Deficiency of protein kinase Cδ reprograms macrophage immunometabolism to suppress pyroptosis and stabilize atherosclerotic plaques.

While atherosclerotic plaque vulnerability drives acute coronary syndrome, the regulatory mechanisms underlying plaque stability remain unclear. Protein kinase Cδ (PKCδ) has been implicated in atherosclerosis progression, but its specific role in plaque vulnerability and the underlying mechanisms require clarification. We analyzed PKCδ expression in human atheroma datas and investigated its role using low-density lipoprotein receptor-knockout mice with global and myeloid-specific PKCδ deletion. Plaque morphology, necrotic core formation, and fibrous cap thickness were evaluated. Macrophage metabolic profiling, mitochondrial function, inflammatory responses, and pyroptosis markers were assessed using biochemical and molecular approaches. Human atheroma analysis revealed elevated PKCδ expression, particularly in macrophages within ruptured plaques. PKCδ deletion in mice reduced necrotic core formation and increased fibrous cap thickness in both global and myeloid-specific models. Mechanistically, macrophage PKCδ deficiency improved mitochondrial fitness by promoting mitochondrial oxidative phosphorylation and elevating α-ketoglutarate (α-KG) levels. This metabolic shift reduced pro-inflammatory responses through PIK3AP1-mTORC2 activation and downregulated NLRP3 inflammasome-mediated pyroptosis. Dimethyl α-ketoglutarate (DKG) supplementation provided similar protective effects. Both human and in vivo analyses revealed PKCδ association with pyroptosis markers, including NLRP3, caspase-1, IL-1β, and GSDMD, whereas PKCδ deficiency reduced their co-localization with CD68⁺ macrophages. In conclusion, PKCδ serves as a key regulator of macrophage inflammation, pyroptosis, and mitochondrial dysfunction in atherosclerotic plaques. PKCδ deficiency promotes metabolic reprogramming that stabilizes plaques through reduced pyroptosis and enhanced mitochondrial function. These findings highlight PKCδ as a potential therapeutic target to reduce acute cardiovascular events by modulating plaque stability.