Targeted Delivery of Schisandrin A to Cardiac Endothelium Alleviates Myocardial Ischemia-Reperfusion Injury via Suppression of Ferroptosis

Purpose: Myocardial microvascular injury plays a critical role in myocardial ischemia‑reperfusion injury (MI/RI), and ferroptosis has emerged as an important contributor to cardiac damage. Although Schizandrin A (Sch) possesses cardioprotective effects, its clinical application is limited by poor stability and low bioavailability. This study aimed to develop a CMEC‑targeted delivery system for Sch and evaluate its ability to attenuate ferroptosis in cardiac microvascular endothelial cells (CMECs), thereby alleviating MI/RI. Methods: A cardiac endothelium‑targeting peptide CRPPR was conjugated to DSPE‑PEG2000 to prepare a Sch‑loaded nanoparticle (CRPPR@Sch). MI/RI was induced in mice by 45‑minute ischemia followed by 6‑hour reperfusion. CRPPR@Sch, free Sch, or non‑targeted DSP@Sch was administered intravenously for seven consecutive days. Cardiac function, infarct size, microvascular integrity and ferroptosis‑related markers were evaluated in vivo. In vitro, CMECs were exposed to hypoxia/reoxygenation (H/R), and ferroptosis was assessed. Results: CRPPR@Sch efficiently accumulated in cardiac endothelial cells, improved cardiac function, reduced infarct size, restored microvascular perfusion, and alleviated CMEC injury. RNA‑seq indicated that CRPPR@Sch suppressed ferroptosis‑related pathways. In vitro and in vivo experiments demonstrated that CRPPR@Sch significantly up‑regulated GPX4 expression, reduced ROS, lipid peroxidation and ferroptosis markers. Moreover, TRIM25 expression was elevated in MI/RI mice and H/R‑injured CMECs. Co‑immunoprecipitation and molecular dynamics simulations revealed that Sch binds to GPX4 and interferes with TRIM25‑mediated GPX4 ubiquitination and degradation. Conclusion: CRPPR@Sch effectively delivers Sch to cardiac endothelium, stabilizes GPX4 by disrupting the TRIM25‑GPX4 interaction, and thus inhibits ferroptosis in CMECs, ultimately protecting against myocardial microvascular injury in MI/RI.