Ross Gerrity confirmed the role of monocytes in atherosclerotic lesions and provided relevant electron microscopic evidence in 1981. Based on this theory, scientists have found that monocytes, driven by other differentiation factors, may differentiate into macrophages in the subendothelial space. Several studies have shown that foam cells are hallmarks of AS. Thus, the scientists speculate that removing excess cholesterol from macrophage-derived foam cells could be one strategy for treating AS in the future. Elucidating the multifaceted functions of monocytes holds promise for uncovering novel therapeutic strategies directed against atheromatous plaques. Investigations into the specific contributions of monocytes and macrophages during atherosclerotic pathogenesis, exemplified by the work of Victoria Stoneman and colleagues, have established the indispensable role these immune cells play in disease development. The following is a detailed description of the exact influence of macrophages on atherosclerotic lesions.

Within atherosclerotic plaques, T lymphocytes, specifically the CD4⁺ and CD8⁺ subsets, are recognized as vital components of adaptive immunity. Following antigen recognition, antigen-presenting cells stimulate CD4⁺ T lymphocytes, triggering their differentiation into T helper and regulatory T cell populations.

Th1 cells can secrete IFN-γ and tumor necrosis factor α (TNF-α), which can be identified by the defining transcription factor T-bet, and further contribute to plaque instability and the inflammatory environment. Moreover, the proinflammatory macrophage subtype observed within plaques is hypothesized to release cytokines that can recruit T cells and promote their inflammatory transformation, which is then amplified by IFN-γ secreted by pro-inflammatory cells. IFN-γ signaling is largely mediated by Janus kinase (JAK) and signal transducers and activator of transcription 1 (STAT1) cytosolic factor pathway^[36]. The latest research has found that m6A modification plays a crucial role in IFN-γ-induced upregulation and is subsequently essential for the development of atherosclerosis through macrophage activation mediated by downstream STAT1^[37]. In another experiment, AAV-6 highly expressing mice were subjected to carotid artery constriction and ligation. The researchers then obtained mice with unstable carotid artery plaques for subsequent experiments. By reducing the IFN-γ levels in T cells, the growth of plaques can be inhibited, and stability can be achieved^[38]. TNF-α is an inflammatory cytokine that participates in the pathogenesis of atherosclerosis and is known as an endothelial cell activator. TNF-α can induce the expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). A previous study has shown that inhibiting TNF-α can reduce atherosclerosis in ApoE^-/- mice^[39].

