PANoptosis in atherosclerotic plaques: Molecular mechanisms, clinical significance, and therapeutic potential.

Atherosclerosis (AS) is a leading cause of cardiovascular disease and occurs in the setting of chronic inflammation and lipid accumulation in the artery walls. A major driver of cardiovascular events is plaque vulnerability, characterized by large lipid-rich necrotic cores and thin fibrous caps. PANoptosis is a hybrid form of apoptosis, pyroptosis and necroptosis and has recently been identified as a critical regulator of plaque instability. This process is executed by the multi-protein PANoptosome complex, with key molecules such as Z-DNA binding protein 1 (ZBP1), receptor-interacting serine/threonine-protein kinase 1 (RIPK1), absent in melanoma 2 (AIM2), and caspases driving inflammation and cell death in macrophages and vascular smooth muscle cells. PANoptosis-related molecules regulating inflammation and necrosis, such as AIM2 and dynamin-related protein 1 (DRP1), also modulate the stability of plaque. For example, targeting PANoptosis pathways, by inhibiting AIM2 or modulating mitochondrial fission, could be a therapeutic intervention. However, the dynamic crosstalk between PANoptosis and other regulated cell death pathways has not been fully clarified. Here, we review molecular mechanisms and clinical significance of PANoptosis in atherosclerosis, as well as the potential of PANoptosis-related molecules as biomarkers and therapeutic targets. Future studies should elucidate the spatiotemporal dynamics of PANoptosis and design targeted therapies to modulate this pathway, which will provide new strategies for the treatment of atherosclerosis.