In the initial stages of AS, endothelial cell damage triggered by various inflammatory responses and ischemic-hypoxia events leads to the release of adhesion and chemotactic cytokines. These cytokines attract monocytes and other leukocytes to the site of inflammation, where they mature and transition into macrophages (23–25). The intracellular accumulation of cholesterol in macrophages activates surface scavenger receptors, facilitating the binding of macrophages to lipoprotein particles and leading to foam cell formation (26, 27). Additionally, lipid accumulation prompts endothelial cells to secrete inflammatory mediators and cytokines, further accelerating AS onset. Additionally, dendritic cells (DCs) accumulating in atherosclerotic plaques play a crucial role in the disease’s progression by presenting oxidized low-density lipoprotein (ox-LDL)-derived antigens, which activate both humoral and adaptive immune responses (28, 29).

In the advanced stages of AS, adaptive immunity, especially cellular immunity, plays a role in T-cell infiltration ( Figure 1 ) (30, 31). Although T cells are not as abundant as monocytes, which undergo differentiation into macrophages, they can penetrate the intima to modulate the functions of innate immune cells and smooth muscle cells. T helper cells 1 (Th1) exert a pro-inflammatory role in AS, for example, by secreting interferon-gamma (IFN-γ), which promotes monocyte infiltration, macrophage differentiation, and foam cell formation. T helper cells 2 (Th2), on the other hand, by secreting interleukin (IL)-4 to play a disease prompting role. T helper cells 17 (Th17), activated under pro-atherogenic conditions, have complex effects because of the various roles of IL-17A at different AS stages. However, undoubtedly, the proportion of Th17 cells increases in patients with acute coronary syndrome. Conversely, regulatory T (Treg) cells are present in atherosclerotic plaques at all stages of AS, although in a smaller proportion (32, 33). Animal studies have reported the exacerbating effects of depleting Tregs in AS, while reintroducing Treg cells mitigates and slows disease progression (34). Mechanistically, Treg cells secrete IL-10, playing a crucial role in preventing AS progression. Additionally, Treg cells secrete transforming growth factor-beta (TGF-β) to inhibit inflammation and the proliferation of smooth muscle cells. While the role of humoral immunity in AS development is little known to us since B cells are occasionally detected in atherosclerotic plaques. Studies on B-cell dynamics in atherosclerotic mice have yielded contradictory results: one indicates B cells mitigate AS, while another suggests B cells exacerbate it following B cell depletion (35–38). This discrepancy underscores the need for a comprehensive examination of B cell populations and their specific functions.

Collectively, these findings indicate that the pathological mechanisms of AS involve the participation of endothelial cells, monocyte-derived macrophages, smooth muscle cells, and immune cells. Consequently, understanding the role of immune interactions during AS progression could pave the way for innovative strategies targeting these immune responses. Furthermore, baicalin can modulate immune cells and their actions in AS progression, positioning it as a promising approach for AS prevention and treatment.

After migrating to the intima, monocytes undergo differentiation into macrophages. These macrophages then engulf large amounts of ox-LDL through scavenger receptors, leading to the formation of foam cells (26). These foam cells play a crucial role in the progression of AS lesions, making the transition of macrophages into foam cells a critical phase in AS development and progression. Consequently, strategies aimed at promoting macrophage apoptosis and preventing of macrophage foam cell formation have emerged as key focus areas in AS prevention and treatment. Baicalin primarily functions by inhibiting macrophage foam cell formation, regulating cholesterol homeostasis, and facilitating macrophage apoptosis. Baicalin triggers macrophage apoptosis by activating three signaling pathways, namely c-Jun N-terminal kinases (JNKs), p38 mitogen activated protein kinase (p38/MAPK), and Steroid Receptor RNA Activator (SRA) (39), in response to lipopolysaccharide (LPS) and acetylated low-density lipoprotein (Ac-LDL), thus preventing foam cell formation in diseased cells. In studies utilizing an LPS-sensitized mouse macrophage model, baicalin demonstrated potential in modulating Protein kinase A (PKA) activity in macrophages, which, in turn, may suppress NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and cell pyroptosis (40). Additionally, Baicalin encourages M2 macrophage polarization and enhances phagocytosis by increasing Mer Tyrosine Kinase (MERTK) receptor expression (41).

Macrophages in AS primarily display two phenotypes: M1 and M2 types. In general, M1 macrophages, also known as classically activated macrophages, are typically involved in the initial pro-inflammatory response. In contrast, M2 macrophages contribute to anti-inflammatory processes and produce anti-inflammatory cytokines. In experiments investigating the effects of baicalin on RAW 264.7 macrophages cell line, it was found that Baicalin inhibited the expression of inflammatory factors IL-1β, IL-6, Tumor Necrosis Factor-α (TNF-α), Cyclooxygenase-2 (COX-2) in macrophage-derived foam cells. This upregulation promoted the expression of immunosuppressive factors TGF-β and IL-10, leading to the polarization of macrophages from M1 to M2 type, which inhibited the inflammatory response during the AS process. Further analysis, combined with relevant literature, revealed a potential association between this mechanism and Baicalin’s activation of the key protein peroxisome proliferator-activated receptor gamma (PPAR-γ) (42, 43). Previous studies have shown that Baicalin exhibits anti-inflammatory activity by inhibiting the activation of the Toll-like Receptor 4 (TLR4)/Myeloid Differentiation primary response 88 (MyD88)/Nuclear Factor-kappa B (NF-κB) cell signaling pathway (44). Recent research has further confirmed that Baicalin inhibits inducible Nitric Oxide Synthase (iNOS) gene functions, providing additional insight into Baicalin’s anti-inflammatory effects in AS (45). Baicalin can also inhibit macrophage proliferation, suppress excessive production of pro-inflammatory cytokines triggered by S100A8/A9, and reduce expression of the NADPH oxidase 2 (NOX2) gene, thereby inhibiting the inflammatory response (46). Despite the increasing understanding of the mechanisms by which Baicalin inhibits macrophage foam formation, further exploration is necessary to investigate its mechanisms for anti-foam cell formation and cholesterol metabolism from multiple perspectives. Additionally, compelling evidence shows that baicalin can reduce CD11c expression on DCs within atherosclerotic plaques, thus inhibiting DC maturation and the development of atherosclerotic lesions (47–49). Baicalin may also promote the transition of conventional DCs into plasmacytoid DCs and alter the expression of functional molecules by blocking the Signal Transducer and Activator of Transcription 5-Inhibitor of DNA binding 2 (STAT5-ID2) pathway, further demonstrating its protective effect against AS (50).

