A chronically high-fat diet (HFD) can cause disorders in lipid metabolism, leading to metabolic syndromes such as obesity, hyperlipidemia (HLP), nonalcoholic fatty liver disease, type 2 diabetes, and cardiovascular diseases [1]. Among these symptoms, HLP is one of the most commonly observed signs of dyslipidemia [2]. In addition to dietary disorders, it has been reported that the causes of hyperlipidemia are diverse, including factors such as psychology, diabetes, pathology, and heredity [3]. Numerous investigations have proven that HLP presents a significant risk factor for developing ischemic heart disease and ischemic stroke [4]. Currently, common treatments for HLP include exercise, diet control, and medication such as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors [5,6]. It is essential to promptly and effectively treat hyperlipidemia to improve patient prognosis and prevent related complications.

The liver is the largest and most important metabolic organs in the body. It plays a crucial role in several metabolic processes, including the metabolism of triglycerides and cholesterol. However, compromised liver metabolism in the face of hepatic lipid accumulation increases in synthesis and secretion of lipids, thereby causing dyslipidemia and creating a vicious cycle [7]. A clinical research found that about half of the patients with HLP also suffered from fatty liver at the same time [8]. It is thought that high triglyceride caused by any reason can lead to hepatic steatosis [9]. Hence, singling out the liver metabolism as the likely promising point for HLP and its associated comorbidities.

Transcription factors are responsible for regulating specific gene expression programs in tissues through their interactions with enhancer elements. These enhancer elements play a crucial role in controlling the expression of genes that are specific to particular cell types [10]. Super-enhancers (SEs) refer to groups of enhancers densely packed in noncoding locations that drive the expression of genes controlling cell identity and disease at elevated levels [11,12]. High levels of master transcription factors, mediator coactivators, and enhancer epigenetic modification marks combine to form these SEs. SEs were initially defined by Chen et al. in 2004 [13], and were later redefined and more clearly identified by Young et al. in 2013 [14]. Compared to typical-enhancers (TEs), SEs differ in size, density and content of transcription factors, and their ability to induce transcription [11]. New avenues for SEs research have been made possible due to the fast advancement of genome-wide sequencing technology in the recent years. Subsequent studies have shown a close relationship between SEs and various diseases such as cancers, immune diseases, cardiovascular diseases, diabetes, neurodegenerative diseases, and liver diseases [15], [16], [17], [18]. Accordingly, there have been many attempts to use SE profiles for disease diagnosis and to design clinical therapeutics targeting SEs, including small-molecule inhibitors (JQ1, iBET762, OTX015, and CPI0610) against SE binding proteins and gene therapy strategies such as transcription activator-like effector nucleases and clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR-Cas9) [16].

The importance of SEs in cell identity and development suggests their potential involvement in the onset and progression of HLP disease. Despite this, the underlying role of SEs in the pathological process of HLP has not been reported. The aim of this study is to identify potential specific SEs of HLP to construct an SEs regulatory network. This network will allow us to explore the pathogenesis of this common disease further and identify new therapeutic targets.