Irx3 ameliorates postmyocardial infarction cardiac dysfunction by regulating both inflammatory and fibrotic pathways
The Iroquois homeobox transcription factor Irx3 is associated with metabolic and hematologic disorders, but its role in cardiac repair after myocardial infarction (MI) remains unclear. This study found that Irx3 expression is significantly downregulated in the hearts of wild-type mice post-MI and in human AC16 cardiomyocytes under oxygen-glucose deprivation (OGD) conditions. Overexpression of Irx3 improved cardiac function, reduced infarct size and myocardial fibrosis, attenuated inflammatory cell infiltration, prolonged survival in MI mice, and suppressed collagen synthesis and proinflammatory cytokine secretion in vitro. Mechanistically, Irx3 directly targets Srpx2 and Ppm1l: it downregulates Srpx2 to enhance AP-1 activity, increase SMAD7 expression, and inhibit TGF-ß/SMAD signaling to limit fibrosis; it upregulates Ppm1l to interact with IKKß, suppress NF-?B signaling, and reduce inflammatory cytokines (IL-1ß, IL-6, TNF-a). RNA sequencing (RNA-seq) of mouse left ventricular tissues and Irx3-overexpressing AC16 cells identified differentially expressed genes enriched in extracellular matrix (ECM) remodeling and inflammation-related pathways, confirming Irx3's coordinate regulation of profibrotic and proinflammatory pathways. These findings highlight Irx3 as a promising therapeutic target for post-MI cardiac repair and functional recovery. Overall design: Left ventricular tissues from C57BL/6J mice assigned to three groups (AAV9-Ctrl + Sham, AAV9-Ctrl + MI, AAV9-Irx3 + MI; n=4 per group), with MI induced by left anterior descending (LAD) coronary artery ligation and samples collected 14 days post-surgery.