The role of Slfn4 in myocardial infarction: mechanisms and implications.

Abstract

Myocardial infarction (MI) is characterized by sudden interruption of coronary blood flow, leading to ischemic damage and cardiomyocyte death. Evidence for new molecular targets remains limited. Here, we investigated the role of Schlafen 4 (Slfn4), identified via bioinformatic screening, in MI pathogenesis. We analyzed GSE46395 microarray data and observed elevated Slfn4 expression in ischemic cardiac tissue. An MI mouse model further confirmed Slfn4 upregulation, which was abrogated by AAV9-mediated shRNA knockdown. Silencing Slfn4 reduced inflammatory cell infiltration and cardiomyocyte apoptosis, leading to lower serum levels of ANP, BNP, cTnT, cTnI, IL-1β, and TNF-α. Notably, Slfn4 knockdown augmented BNIP3-dependent mitophagy, evidenced by upregulated LC3 I/II, decreased P62, and reduced mitochondrial proteins (COX IV, TOMM20), while also suppressing DRP1-mediated mitochondrial fission. In cultured H9C2 cells subjected to hypoxia, Slfn4 knockdown likewise diminished apoptosis and enhanced BNIP3-associated mitophagy, whereas BNIP3 silencing reversed these protective effects, underscoring the importance of BNIP3-mediated mitophagy in Slfn4-driven cardioprotection. These findings indicate that Slfn4 promotes MI-induced damage by inhibiting BNIP3-mediated mitophagy and exacerbating mitochondrial fission. By contrast, Slfn4 knockdown fosters cardiomyocyte survival, highlighting its therapeutic potential for MI. Overall, our data suggest that modulating Slfn4 expression may preserve mitochondrial quality control, attenuate inflammation and apoptosis, and improve cardiac function following ischemic injury. .