LRP1 in atherosclerosis: a hierarchical view of regulatory mechanisms and epigenetic knowledge gaps

Inflammation is a central driver of vascular dysfunction and plays a pivotal role in the initiation and progression of atherosclerosis. This chronic inflammatory condition arises from complex molecular, cellular, and epigenetic interactions within vascular and immune networks. Monocytes and macrophages act as key mediators of plaque development, integrating lipid handling and inflammatory signaling. Low-density lipoprotein receptor-related protein 1 (LRP1) has emerged as a multifunctional receptor at the interface between lipid metabolism and immune regulation, modulating Toll-like receptor pathways and inflammatory responses in a context-dependent manner. Here, we review current evidence on the regulatory mechanisms controlling LRP1 expression and propose a hierarchical framework in which transcription factor-mediated and non-coding RNA-mediated mechanisms represent the most strongly supported layers of regulation. In contrast, although epigenetic processes broadly influence vascular inflammation, direct chromatin-level interrogation of the LRP1 locus remains limited. Together, this framework highlights key knowledge gaps and provides a conceptual basis for understanding how multi-layered regulation of LRP1 contributes to vascular inflammation and plaque progression.