On the contrary, Tregs are thought to possess an anti-atherosclerotic effect, because they can release anti-inflammatory cytokines like TGF-β and IL-10. Endothelial-to-mesenchymal transition (EndMT) has been identified as a critical driver of vascular inflammation and atherosclerosis, and TGF-β is a key mediator of EndMT^[40]. In endothelial cells, activation of TGF-β signaling is a key driver of atherosclerosis progression. It induces endothelial-to-mesenchymal transition, converting endothelial cells into fibroblast-like cells, while upregulating adhesion molecules such as VCAM-1, ICAM-1, and pro-inflammatory chemokines, thereby exacerbating vascular inflammation and plaque instability^[41,42]. Studies have confirmed that TGF-β2 is the most effective subtype in inducing EndMT, and oxidative stress and hypoxia can synergistically enhance this process^[43]. At the same time, an imbalance between collagen and matrix metalloproteinases results in a thinner fibrous cap and an easier rupture of the plaque, and the quantity is positively correlated with human unstable plaques^[44,45]. Therefore, regulatory T cells can inhibit effector T cell activity, whereas enhanced effector T cell activity promotes the pathological process of atherosclerosis^[46]. In addition, single-cell sequencing techniques have shown that the number of Tregs in enlarged atherosclerotic plaques is greatly reduced. This, in turn, could help explain the protective role of Tregs in atherosclerotic disease. Th17 (T helper type 17) cells are characterized by their ability to secrete the inflammatory mediator IL-17 through several pathways to promote AS, in contrast to the protective effects of Tregs. High expression of IL-17 is associated with increased inflammation within the plaque, reduced smooth muscle cell content, and thinning of the fibrous cap, leading to an increased risk of plaque rupture. However, some studies have also found that IL-17 can stimulate smooth muscle cells to produce type I collagen, promoting thickening of the fibrous cap and thereby stabilizing the plaque [Figure 4]. The impact of IL-17 on plaque stability may be regulated by the local immune environment, such as the levels of IFN-γ and Treg cells^[47]. Specifically, in an inflammatory environment characterized by high IFN-γ, high IL-23, and low IL-10, IL-17 mainly exerts a pathogenic role: it induces neutrophil and monocyte recruitment into the plaque by inducing chemokines^[48]; it synergistically enhances the production of pro-inflammatory factors such as IL-6 and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in combination with TNF-α and IFN-γ; it upregulates matrix metalloproteinases to degrade collagen, weaken the fibrous cap, and increase the risk of plaque rupture^[49]; and it collaboratively promotes neovascularization and hemorrhage within the plaque with TNF-α^[50]. IL-17/IFN-γ double-positive T cells are present in human coronary artery plaques and synergistically enhance the inflammatory response; in ApoE^-/^- mice, IL-17 deficiency can reduce vascular inflammation and lesions^[51]. Conversely, in a regulatory microenvironment characterized by high TGF-β, high IL-10, and low IFN-γ, IL-17 exerts a protective role: it stimulates smooth muscle cells to synthesize type I collagen, increases the thickness of the fibrous cap, and enhances plaque stability^[52]; it inhibits the Th1 response through negative regulation with IFN-γ, indirectly reducing inflammation; it inhibits the expression of VCAM-1 in endothelial cells and reduces the recruitment of T cells and monocytes to the plaque; and, under the combined action of TGF-β and IL-6, certain Th17 cell subsets can simultaneously produce IL-10 and exert anti-inflammatory effects^[53,54]. Key evidence includes: IL-17 expression in human carotid artery plaques is positively correlated with smooth muscle cell and collagen content^[55]; in Low-density lipoprotein receptor knockout (LDLR^-/-) mice, supplementation with recombinant IL-17 can reduce plaque area, accompanied by a decrease in IFN-γ and an increase in IL-10; and in patients with acute myocardial infarction, the combination of low IL-17 and high VCAM-1 is associated with a higher 2-year risk of major cardiovascular events, suggesting that IL-17 may exert a protective effect by inhibiting VCAM-1^[56] [Table 1]. The CC chemokine ligand 18 (CCL18) is considered to be a T-cell chemokine, which is produced by monocytes and CD4⁺T cells. Its receptor, CCR6, is expressed in T-cell subtypes such as Treg and Th17 cells^[57]. Moreover, CCL18 promotes IL-6 secretion, which in turn drives Tregs to differentiate into pathogenic Th17 cells. Therefore, maintaining the balance of Th17/Treg provides insight into the treatment of AS. Moreover, this is the first time that the CCL18/CCR6 chemokine pathway has been considered as a target for atherosclerosis intervention^[57].

Cytotoxic CD8⁺ T cells exert a dual effect on AS depending on disease stage: in early atherosclerosis, they may promote plaque vulnerability by reducing monocyte recruitment; in advanced disease, they can reduce macrophage and Th1 cell populations and exert protective effects. Thus, it is crucial to elucidate the dominant mechanisms by which CD8⁺ T cells influence atherosclerosis. Wang et al.^[58] carried out a series of controlled experiments and suggested that, compared with stable plaques, the amount of CD8⁺ T cells was significantly lower in unstable plaques, which is instructive to support van Duijn’s conclusion^[59] mentioned above. Vos et al. have found that Casitas B-lymphoma proto-oncogene-B (CBL-B), which exists in macrophages and T cells, can specifically increase the activation of pro-inflammatory CD8⁺ T cells; however, excessive activation leads to T cell depletion. Thus, CD8⁺ T cells may lose their pro-atherogenic role, which is the reason why plaque was reduced in CBL-B deficiency mice^[60]. This makes CBL-B a potential therapeutic target.

