Systemic lupus erythematosus (SLE) is a typical autoimmune illness marked by abnormalities in the innate and adaptive immune systems (Tsokos, 2011). There have been consistent reports indicating that the morbidity of SLE patients with atherosclerosis (AS)-related diseases is several times that of the general population, which frequently demonstrates significant organ vascular atherosclerosis in young and middle age (Tselios et al., 2019). AS entails metabolic and nutritional imbalance. Glucocorticoids, various immunosuppressants, and anti-malarial drugs such as hydroxychloroquine are used to treat SLE and AS. Although it is partially effective, it cannot prevent renal and cardiovascular disease (CVD) (Fava and Petri, 2019; Gustafsson et al., 2012), and the majority of immunosuppressive drugs cause liver and kidney damage (Blumenfeld et al., 2011; Mukwikwi et al., 2020). Therefore, better medications that can treat SLE in conjunction with AS are urgently required.

Traditional Chinese medicine (TCM) is being utilized to treat autoimmune illnesses and metabolic problems at present (Ma et al., 2016). Jieduquyuziyin prescription (JP) is an effective treatment for autoimmune diseases, as has been widely demonstrated (Ji et al., 2020, 2022). It was initially proposed in 1999 and has been utilized in clinical settings for over 20 years. It originated from traditional Chinese medicine classics, synopsis of prescriptions of the golden chamber, winning the second prize in the China National Science and Technology Progress Award (Wen et al., 2019). Previous studies have shown that JP has anti-inflammatory properties, regulating the adverse effects of glucocorticoids to avoid lupus nephritis in MRL/lpr mice and their BMDM (Ji et al., 2020; Liu et al., 2022). Additionally, active component of JP, paeoniflorin, modulates immunity and prevents the activation of inflammatory pathways in lupus nephritis (Liang et al., 2021). Sheng-ma-bie-jia-tang (SMBJT), an additional representative TCM formulation, has been lauded for its clinical efficacy in treating SLE (Huang et al., 2015). In a previous network analysis, we discovered that the SMBJT components could significantly inhibit Toll-like receptor 9 (TLR9) signaling in SLE. According to a previous study, autoantibodies can serve as TLR9 ligands. TLR is regarded as one of the primary stimuli that activate aberrant adaptive immune responses in SLE patients (Tilstra et al., 2020). In addition, TLR9 is closely associated with the development of atherosclerosis and is a target of AS (Fukuda et al., 2019). As we already know, the primary component of JP is similar to that of SMBJT, providing a summary of JP's effect on TLR9 signaling.

Macrophages is essential for AS lesions (Moore et al., 2013). The function of cholesterol efflux of macrophages is mediated by ABC transporters through regulated membrane cholesterol efflux in reverse cholesterol transport (RCT) (Shimizu et al., 2014). A function of RCT is to maintain the equilibrium of lipid metabolism in the cells and prevent the formation of foam cells, thereby preventing the occurrence of AS. In addition, some researchers (Zhu et al., 2010) suggests that genetic deletion of ABC transporters can lead to the depletion of cholesterol-rich domains in macrophages and the recruitment of TLR signaling to activate downstream pathways in a MyD88-dependent manner, pointing to the potential therapeutic benefits of therapy.

Here, we demonstrated the effect of JP on the spleen index, inflammation in serum and organs, autoantibodies, atherosclerotic plaque, markers of lipid metabolism, and molecular pathway mechanisms in pristane-induced apolipoprotein E-deficient (ApoE−/−) mice with SLE and AS. In the meantime, we used TLR signaling and the metabolism of cholesterol efflux as the entry point. In addition, we provided in vivo and in vitro experimental evidence for JP as a treatment for SLE combined with AS.