# IRF7 orchestrates maladaptive smooth muscle cell phenotype switching in atherosclerosis

## TL;DR

This study identifies IRF7 as a key driver of harmful smooth muscle cell changes in atherosclerosis, which could lead to new treatments for unstable artery plaques.

## Contribution

The study identifies IRF7 as a master regulator of pathogenic smooth muscle cell transdifferentiation in atherosclerosis.

## Key findings

- IRF7 orchestrates the transition of smooth muscle cells into pro-inflammatory macrophage-like cells in atherosclerotic plaques.
- SMC-specific knockdown of Irf7 reduces plaque progression and stabilizes fibrous caps in mice.
- High IRF7 expression correlates with plaque instability in human atherosclerosis.

## Abstract

Smooth muscle cells (SMCs) exhibit remarkable plasticity, undergoing extensive phenotypic switching to generate a highly heterogeneous population within atherosclerotic plaques. While recent studies have highlighted the contribution of SMC-derived macrophage-like cells to plaque inflammation, the specific molecular drivers governing the transition to these pathogenic states remain poorly understood.

Here, we re-analyzed single-cell RNA sequencing data from lineage-traced mice to dissect SMC heterogeneity during atherogenesis. Trajectory analysis revealed that SMCs transdifferentiate into a distinct pro-inflammatory macrophage-like subpopulation (macrophage 4) via an intermediate “stem–endothelial–monocyte" cell state. Integrated gene regulatory network inference and in silico perturbation modeling identified interferon regulatory factor 7 (IRF7) as a master transcriptional regulator orchestrating this specific pathogenic transition.

Clinically, IRF7 expression was significantly upregulated in unstable and advanced human atherosclerotic plaques, correlating strongly with inflammatory macrophage burden. In vivo, ApoE−/− mice challenged with a high-fat diet exhibited robust upregulation of IRF7 in aortic plaques, which co-localized with macrophage markers. Crucially, SMC-specific knockdown of Irf7 using an AAV-SM22α-shIRF7 vector significantly attenuated atherosclerotic plaque progression, reduced necrotic core formation, and enhanced fibrous cap stability. Mechanistically, Irf7 silencing preserved the contractile SMC phenotype and inhibited the accumulation of pro-inflammatory SMC-derived macrophage-like cells within the lesion.

These findings identify IRF7 as a critical checkpoint in maladaptive SMC phenotype switching. We demonstrate that IRF7 drives the transdifferentiation of SMCs into a pro-inflammatory macrophage-like state, thereby fueling plaque instability. Consequently, therapeutic strategies capable of inhibiting IRF7-mediated SMC plasticity may prove effective in stabilizing vulnerable atherosclerotic plaques.

Graphical AbstractSingle-cell RNA sequencing identifies the trajectory of SMC transdifferentiation into a pro-inflammatory macrophage-like state with IRF7 as the master regulator of this pathogenic transition. In human plaques, high IRF7 expression correlates with plaque instability. In vivo SMC-specific knockdown of Irf7 inhibits the maladaptive phenotypic switching and stabilizes the atherosclerotic plaque.

Single-cell RNA sequencing identifies the trajectory of SMC transdifferentiation into a pro-inflammatory macrophage-like state with IRF7 as the master regulator of this pathogenic transition. In human plaques, high IRF7 expression correlates with plaque instability. In vivo SMC-specific knockdown of Irf7 inhibits the maladaptive phenotypic switching and stabilizes the atherosclerotic plaque.