Master Regulator IRF7 Reprograms Smooth Muscle Cells, Driving Atherosclerotic Plaque Instability
Atherosclerosis, a chronic inflammatory disease underlying most heart attacks and strokes, involves vascular smooth muscle cells (VSMCs) in plaque development. These cells can either stabilize plaques or contribute to inflammation and tissue breakdown. Previously, the molecular signals guiding VSMC identity switching were not well defined. There has been a need to identify mechanisms driving harmful VSMC changes that promote plaque instability.
IRF7 Identified as a Key Driver of Plaque Destabilization
Researchers from the Naval Medical University and partner institutions have reported a significant breakthrough: interferon regulatory factor 7 (IRF7), a key immune-related transcription factor, actively reshapes VSMC behavior during atherosclerosis. The study, published on December 27, 2025, in Precision Clinical Medicine, indicates that IRF7 drives smooth muscle cells to transform into inflammatory, macrophage-like cells within arterial plaques. This transition accelerates plaque progression and destabilization, providing insight into how cellular identity changes contribute to plaque rupture risk.
Unveiling the Mechanism: From Single-Cell Analysis to Master Regulator
The research team utilized single-cell RNA sequencing with lineage-tracing models to map VSMC evolution during plaque development. Their analysis showed that VSMCs diverge into distinct macrophage-like states, with a pro-inflammatory subpopulation expanding during advanced disease stages. Gene regulatory network analysis identified IRF7 as a master transcriptional regulator of this pathogenic transition. Computational modeling further suggested that suppressing IRF7 would reverse VSMCs away from the inflammatory state.
"IRF7 drives smooth muscle cells to transform into inflammatory, macrophage-like cells within arterial plaques. This transition accelerates plaque progression and destabilization."
Experimental Confirmation and Human Relevance
Experimental confirmation in mice with smooth muscle-specific knockdown of Irf7 showed smaller atherosclerotic plaques, reduced lipid and necrotic tissue, and thicker, collagen-rich fibrous caps, all indicators of enhanced plaque stability. Crucially, these protective effects occurred without altering blood lipid levels, suggesting a direct role within the vessel wall. Human plaque transcriptomic data further supported these findings, with elevated IRF7 expression observed in unstable and advanced lesions, correlating with macrophage accumulation and inflammatory burden.
A New Therapeutic Opportunity
The findings establish IRF7 as a key molecular switch linking smooth muscle cell plasticity to plaque vulnerability. This research challenges the traditional view of VSMCs as passive structural components and suggests they actively acquire inflammatory properties under IRF7's control. Current atherosclerosis therapies primarily target systemic cholesterol. By identifying IRF7 as a driver of inflammatory VSMC reprogramming, this study presents a potential new therapeutic opportunity focused on the vessel wall.
"Targeting IRF7 or its downstream pathways could help prevent VSMCs from entering a harmful inflammatory state, stabilizing plaques without affecting lipid metabolism or immune defense, potentially complementing existing treatments."