Potent Suppression of Heme-Induced Ferroptosis in Cardiomyocytes Enhances Cardiac Function Following Myocardial Infarction/Reperfusion Injury

Myocardial ischemia-reperfusion injury (MIRI) significantly worsens outcomes following myocardial infarction, primarily due to microvascular obstruction-induced myocardial hemorrhage in deeper regions. This hemorrhage leads to heme accumulation and triggers ferroptosis, a crucial pathological mechanism recently identified. Existing pharmacological treatments are ineffective and fail to reach the infarct core. To address this issue, we developed DecAS-PC@NM, a novel heme-responsive biomimetic vesicle loaded with decursin, an anti-ferroptosis herbal monomer. The vesicle is composed of synthetic phosphatidylcholines derived from artemisinin and thioether, engineered to disassemble and release decursin in response to heme-triggered reactive oxygen species that oxidize the thioether within the phospholipid bilayer. Incorporation of neutrophil membranes enhances targeting to the lesion. In vitro and in vivo studies demonstrated that DecAS-PC@NM effectively accumulates in the infarct core, counteracts ferroptosis and inflammatory responses, and significantly improves cardiac function. This targeted approach offers a promising therapeutic strategy for MIRI by specifically addressing heme accumulation and ferroptosis. Overall design: In this study, C57BL/6 mice were used to investigate the protective effects of Decursin on myocardial ischemia-reperfusion injury. A total of 18 mice were randomly divided into three groups, with 6 mice in each group:SHAM Group, IR (Ischemia-Reperfusion) Group, IR + Decursin Group. All mice were sacrificed at 7 days post-surgery, and heart tissues were collected for RNA sequencing (RNA-seq) analysis. This design aims to elucidate the molecular mechanisms by which Decursin may confer cardioprotective effects in the context of ischemia-reperfusion injury, with a focus on gene expression changes associated with the treatment.