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Unveiling the miR‑26a‑5p/MSMO1/7‑DHC Axis: A Novel Therapeutic Target in Myocardial Ischemia-Reperfusion Injury
Yonglin Fu1, Bingjie Han2, Jiankai Zhang1
1School of Basic Medical Sciences, Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, Guangdong Medical University, Dongguan, 523808, China.
Abstract:
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.
Insights
MicroRNA-26a-5p targets MSMO1 to regulate ferroptosis in myocardial ischemia-reperfusion injury (MIRI). Engineered exosomes delivering miR-26a-5p show therapeutic potential for MIRI by reducing cardiac damage and fibrosis.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- Ferroptosis is a key mechanism in myocardial ischemia-reperfusion injury (MIRI).
- Cholesterol biosynthesis pathway dysregulation contributes to MIRI.
- MicroRNAs (miRNAs) are emerging regulators in cardiovascular diseases.
Purpose of the Study:
- To investigate the role of MSMO1 in ferroptosis during MIRI.
- To identify upstream regulators of MSMO1 in the context of MIRI.
- To develop and evaluate an exosome-based therapeutic strategy for MIRI.
Main Methods:
- Investigated MSMO1's role in ferroptosis using cellular and mouse MIRI models.
- Identified miR-26a-5p as an upstream regulator of MSMO1 via molecular assays.
- Developed engineered exosomes for targeted delivery of miR-26a-5p.
- Assessed therapeutic efficacy by measuring cardiac injury biomarkers, antioxidant capacity, and fibrosis.
Main Results:
- Downregulation of miR-26a-5p led to MSMO1 suppression, reduced 7-DHC accumulation, and increased lipid peroxidation and ferroptosis in MIRI.
- Engineered exosomes delivering miR-26a-5p significantly attenuated cardiac injury biomarkers (cTnI, CK-MB).
- Exosome therapy restored systemic antioxidant capacity and reduced early myocardial fibrosis in MIRI models.
Conclusions:
- MSMO1 is a novel regulator of ferroptosis in MIRI, modulated by miR-26a-5p.
- Engineered exosomes delivering miR-26a-5p represent a promising cell-free therapeutic platform for MIRI.
- This study offers a new therapeutic strategy targeting ferroptosis in MIRI.
