Atherosclerosis (AS) is one of the most common cardiovascular diseases and a leading cause of death and disability worldwide. Although the clinical diagnosis and treatment approach of the condition are constantly improving, its morbidity and mortality continue to rise every year [1]. As a chronic inflammatory disease of the large arteries, the pathogenesis of AS involves the focal accumulation of low-density lipoprotein (LDL) cholesterol, and its oxidized products in the tunica intima, stimulating endothelial cell activation and monocytes recruitment, and triggering a series of inflammatory responses. During disease progression, monocytes differentiate into macrophages, engulf LDL to form foam cells, which gradually develop into atherosclerotic plaques [[2], [3], [4]]. Inflammation is considered a hallmark of AS, and its inhibition can effectively prevent or treat AS [5].

Nuclear factor κB (NF-κB) is a key regulator of vascular inflammatory reactions and drives the expression of various atherogenic molecules, including TNF-α and IL-1β. Therefore, abnormal activation of the NF-κB pathway is closely associated with AS development [6,7]. In the inflammatory microenvironment, pro-inflammatory factors can futher stimulate NF-κB to respond to inflammation, which leads to or enhances the expression of a series of inflammatory factors such as IL-6 [8]. During the development of AS, some inflammatory chemokines, such as CXCL2 and CXCL3, have been found to be involved in mediating recruitment, chemotaxis, and proliferation of monocytes and neutrophils in the lesion [[9], [10], [11]], further accelerating the development of AS. This series of inflammatory reactions continues to develop until the formation of atherosclerotic plaques in the arteries [12,13].

Sirtuins is a NAD + -dependent class III histone deacetylase and mono-ADP-ribosyltransferase that play a crucial role in various cellular processes, including cell metabolism, oxidative stress, and cell senescence [14,15]. Seven different sirtuins, Sirt1 to Sirt7, have been identified in mammals. Among them, Sirt4, Sirt3, and Sirt5 exist in the mitochondria of cells and are highly expressed in the heart, brain, liver, and islet β cells [16]. Sirt4 has been shown to play an essential role in cardiovascular diease. Liu et al. found that expression of Sirt4 in H9c2 cells under hypoxia decreased significantly. When Sirt4 was overexpressed, the activity of H9c2 cells under hypoxia was significantly increased, while the activity of caspase-3/7 was significantly decreased [17]. Luo et al. found that Sirt4 played a positive regulatory role in Angiotensin II-induced cardiac hypertrophy. Mice overexpressing heart-specific Sirt4 showed a more significant myocardial hypertrophy and higher ROS levels under Angiotensin II stimulation [18]. However, the effect of Sirt4 on AS and its underlying mechanisms have not been clearly confirmed. This study aimed to explore the effect of Sirt4 gene dificiency on AS and its possible mechanism. At the same time, the effect of NF-κB was specifically blocked by BAY11-7082, and futher reverse verification was carried out in vitro. This study provides a feasible new strategy for clinical diagnosis and treatment of AS.