The Dual Role of the TRAIL-DR5 Signaling Axis in Cardiovascular Disease: From Molecular Mechanisms to Targeted Therapies.

The TRAIL-DR5 signaling axis exhibits a pronounced "double-edged sword" nature in cardiovascular diseases, embodying both deleterious and protective roles. On one hand, it contributes to pathology by promoting cardiomyocyte apoptosis and enhancing inflammatory responses, thereby driving the progression of conditions such as myocardial ischemia-reperfusion injury, atherosclerotic plaque destabilization, and heart failure. On the other hand, under specific contexts, TRAIL-DR5 signaling can exert protective effects through mechanisms including the regulation of angiogenesis, suppression of inflammation, and facilitation of tissue repair. This functional dichotomy likely stems from cell-type specificity, dynamic microenvironmental changes, and crosstalk with other signaling pathways-such as NF-κB, MAPK, and autophagy-related processes. This review systematically examines the molecular mechanisms underlying TRAIL-DR5 signaling and its multifaceted involvement in acute myocardial infarction, heart failure, atherosclerosis, and atrial fibrillation. Furthermore, it explores targeted therapeutic strategies, including: DR5 agonists (such as monoclonal antibodies and small molecule compounds) for selective clearance of pathological cells; inhibitors (for instance, soluble DR5-Fc fusion proteins and siRNAs) to block deleterious signaling; and combination therapies (eg, with kinase inhibitors) to achieve synergistic efficacy. We propose that future investigations should prioritize the development of highly specific biomarkers, the refinement of targeted delivery systems, and a deeper mechanistic understanding of cellular and disease-stage heterogeneity. Such advances will be essential to propel the field from broad-spectrum treatments toward precision interventions, offering innovative solutions for complex cardiovascular disorders.