in CFs in human MI single-cell RNA-sequencing datasets. In vitro, AA inhibited TGF-β1-induced CF proliferation, migration, and myofibroblast differentiation by suppressing p38/JNK phosphorylation, limiting GATA3 nuclear translocation, and reducing H3K9ac levels, thereby decreasing transcription of α-SMA, Col1a1, and Col3a1. AA protects against post-infarction MF by suppressing the p38/JNK-GATA3 pathway and downregulating H3K9ac-dependent epigenetic activation, supporting AA as a potential antifibrotic strategy and therapeutic candidate for cardiac fibrosis.