ABSTRACT NUMBER: ESOC2026A1394 YY1 IN MONOCYTES PROMOTES INTRACRANIAL ATHEROSCLEROTIC STENOSIS VIA ROCK1-MEDIATED OXIDATIVE PHOSPHORYLATION

Abstract Background and aims Intracranial atherosclerotic stenosis (ICAS) is a major cause of ischemic stroke with a high recurrence risk, yet current drugs show limited efficacy in reducing recurrence rates. Monocytes are central to ICAS plaque inflammation and instability, yet their regulation is unclear. The transcription factor Yin Yang 1 (YY1) is involved in energy metabolism and inflammatory responses. This study aims to elucidate the role and molecular mechanisms of YY1 in monocytes during the progression of ICAS. Methods Peripheral blood samples were collected from patients with and without recurrent ICAS for single-cell RNA sequencing (scRNA-seq) to explore the cellular subpopulations and gene expression profiles during the ICAS progression. Conditional knockout mice of YY1 and ICAS mice were first constructed. Plaque burden was assessed using MRI, tissue-clearing 3D imaging, immunofluorescence, and HE. Mitochondrial ultrastructure was examined by transmission electron microscopy. In vitro, THP-1 monocytes were treated with oxidized low-density lipoprotein (ox-LDL), and YY1 was knocked down to detect ATP, mitochondrial membrane potential, and oxidative phosphorylation activity. Results Single-cell RNA sequencing revealed elevated YY1 expression in CD14+ monocytes in recurrent ICAS patients. YY1 deficiency reduced atherosclerotic plaque burden and mitochondrial damage. YY1 knockdown alleviated the decline in ATP and improved mitochondrial membrane potential. Mechanistically, YY1 regulates monocyte energy metabolism and promotes ICAS progression through ROCK1-mediated oxidative phosphorylation. Finally, activation of ROCK1 partially aggravated plaque lesions in ICAS mice. Conclusions These findings reveal a previously unknown role of monocyte YY1 in ICAS and highlight the YY1/ROCK1 axis as a potential therapeutic target. Conflict of interest Lingting Jin, Gang Li: nothing to disclose