This evidence shows that AS is a complex immune disease, and the complex interactions among various immune cells lead to the persistent balance of protective and pro-atherogenic effects during the atherogenic process. Based on the theories mentioned above, T cell regulation is another major therapeutic strategy for AS. A better understanding of the exact function of T cells in atherosclerotic lesions and their mechanisms of action will provide a new basis for the future development of therapies that specifically target T cell subsets to combat atherosclerosis.

Like T cells, B cells express diverse roles through various subtypes such as B1, B2, and regulatory B cells (Breg). However, B cells are less abundant than T cells in atherosclerotic lesions. B1 cells are characterized by the secretion of IgM antibodies in a T-cell-independent manner. Subsequently, studies have found that antibodies against ox-LDL are produced by B1 cell-derived plasma cells. This finding provides another link between B cells involved in humoral immunity and atherosclerotic disease. These antibodies specifically bind to oxidized LDL, resulting in decreased macrophage uptake, diminished foam cell generation, and suppression of inflammatory pathways, ultimately exerting a protective effect in atherosclerosis. Similarly, Bregs can contribute to plaque stabilization and inhibit inflammatory processes by releasing the anti-inflammatory cytokine IL-10. This enables them to regulate the inflammatory process, thereby inhibiting the formation of atherosclerotic plaques. In contrast, B2 cells secrete pro-inflammatory cytokine interferon-γ and pathogenic IgG antibodies, which may exacerbate atherosclerotic mechanisms at the lesion site. In summary, the role of B cells is subset-specific and can be divided into subsets that promote atherosclerosis and subsets that inhibit AS.

Natural Killer (NK) cells, traditionally known for their role in antiviral and antitumor immunity, have been increasingly implicated in the pathogenesis of atherosclerosis. NK cells have been detected within human and murine atherosclerotic plaques, predominantly in advanced lesions, necrotic cores, and plaque shoulder regions^[61]. Moreover, elevated circulating NK cell counts have been reported in patients with advanced atherosclerosis, suggesting their active involvement in disease progression.

NK cell recruitment is mediated by chemokines and cytokines and involves interactions with macrophages and dendritic cells. Activating receptor ligands expressed by macrophages and endothelial cells enhance NK cytotoxicity. Ox-LDL and cholesterol crystals also influence NK cell function^[62].

However, different experimental models have yielded conflicting results regarding the exact role of NK cells. Some studies report that NK cell deficiency or depletion in mice reduces plaque size and inflammation, supporting a pro-atherogenic role. For example, NK depletion in ApoE^-/- mice attenuated atherosclerosis. Conversely, other models, such as mice lacking NK function, showed no significant difference or even increased lesion development. This discrepancy may arise from differences in mouse strains, methods of NK cell depletion, or compensatory immune mechanisms^[63,64].

In conclusion, while strong evidence supports a pro-inflammatory and plaque-destabilizing role for NK cells in atherosclerosis, their full contribution remains incompletely defined due to contradictory experimental findings. Clarifying these divergent results is important for developing NK cell-targeted therapies.

Beyond monocytes, macrophages, T/B lymphocytes, and NK cells, several innate immune cell types, including neutrophils, mast cells, and dendritic cells (DCs), play crucial roles in the pathogenesis of atherosclerosis. DCs serve as pivotal bridging cells between innate and adaptive immunity by internalizing ox-LDL, presenting antigens to T cells, and secreting pro-inflammatory mediators that promote lesion progression^[65,66].

