The role of interferon regulatory factors in atherosclerosis: from cell type-specific mechanisms to therapeutic strategies

Interferon regulatory factors (IRFs) constitute a family of transcription factors that orchestrate innate and adaptive immune responses, metabolic regulation, and cellular homeostasis. Emerging evidence demonstrates that IRF1–IRF9 play central immunometabolic roles in the formation, progression, and destabilization of atherosclerotic lesions. Pro-inflammatory IRFs, particularly IRF1, IRF3, IRF5, and IRF7, promote endothelial activation, M1 macrophage polarization, pyroptosis, impaired efferocytosis, and maladaptive phenotypic transformation of vascular smooth muscle cells (VSMCs), thereby amplifying vascular inflammation and leading to plaque vulnerability. In contrast, IRF2 and IRF4 exhibit anti-inflammatory and immunoregulatory properties, restraining excessive interferon signaling, supporting M2 macrophage polarization, and maintaining Treg/Th2 homeostasis. IRF8 and IRF9 display highly context- and cell-specific functions, integrating Dendritic cells (DCs) antigen presentation, T-cell activation, and VSMC remodeling with systemic metabolic cues. Therapeutically, both direct and indirect targeting strategies for IRFs are emerging, including small-molecule inhibitors, epigenetic modulators, upstream pathway blockade, microRNA-based interventions, and nutraceutical approaches. However, given their essential roles in antiviral immunity, future translational efforts must prioritize cell-and tissue-specific IRF modulation strategies to prevent systemic immunosuppression. Collectively, IRFs represent a convergent molecular axis linking immune activation, metabolic disturbance, and hemodynamic stress. A deeper understanding of IRF signaling networks, guided by single-cell multi-omics, genetic stratification, and precision delivery systems, may enable the development of immune-metabolic therapies to address residual inflammatory risk in atherosclerotic cardiovascular diseases.