Front Immunol. 2026 Jul 1;17:1791961. doi: 10.3389/fimmu.2026.1791961. eCollection 2026.
ABSTRACT
Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid metabolic dysregulation and vascular cell phenotypic switching. Its progression is governed by intricate interactions between immune and vascular cells within multi-layered molecular networks. This review synthesizes recent evidence on the specific roles of key regulatory proteins in atherogenesis. We first examine how epigenetic modifiers, notably histone deacetylases, Sirtuins, EZH2, and TET2, remodel chromatin to activate pro-inflammatory gene programs. Subsequently, we delineate how critical transcription factors, such as KLFs, PPARs, Nrf2, and BACH1, couple metabolic homeostasis with anti-inflammatory responses. Furthermore, we detail how specific membrane signaling axes, including Eph receptors, Notch, and the SIRPĪ±-CD47 checkpoint, alongside RIPK-mediated cell death pathways, govern endothelial dysfunction, macrophage polarization, and efferocytosis. We also discuss the contributions of UCP and ANGPTL proteins to cellular metabolism and inflammasome regulation. Notably, we propose an integrative perspective on cross-tier signaling crosstalk, highlighting complex feedback loops among histone deacetylases, KLFs, and Eph receptors that amplify vascular inflammation. Ultimately, comprehensively elucidating these immuno-vascular networks will pave the way for next-generation, precision-targeted therapies to mitigate the global burden of cardiovascular disease.
PMID:42459705 | PMC:PMC13368522 | DOI:10.3389/fimmu.2026.1791961