Neutrophils infiltrate plaques predominantly during acute phases, releasing ROS, proteases, and neutrophil extracellular traps (NETs)^[67,68]. While these processes aid in the clearance of necrotic debris, they also degrade elastic fibers within the fibrous cap through elastase activity, leading to cap thinning and increased plaque vulnerability. Pharmacological inhibitors of NET formation, such as cilastatin sodium (SVT), have thus been proposed as novel strategies for plaque stabilization^[69].

Mast cells accumulate progressively within plaques and degranulate to release a variety of cytokines, directly exacerbating local inflammation and promoting thrombotic events. Clinical correlations indicate that heightened mast cell activation is associated with parameters of plaque vulnerability, suggesting that mast cell stabilizers hold therapeutic promise^[70].

Emerging evidence positions extracellular vesicles (EVs) and their non-coding RNA (ncRNA) cargo as novel mediators in the pathogenesis of atherosclerosis, bridging the gut-heart axis and liver-vascular crosstalk. Bacterial EVs (BEVs) from pathogens such as Helicobacter pylori and Porphyromonas gingivalis deliver lipopolysaccharide and virulence factors directly into arterial cells, triggering endothelial dysfunction, NLRP3 inflammasome activation, foam cell formation, and vascular calcification^[71]. Conversely, BEVs from commensal Akkermansia muciniphila and probiotics reinforce intestinal barrier integrity and promote anti-inflammatory M2 macrophage polarization, thereby limiting systemic inflammation and atherogenesis. Beyond the gut, hepatocyte-derived EVs enriched with miR-1 under non-alcoholic fatty liver disease conditions transfer this miRNA to endothelial cells, where it suppresses KLF4 and activates nuclear factor kappa B (NF-κB), driving vascular inflammation and plaque progression^[72]; inhibition of miR-1 markedly reduces atherosclerosis in mice. Collectively, these findings establish EV-ncRNA axes as critical regulators of AS, offering novel diagnostic biomarkers and therapeutic targets independent of traditional lipid pathways^[73,74].

The inflammatory caspase subfamily includes caspases1, 4 and 5 in human and caspases11 in rodents^[77,78]. According to the dependent caspase, pyroptosis-related signaling pathways can be divided into classical pathways mediated by caspase-1 and non-classical pathways mediated by caspase-4/5/11.

Gasdermin D (GSDMD) is a member of the gasdermin protein family that forms membrane pores. GSDMD is the common substrate of caspases in both of the above pathways. Thus, it is considered to be a key effector of pyroptosis, inducing cell rupture, the release of large amounts of Interleukin-18 (IL-18) and IL-1β, and inflammation.

In the classical pathway, activated caspase-1 can cleave GSDMD to generate GSDMD-NT, which inserts into cell membranes to form pores, increases membrane permeability, induces cell swelling and rupture, and promotes the release of cellular contents [Figure 5]. Recent studies have shown that GSDMD-NT palmitoylation can control a key regulatory mechanism for the properties of GSDMD, namely membrane localization and activation. This provides a possible target for the treatment of inflammatory diseases. On the other hand, activated caspase-1 can cleave pro-IL-1β and pro-IL-18, activating them to form mature IL-1β and IL-18, which are released into the extracellular space through membrane pores to amplify the inflammatory response and eventually lead to pyroptosis. IL-1β may have both beneficial and adverse effects on the development of atherosclerotic plaques. However, it is generally accepted that its adverse effects predominate, which warrants further study. Compared with IL-1β, although fewer studies have examined IL-18, it also has pro-atherogenic effects in mice and humans. In contrast, Shao Feng’s lab conducted a series of experiments and found that human caspase-4/5 and mouse caspase-11 bind bacterial LPS, which is responsible for further activation of the pyroptosis pathway [Figure 5]. This pathway is not associated with the cleavage of inflammatory cytokines pro-IL-1β and pro-IL-18.

