Targeting PANoptosis in atherosclerosis: bridging cell death mechanisms and therapy.

Atherosclerosis (AS), a chronic inflammatory disease characterized by pathological cell death, remains a major cause of cardiovascular morbidity and mortality worldwide. PANoptosis, a recently defined form of inflammatory programmed cell death that integrates pyroptosis, apoptosis, and necroptosis, has attracted increasing attention. Transcriptomic analyses have revealed the upregulation of PANoptosis-related genes in atherosclerotic plaques, suggesting a potential role in disease progression. However, the precise molecular mechanisms through which PANoptosis contributes to AS remain largely undefined. In this review, we comprehensively explore the hypothetical upstream triggers and signaling pathways that may induce PANoptosis in vascular cells under pro-atherogenic conditions, such as dysregulated mitochondrial dynamics, mitochondrial oxidative stress and disturbed shear stress. We also discuss candidate PANoptosomes potentially involved in atherosclerotic contexts, such as ZBP1-, AIM2-, and RIPK1-dependent complexes. Although no selective inhibitors of PANoptosis have been developed, we summarize pharmacological agents targeting core components of the PANoptotic pathway and evaluate their potential implications in therapeutic strategies for AS.