Ninjurin-1 drives atherosclerosis progression via NF-κB/CXCL-8 activation in endothelial cells

Zhihong Sun¹Wenjuan Ma²Feng Ye¹Nana Ren¹Ke Shen^1*Nan Dong^1*

• ¹Shaoxing Central Hospital, Shaoxing, China
• ²Soochow University, Taipei City, Taiwan

Atherosclerosis represents the leading cause of cardiovascular mortality, with persistent inflammation driving residual risk despite lipid-lowering therapies. While Ninjurin-1 (Ninj1) has been implicated in inflammatory diseases, its endothelial-specific role in atherosclerosis remains unclear. Through integrated molecular, functional, and histological analyses, we demonstrate that Ninj1 is predominantly localized to vascular endothelial cells and is markedly upregulated during atherosclerosis. Ninj1 silencing in endothelial cells suppressed NF-κB signaling and its key inflammatory mediator CXCL-8, conferring protection against ox-LDL-induced endothelial dysfunction by enhancing proliferation and migration while reducing apoptosis (all p < 0.05). In ApoE-/- mice, pharmacological Ninj1 inhibition with mPN12 peptide significantly attenuated plaque development and lipid accumulation while preserving collagen content. Our results provide the first evidence that endothelial Ninj1 functions as a novel activator of the NF-κB/CXCL-8 axis, establishing its causal role in atherogenesis and highlighting its potential as a targeted anti-inflammatory therapy.