Previous studies have confirmed that caspase-1-induced increase in IL-1β and IL-18 can promote atherosclerosis and increase plaque instability. The important role of caspase in pyroptosis has attracted considerable attention and has become a new therapeutic target for many human diseases^[79,80]. In murine models of atherosclerosis (e.g., ApoE^-/^- or Ldlr^-/^- mice), genetic deletion of GSDMD^[81] or pharmacological inhibition of NLRP3^[82-84] significantly reduced plaque burden and inflammation.

In vitro studies have demonstrated that caspase-1-mediated cleavage of GSDMD and pro-IL-1β/pro-IL-18 is sufficient to induce pyroptosis in human macrophages, endothelial cells, and VSMCs upon stimulation with ox-LDL or cholesterol crystals. Although GSDMD-mediated pyroptosis is closely related to atherosclerosis, current studies remain limited in their exploration of its cellular pathways and molecular mechanisms. To further investigate the localization of GSDMD in various atherosclerotic cell components, Fan et al. conducted relevant research. In 2024, they provided a novel therapeutic target mechanism for GSDMD-associated atherosclerosis^[81]. They established two groups of mice, including ApoE^-/- mice and GSDMD^-/- ApoE^-/- mice, which demonstrated that GSDMD exists in macrophages by using single-cell RNA sequencing^[85] and found that GSDMD inhibitor Y1 can also be used to prohibit the promotion of atherosclerosis. However, whether GSDMD affects pyroptosis in other cell types, such as ECs and VSMCs, remains to be investigated.

The nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is widely expressed in human immune cells, such as monocytes, macrophages, T cells, and B cells. To demonstrate the expression of pyroptosis-related proteins in human coronary arteries and their relationship with AS, Zhou et al. performed immunohistochemical analysis of 40 human coronary artery specimens and showed that AS severity was positively correlated with caspase-1 and NLRP3 expression^[86]. NLRP3 is involved in inflammation that leads to atherosclerosis. Moreover, the main components of the NLRP3 inflammasome are cytosolic pattern recognition receptors (PRRs), the apoptosis-associated spec-like protein containing a CARD (adaptor ASC), and caspase-1^[87]. In response to various endogenous or exogenous stimuli, the NLRP3 inflammasome in different tissues and organs recognizes pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), including ox-LDL and cholesterol crystals [Figure 5]. When the NF-κB transcription factor is activated, NLRP3 expression is upregulated. This inflammasome activates downstream inflammation-related signaling pathways to promote the production of pro-inflammatory cytokines, which can further increase the risk of plaque rupture. The FAO pathway reduces NLRP3 activation, thereby inhibiting macrophage production of IL-1β, a cytokine that promotes the inflammatory response. Recently, it has been found that the NLRP3 inflammasome pathway is dependent on the activation signal IκB kinase β (IKKβ) and can be independent of NIMA-related kinase 7 (NEK7)^[88]. With further study, researchers have demonstrated that under low-shear stress (LSS), the phosphorylation level of Inhibitor of Nuclear Factor Kappa-B Kinase Subunit Epsilon (IKKε) in endothelial cells increases, thereby promoting activation of signal transducer and activator of STAT1^[89]. Activated STAT1 binds to the NLRP3 promoter region, resulting in cellular pyroptosis. In addition, STAT1 activation promotes the secretion of pro-inflammatory factors by driving macrophage polarization toward the M1 subtype, leading to unstable plaque formation and aggravation of atherosclerotic lesions.

In addition to promoting AS, NLRP3 may also contribute to neurological disorders such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Therefore, MCC950 may offer therapeutic potential for these diseases and broaden its clinical application. NLRP3 inhibitors are entering clinical trials, but their best indications are still being explored. NLRP3 inhibitors may serve as anti-inflammatory drugs for inflammatory diseases that currently lack effective treatment^[90].

