MG53 as a Potential Therapeutic Target for Myocardial Infarction Injury

Introduction: Myocardial infarction (MI) leads to irreversible cardiomyocyte loss and progressive ventricular remodeling largely driven by oxidative stress, inflammation, and mitochondrial dysfunction. Mitsugumin 53 (MG53/TRIM72) is a muscle-enriched membrane-repair protein that has emerged as a multifunctional regulator of cellular antioxidant responses, mitochondrial integrity, and anti-inflammatory signaling. This review synthesizes current evidence on the MG53’s mechanisms and therapeutic potential in MI. Methods: We performed a narrative review of preclinical and translational literature focusing on MG53 in cardiac injury. Databases searched included PubMed and Google Scholar (through 2025), using keywords "MG53," "TRIM72," "myocardial infarction," "isch-emia-reperfusion," "recombinant MG53," and "cardioprotection." Relevant mechanistic studies, recombinant protein interventions, and reports on the MG53’s systemic effects and safety were prioritized. Results: Preclinical studies demonstrate that MG53 promotes plasma-membrane resealing, preserves mitochondrial membrane potential, reduces mitochondrial ROS production, attenuates mitophagy, and upregulates endogenous antioxidant enzymes (e.g., HO-1, catalase, SOD). Recombinant human MG53 (rhMG53) or MG53 overexpression reduces infarct size, limits cardiomyocyte apoptosis, and improves functional recovery in rodent ischemia–reperfusion models. Additional benefits include suppression of NF-κB–mediated inflammation and modulation of necroptotic pathways via RIPK1 ubiquitination. However, there are conflicting data: chronic MG53 upregulation in some models has been associated with insulin signaling perturbation, and human data remain limited with variable reports on the cardiac MG53 expression and circulating levels. Safety, pharmacokinetics, and optimal delivery strategies for rhMG53 require further characterization. Conclusion: MG53 represents a promising cardioprotective target for MI through multimodal actions on membrane repair, mitochondrial protection, and antioxidant gene regulation. Translation to clinical therapy will require rigorous preclinical safety profiling, clarification of MG53’s systemic metabolic effects, and well-designed early-phase studies to evaluate pharmacology, dosing, and efficacy in humans. Future studies should explicitly address human expression patterns and reconcile metabolic concerns to safely harness MG53-based in-terventions.