Irx3 ameliorates post myocardial infarction cardiac dysfunction by regulating both inflammatory and fibrotic pathways

The Iroquois homeobox transcription factor Irx3 has been implicated in metabolic and hematological disorders, but its role in cardiac repair after myocardial infarction (MI) remains unclear. In this study, Irx3 expression was significantly reduced in C57BL/6 J mouse hearts after MI. Irx3 was predominantly expressed in cardiac fibroblasts, followed by cardiomyocytes. Fibroblast-specific overexpression of Irx3 reduced infarct size and fibrosis, thereby improving cardiac function. Cardiomyocyte-specific overexpression of Irx3 attenuated inflammation and improved cardiac function. Conversely, cell type–specific knockdown of Irx3 exacerbated fibrosis and inflammation, leading to impaired cardiac function. Mechanistically, Irx3 inhibited cardiac fibrosis in cardiac fibroblasts by regulating the Srpx2/AP-1/SMAD7/TGFβR1/SMAD3 signaling pathway. In cardiomyocytes, Irx3 reduced the production of pro-inflammatory cytokines by modulating the Ppm1l/NF-κB signaling pathway, thereby attenuating inflammation and fibrosis and promoting cardiac repair and functional recovery. Finally, in vivo rescue experiments further confirmed that Srpx2 overexpression abolished the cardioprotective effects of Irx3. Together, these findings identify Irx3 as a potential therapeutic target for post-MI cardiac repair.