Energy metabolism occurs primarily in mitochondria, which are involved in the production of ROS. However, excessive accumulation of ROS can induce mitochondrial dysfunction, which plays an important role in the pathogenesis of many diseases. Reactive oxygen species are further involved in pyroptosis and foam cell formation in atherosclerosis. Oxidative stress is also considered to be one of the pathogenic mechanisms of AS. Increased ROS promotes the expression of inflammatory and adhesion molecules and promotes ox-LDL formation. Recently, more and more studies have proved that excessive ROS can contribute to EC pyroptosis by upregulating the expression of NLRP3 [Figure 5]. With further research, it has been found that pathological stimuli, such as ox-LDL, hyperglycemia, nicotine, and Ang II, can increase ROS in endothelial cells, thereby activating the NLRP3 inflammasome. In addition, M1 macrophages, which have pro-inflammatory effects, can also produce ROS and promote the development of an inflammatory response, then lead to damaged ECs^[85].

One of the key mechanisms by which cholesterol crystals induce pyroptosis is that lysosomes rupture, releasing their contents into the cytoplasm, thereby activating the NLRP3 inflammasome. However, recent studies have found that Endoplasmic Reticulum (ER) cholesterol accumulation promotes inflammasome activation, underscoring the importance of elevated ER cholesterol in activating the NLRP3 inflammasome. In addition, cholesterol crystals can stimulate excessive ROS production, thereby inducing the activation of the NLRP3 inflammasome and caspase-1.

Early results showed that cholesterol crystals accumulate in ABCA1/ABCG1-deficient macrophages, where the expression of NLRP3, caspase-1, and IL-1β is increased, and inflammasome activation is initiated. In addition, the lack of ABCA1/ABCG1 in macrophages also leads to excessive accumulation of cholesterol^[91]. Based on this mechanism, Hou et al. found that Xinmaikang (XMK) can down-regulate the expression of NLRP3, IL-1β and Caspase-1, and can alleviate AS in ApoE^-/- mice^[92]. The liver X receptor (LXR) is the most common nuclear receptor that can regulate cholesterol. It is characterized by not only regulating cholesterol metabolism but also exerting anti-inflammatory effects and reducing intracellular cholesterol accumulation. LXRs can effectively prevent AS by inhibiting the NLRP3 inflammasome and NF-κB. In addition, LXR agonists have been shown to increase the expression of ABCA1 to reduce pyroptosis, thereby reducing atherosclerosis in ApoE^-/- mice^[93]. 7-Ketocholesterol (7KC) is the oxidized product of cholesterol oxidation in low-density lipoprotein. 7KC has been shown to induce macrophage reprogramming and foam cell formation; therefore, it can be developed as a potential therapeutic target for AS.

Ox-LDL can directly or indirectly trigger pyroptosis. On the one hand, ox-LDL can be directly recognized and activate downstream signaling pathways that promote the transcription of pro-IL-1β and pro-caspase-1. Secondly, ox-LDL can induce oxidative stress and mitochondrial dysfunction through multiple mechanisms, resulting in increased ROS production; elevated ROS further exacerbates mitochondrial dysfunction.

Activated NF-κB has been shown to promote pyroptosis through a variety of mechanisms, such as ROS production, ER stress, and mitochondrial dysfunction. NF-κB signaling is thought to be a key factor in atherosclerotic complications and has a connection with CVD. At the cellular level, NF-κB is involved in monocyte differentiation, transformation of macrophage subtypes, and transformation into foam cells. In response to pro-atherosclerotic factors such as ox-LDL, it promotes NF-κB activation, induces endothelial cell dysfunction and inflammation, and promotes monocyte recruitment to the subendothelial intima. Moreover, this EC dysfunction in turn leads to the activation of NF-κB signaling. NF-κB can be detected to increase in VSMCs in atherosclerotic lesions, thereby mediating the decrease of VSMC contractility^[94,95]. Therefore, targeting NF-κB has gradually become a major focus of research worldwide.