Adaptive immunity plays a crucial role in both the onset and progression of AS (23). Activated T cells, which have encountered antigens before, are present within atherosclerotic plaques. Studies using immunodeficient apo E ^−/− animal models, which lack both T cells and B cells, have shown fewer atherosclerotic events compared with their immunocompetent counterparts (51, 52). This evidence underscores the pro-atherosclerotic influence of T cells and suggests that immunosuppressive strategies may be beneficial for treating AS. Treg cells, in particular, contribute to the protection against AS development by releasing anti-inflammatory cytokines such as IL-10 and TGF-β. Supporting this notion, baicalin can enhance Forkhead Box P3 (Foxp3) expression, thereby promoting the differentiation of Treg cells within atherosclerotic plaques, and exerting anti-arteriosclerotic effects (22, 53, 54). The underlying mechanism is believed to involve baicalin’s inhibition of the Mammalian Target of Rapamycin (mTOR) pathway, leading to downregulated expression of Ras homolog gene family, member A (RhoA), Rho-Associated Coiled-Coil-Containing Protein Kinase 1 (ROCK1), phosphorylated STAT4 (p-STAT4), and p-STAT3, while simultaneously increasing phosphorylated STAT5 expression. The latter directly interacts with the Foxp3 gene, enhancing Treg cell function. Additionally, baicalin can influence the gut microbiome in an ulcerative colitis animal model, balancing Treg/Th17 ratios (55) and exhibiting anti-inflammatory properties. This suggests potential for further research into baicalin’s effects on the microbiome in AS. Baicalin also inhibits Th17 cell differentiation by downregulating IL-6 and Retinoic Acid Receptor-Related Orphan Receptor Gamma (RORctγ) expression (56). Yet, its effect on the Th1 cell population, which secretes IFN-γ and contributes to AS progression, remains less explored, warranting further investigation. Overall, the evidence supports baicalin’s immunomodulatory benefits in AS, particularly regarding Treg/Th17 balance.

Baicalin’s effect extends beyond adaptive immune cells, also influencing humoral immunity. However, the relationship between humoral immunity and AS presents conflicting evidence, necessitating further research (23). Baicalin is reported to significantly boost B cell proliferation and IL-12 production through its interaction with TLR4 (57). Additionally, by modulating signaling pathways such as NF-κB or Phosphoinositide 3-kinase/Protein Kinase B (PI3K/Akt), which are critical for B cell survival and homeostasis, Baicalin can potentially influence the lifespan and turnover of B cells which eventually affecting the quantity and quality of antibodies produced by B cells. The interplay between innate and adaptive immunity in the onset and progression of AS highlights the potential of baicalin as a therapeutic agent, primarily through its ability to regulate immune homeostasis.

Inflammation is a critical driver at all stages of AS, with chemokines, pro-inflammatory cytokines, adhesion molecules, and inflammatory signaling pathways (5) playing pivotal roles. The NF-κB signaling pathway, in particular, promotes AS by increasing the production of pro-inflammatory cytokines and chemokines such as IL-6, IL-1, Intercellular Adhesion Molecule-1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1), and TNF-α. Therefore, inhibiting NF-κB activation is effective in reducing AS incidence. Baicalin can suppress cytokine and chemokine production by inhibiting NF-κB activation in both in vitro and in vivo studies. Baicalin pretreatment to human umbilical vein endothelial cells confers protection from damage induced by vascular inflammation, which is similar to the early stages of AS, by suppressing NF-κB activity (58, 59). Baicalin can enhance SIRT expression in models of cardiovascular AS, acting as an inhibitor of NF-κB. This suppression of NF-κB leads to a reduction in the secretion and activation of downstream inflammatory factors (60). Additionally, baicalin influences the Wnt pathway, a crucial cellular signaling network involved in numerous biological processes, playing a significant anti-atherosclerotic role. Baicalin also promotes the activation of the Wingless-related integration site/Dickkopf-1 (Wnt/DKK1) pathway, potentially mitigating AS progression (61). Baicalin can also decrease the levels of inflammatory factors by promoting the phosphorylation of glycogen synthase kinase 3β (GSK3β), enhancing β-catenin expression and nuclear translocation, which is associated with the Wnt pathway (62). In summary, these findings underscore baicalin’s role in attenuating inflammatory responses, thereby decreasing the degree of AS progression.