A Unified Model of Cardiovascular Injury: How PANoptosis Connects Atherosclerotic Inflammation to Myocardial Death

Significance: Cardiovascular disease is traditionally viewed through fragmented lenses—atherosclerosis, ischemia–reperfusion injury, and heart failure as distinct entities. Emerging evidence positions PANoptosis, an integrated cell-death program combining pyroptosis, apoptosis, and necroptosis, as a unifying driver of inflammation and tissue destruction along the athero-myocardial axis. This synthesis reframes cardiovascular pathology as a continuum governed by shared immunometabolic triggers and coordinated cell-death machinery. Recent Advances: We outline how upstream nucleic acid sensors, notably Z-DNA binding protein 1 ( ZBP1 ) and absent in melanoma 2, orchestrate PANoptosome assembly, engaging receptor-interacting protein kinase (RIPK)1, RIPK3, Caspase-8, gasdermin D (GSDMD), mixed lineage kinase domain-like, and executioner caspases to produce multimodal lytic death. In the vasculature, disturbed flow activates Piezo1–Calpain signaling. This mechanotransduction is proposed to lower the threshold for endothelial PANoptosis, partly through mitochondrial Ca 2+ overload, reactive oxygen species (ROS) generation, and mitochondrial DNA (mtDNA) release. Concurrently, macrophage uptake of oxidized lipids triggers a mitochondria–stimulator of interferon genes–GSDMD feed-forward loop. This process expands necrotic cores and destabilizes plaques. In ischemic myocardium, succinate-driven reverse electron transport generates a ROS burst during reperfusion, causing mtDNA release and ZBP1 -dependent PANoptosis in cardiomyocytes. This cascade propagates systemic inflammation through defective efferocytosis, bone-marrow trained immunity, and extracellular vesicle (EV) cargo transfer, ultimately driving fibrosis and heart failure. Critical Issues: Several conceptual and translational issues remain critical. Vascular and myocardial injuries may share core PANoptotic machinery, but they are linked systemically through inflammatory, metabolic, and immune feedback loops rather than by a simple linear cascade. Co-activation of pyroptosis, apoptosis, and necroptosis should be distinguished from true molecular shunting within PANoptosomes. Emerging EV-based propagation mechanisms require careful interpretation, and therapeutic windows differ across endothelial injury, plaque progression, reperfusion injury, and remodeling. Future Directions: Future strategies should prioritize nanomedicine-enabled precision delivery, metabolic reprogramming, and time-sensitive intervention across the athero-myocardial axis. Innovation: This review proposes an athero-myocardial axis in which vascular and myocardial injuries share core PANoptotic machinery while being linked systemically through inflammatory, metabolic, and immune feedback loops. It differentiates co-activation from true molecular shunting within PANoptosomes, clarifies emerging EV-based propagation mechanisms, and maps time-sensitive therapeutic windows across endothelial injury, plaque progression, reperfusion injury, and remodeling. Antioxid. Redox Signal. 00, 000–000.