Artemisinin has been found to be widely used in the treatment of malaria, but it has also recently been found to be useful in inflammatory diseases by inhibiting NF-κB either through direct binding or by suppressing upstream signaling pathways. Doublecortin-like kinase 1 (DCLK1) has been shown to promote activation of the NF-κB pathway and subsequently the secretion of inflammatory mediators. DCLK1 deficiency or pharmacological inhibition can block the progression of AS. Scutellarin reduces NLRP3 inflammasome activation via the NF-κB/NLRP3 signaling pathway and has a protective effect on the heart through its anti-inflammatory properties. Rnd3 has a protective effect against endothelial cell pyroptosis by inhibiting tumor necrosis factor receptor-associated factor 6 (TRAF6) ubiquitination, thereby suppressing NF-κB activation and promoting TRAF6 degradation. In addition, TRAF6-specific deficiency counteracts Rnd3-induced exacerbation of endothelial cell pyroptosis both in vivo and in vitro. These findings establish a strong link between Rnd3 and the TRAF6/NF-κB/NLRP3 signaling pathway in endothelial cells, suggesting that Rnd3 plays an important role in preventing pyroptosis. He et al.^[96], have demonstrated that MgCl₂ can inhibit the expression of pyroptosis-related molecules and the secretion of IL-1β and IL-18 by downregulating the NF-κB signaling pathway, which can further reduce ox-LDL-induced pyroptosis of vascular smooth muscle cells. These findings provide a promising basis for targeting NF-κB in AS.

As scientists continue to study AS, they are gradually realizing that the immune system is closely linked to atherosclerosis. As such, pharmaceutical companies can use these theories as targets to develop new drugs for patients with atherosclerosis. The role of immunomodulatory strategies in the treatment of atherosclerosis has attracted great attention, offering novel therapeutic approaches that are quite different from traditional lipid-lowering therapies. In traditional treatment of AS, clinicians focus on lowering LDL, with typical medications such as statins^[97] and PCSK9 inhibitors^[98].

Clinical studies have shown that statins are HMG-CoA reductase inhibitors and play a key role in preventing atherosclerosis by improving endothelial function and stabilizing plaques. Statins were originally marketed as powerful lipid-lowering drugs, but recent studies have shown that they can also reduce pyroptosis. In addition, clinical practice has shown that the risk of AS does not always decrease after statin use, prompting further investigation. In 2015, Altaf demonstrated that a high dose of rosuvastatin can suppress the inflammatory development of atherosclerosis by downregulating NLRP3 expression, which helped improve our understanding of the pathogenesis and management of atherosclerosis. Recent studies have shown that atorvastatin inhibits upstream components of the NLRP3 activation pathway, reducing the secretion of IL-1β, IL-18, and GSDMD. Additionally, it can reduce the immune response and the accumulation of lipid in macrophage^[99]. Notably, simvastatin and mevastatin can also inhibit NLRP3 in ECs, which is activated by ox-LDL. These findings have indicated that statins are gradually gaining the attention of researchers. While statins are widely believed to have cholesterol-lowering effects, they have also been linked to an increased likelihood of developing diabetes and myopathy^[100].

Some studies have shown that adding a Proprotein convertase subtilisin/Kexin 9 (PCSK9) inhibitor to existing statin treatment can not only improve lipid levels but also accelerate the regression of coronary atherosclerosis^[101]. PCSK9 can bind to the LDL receptor (LDLR) and induce its degradation, thereby increasing circulating LDL levels. Therefore, PCSK9 inhibitors have become an important pillar in the treatment of cardiovascular-related diseases due to their ability to reduce LDL. However, further research has shown that PCSK9 is also closely related to immunity and oxidative stress.

