Atherosclerosis underlies most heart attacks and strokes and is now recognized as a chronic inflammatory disease rather than a simple disorder of cholesterol deposition. While immune cells such as macrophages have been widely studied, emerging evidence shows that vascular smooth muscle cells also play a central role in plaque development. These cells exhibit remarkable plasticity, contributing either to plaque stabilization or to inflammation and tissue breakdown. However, the molecular signals that determine whether smooth muscle cells adopt protective or pathogenic identities have remained poorly defined. Based on these challenges, there is a critical need to identify the regulatory mechanisms that drive harmful smooth muscle cell phenotype switching and promote plaque instability.
Researchers from the Naval Medical University and collaborating institutions report that a key immune-related transcription factor actively reshapes the behavior of vascular smooth muscle cells during atherosclerosis. Published (DOI: https://doi.org/10.1093/pcmedi/pbaf039) on December 27, 2025, in Precision Clinical Medicine, the study demonstrates that interferon regulatory factor 7 (IRF7) drives smooth muscle cells to transform into inflammatory, macrophage-like cells within arterial plaques. This transition accelerates plaque progression and destabilization, offering new insight into how cellular identity changes contribute to the risk of plaque rupture and cardiovascular events.
The team combined single-cell RNA sequencing with lineage-tracing models to map how smooth muscle cells evolve during plaque development. Their analyses revealed that, rather than following a single differentiation path, smooth muscle cells diverge into distinct macrophage-like states. Among these, one specific subpopulation displayed a strongly pro-inflammatory profile and expanded during advanced disease stages.
Gene regulatory network analysis identified IRF7 as a master transcriptional regulator controlling this pathogenic transition. Computational modeling predicted that suppressing IRF7 would reverse smooth muscle cells away from the inflammatory state. These predictions were confirmed experimentally: in mice with smooth muscle–specific knockdown of Irf7, atherosclerotic plaques were smaller, contained less lipid and necrotic tissue, and exhibited thicker, collagen-rich fibrous caps—hallmarks of enhanced plaque stability.
Importantly, the protective effects of IRF7 inhibition occurred without altering blood lipid levels, indicating a direct role within the vessel wall. Human plaque transcriptomic data further supported these findings, showing elevated IRF7 expression in unstable and advanced lesions, where it correlated strongly with macrophage accumulation and inflammatory burden. Together, the results establish IRF7 as a key molecular switch linking smooth muscle cell plasticity “Our findings challenge the traditional view that smooth muscle cells are passive structural components of atherosclerotic plaques,” said one of the study’s senior authors. “We show that these cells can actively acquire inflammatory properties under the control of IRF7, directly contributing to plaque vulnerability. By pinpointing IRF7 as a central regulator of this process, we provide a clearer mechanistic explanation for how chronic inflammation arises within the vessel wall and why some plaques are more prone to rupture than others.”
Current therapies for atherosclerosis primarily target systemic cholesterol levels, yet many patients remain at high risk due to persistent plaque inflammation. By identifying IRF7 as a driver of inflammatory smooth muscle cell reprogramming, this study highlights a new therapeutic opportunity focused on the vessel wall itself. Targeting IRF7 or its downstream pathways could help prevent smooth muscle cells from entering a harmful inflammatory state, thereby stabilizing plaques without compromising lipid metabolism or immune defense. Such strategies may complement existing treatments and reduce the residual risk of heart attack and stroke associated with plaque rupture.
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References
DOI
10.1093/pcmedi/pbaf039
Original Source URL
https://doi.org/10.1093/pcmedi/pbaf039
Funding information
This study was supported by the National Natural Science Foundation of China (grant No. 32171387).
About Precision Clinical Medicine
Precision Clinical Medicine (PCM) commits itself to the combination of precision medical research and clinical application. PCM is an international, peer-reviewed, open-access journal that publishes original research articles, reviews, clinical trials, methodologies, perspectives in the field of precision medicine in a timely manner. By doing so, the journal aims to provide new theories, methods, and evidence for disease diagnosis, treatment, prevention and prognosis, so as to establish a communication platform for clinicians and researchers that will impact practice of medicine. The journal covers all aspects of precision medicine, which uses novel means of diagnosis, treatment and prevention tailored to the needs of a patient or a sub-group of patients based on the specific genetic, phenotypic, or psychosocial characteristics. Clinical conditions include cancer, infectious disease, inherited diseases, complex diseases, rare diseases, etc. The journal is now indexed in ESCI, Scopus, PubMed Central, etc., with an impact factor of 5.0 (JCR2024, Q1). For further information, please refer to the journal homepage: https://academic.oup.com/pcm