Unveiling the miR‑26a‑5p/MSMO1/7‑DHC Axis: A Novel Therapeutic Target in Myocardial Ischemia-Reperfusion Injury.

Ferroptosis plays a critical role in myocardial ischemia-reperfusion injury (MIRI). Here, we discovered that MSMO1, a key enzyme in the cholesterol biosynthesis pathway, regulates ferroptosis in MIRI, and identified miR-26a-5p as an upstream regulator of MSMO1. During MIRI, downregulation of miR-26a-5p led to suppression of MSMO1, reduction of 7-DHC accumulation, and promotion of lipid peroxidation and ferroptosis. To translate this mechanism, we developed engineered exosomes delivering miR-26a-5p. In cellular and mouse MIRI models, this intervention significantly attenuated serum levels of cardiac injury biomarkers (cTnI and CK-MB), restored systemic antioxidant capacity, and attenuated early myocardial fibrosis. This work provides a novel therapeutic strategy for MIRI and provides preclinical evidence supporting the potential of engineered exosomes as a cell-free therapeutic platform.