Metformin can improve macrophage dysfunction, inhibit foam cell formation, and even suppress NLRP3 inflammasome formation^[102]. Therefore, the clinical application of metformin has expanded from a first-line hypoglycemic drug for diabetes to a potential agent for delaying AS. Previous studies have shown that activation of mTORC1 (mTOR complex 1) can promote atherosclerosis. However, Studies have shown that the mTORC2 pathway inhibits AS, suggesting that treatment aimed at regulating mTOR needs to pay attention to this pair of balanced but opposite signaling pathways. In addition, the nuclear factor of activated T-cells (NFAT) plays an important role in T cells and has increasingly been implicated in cardiovascular diseases. Liu et al. showed that t foam cell formation increased in NFATC3-deficient mice, and this increase was negatively correlated with plaque instability^[103]. C-type natriuretic peptide (CNP) has been shown to degrade HIF-1α and enhance plaque stability, suggesting a novel protective effect against atherosclerosis^[104]. Additionally, Li et al. had shown that Immune Responsive Gene 1 (IRG1), which is mainly expressed in macrophages and neutrophils, is upregulated in atherosclerotic plaques. 4-octyl itaconate (4-OI), a metabolite produced by IRG1, can be considered a promising treatment for atherosclerosis by establishing beneficial plaques^[105].

Sulfonylureas, such as glyburide, which are used to treat type 2 diabetes mellitus (T2DM), have been shown to inhibit NLRP3 signaling. Oridonin, as a common Chinese medicine, has been demonstrated to inhibit the assembly and activation of the NLRP3 inflammasome^[90]. In addition to MCC950, various NLRP3 inhibitors (such as oridonin and VX765) and HINT2 overexpression can inhibit pyroptosis. However, clinical application still requires toxicity assessment.

The pro-inflammatory M1 subtype plays a key role in AS progression; thus, inhibiting macrophage polarization toward anti-inflammatory subtypes may provide a new therapeutic strategy. In fact, SNX10 (sorting nexin10) accumulates in arterial plaques. You et al.^[106] had demonstrated that SNX10 deficiency can reduce foam cell formation, promote macrophage polarization toward an anti-inflammatory phenotype through the Lck/Yes-related novel protein tyrosine kinase (Lyn)-protein kinase B (Akt)-transcription factor EB (TFEB) signaling pathway, and disrupt the balance between glycolysis and mitochondrial oxidative phosphorylation.

In addition to the drugs mentioned above, a new treatment method, vaccines, has also attracted the attention of researchers. Rheumatoid arthritis and multiple sclerosis are inflammatory diseases with complex autoimmune processes that can be targeted by vaccination strategies. Atherosclerosis has also been shown in recent studies to be an autoimmune disease, similar to the two diseases mentioned above. Therefore, vaccination is considered to prevent atherosclerosis^[111].

As research continues to advance, scientists are focusing not only on drug innovation but also on more effective drug delivery methods. Current routes of administration can cause drug side effects in tissues outside the lesion site. To enable more precise diagnosis and drug delivery, nanoparticles have attracted widespread attention. Compared with traditional drug delivery means, this novel technology can reduce adverse effects related to medicine. It can also maximize drug efficacy with fewer doses by targeting the drug specifically to sites of inflammation. In particular, studies have shown that nanoparticles can specifically target sites of macrophage aggregation, accurately locate lesions, and release nanoparticle-loaded drugs precisely where they are needed. However, this has only been demonstrated in animal models, and its effect on human clinical treatment remains unknown. Thus, translating these findings from theory to practice remains challenging. Beyond vaccines and nanoparticles, bispecific T-cell engager (BiTE) technology has emerged as a novel immunotherapeutic strategy for atherosclerosis. Amrute et al.^[112] identified fibroblast activation protein (FAP) as a specific marker of modulated smooth muscle cells (SMCs) in human coronary plaques using single-cell multiomics and spatial transcriptomics. They developed a half-life-extended anti-FAP BiTE that redirects T-cell cytotoxicity to eliminate FAP⁺ modulated SMCs. In ApoE^-/^- mouse models, anti-FAP BiTE treatment significantly reduced plaque burden, increased fibrous cap thickness and collagen content, and remodeled the plaque cellular landscape. This proof-of-concept study demonstrates that immunotherapeutic depletion of pathogenic stromal cells, independent of lipid lowering, represents a promising precision medicine approach for coronary artery disease.