Therapeutic Regulation of the Wnt/β-catenin Pathway by Traditional Chinese Medicine: Emerging Strategies in Atherosclerosis Management

Therapeutic Regulation of the Wnt/β-catenin Pathway by Traditional Chinese Medicine: Emerging Strategies in Atherosclerosis Management | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 26 March 2026 V1 Latest version Share on Therapeutic Regulation of the Wnt/β-catenin Pathway by Traditional Chinese Medicine: Emerging Strategies in Atherosclerosis Management Authors : Chaoyang Zhang , Yujie Yu , Shu Dai , Dong Liu , Mengling Zhou , Jianlan Zhang , and Yunxia Li [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.177452357.77869690/v1 162 views 90 downloads Contents Abstract CONTENTS Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Atherosclerosis (AS), recognized by the World Health Organization (WHO) as a critical global public health challenge, serves as the primary pathological basis of cardiovascular diseases. Its hallmark pathological features include lipid deposition in the vascular intima, formation of atheromatous plaques, and fibrous cap thickening. These changes reduce vascular compliance, cause luminal stenosis, and culminate in end-organ ischemia. The Wnt/β-catenin pathway, an evolutionarily conserved core transduction cascade, plays pivotal roles in the pathophysiology of diverse diseases by orchestrating critical biological processes such as cell proliferation, differentiation, and metabolic homeostasis. Recent studies have revealed its essential regulatory functions in multiple key stages of AS progression, including endothelial dysfunction, vascular inflammatory responses, and vascular remodeling. Traditional Chinese Medicine (TCM) demonstrates unique advantages in AS prevention and treatment through its holistic synergistic characteristics of ”multi-component, multi-target, multi-pathway” regulation. Current evidence indicates that active components of TCM and compound formulations can modulate the Wnt/β-catenin pathway to exert multiple biological effects, including anti-inflammatory and antioxidant actions, regulation of macrophage activation, inhibition of abnormal vascular smooth muscle cell proliferation and migration, and improvement of lipid metabolism disorders, thereby retarding AS progression. Therefore, this article analyzes the Wnt/β-catenin pathway’s molecular features and its regulatory role in AS progression, while reviewing recent TCM interventions targeting this pathway. By elucidating the Wnt/β-catenin pathway’s role, this study supports the rational design of clinical interventions and next-generation AS therapeutics. Additionally, the study discusses TCM toxicological principles in its conclusion, offering practical references to enhance TCM’s clinical efficacy in AS treatment. [Article Type]: Review Article [Article Title]: Therapeutic Regulation of the Wnt/β-catenin Pathway by Traditional Chinese Medicine: Emerging Strategies in Atherosclerosis Management [ Running Title]: TCM Targets Wnt/β-catenin in Atherosclerosis [Author Names] Chaoyang Zhang, Yujie Yu, Shu Dai, Dong Liu, Mengling Zhou, Jianlan Zhang, Yunxia Li * [Affiliations] 1 School of Pharmacy, Chengdu University of Traditional Chinese Medicine, 2 Chinese Medicine Germplasm Resources Innovation and Effective Uses Key Laboratory of Sichuan Province, 3 Key Laboratory of Standardization of Chinese Medicine (Chengdu University of Traditional Chinese Medicine), Ministry of Education, Chengdu 611137, China [E-mail address] Chaoyang Zhang ( [email protected] ), Yujie Yu ( [email protected] ), Shu Dai ( [email protected] ), Dong Liu ( [email protected] ), Mengling Zhou ( [email protected] ), Jianlan Zhang ( [email protected] ) and Yunxia Li ( [email protected] ) [Correspondence] Yunxia Li ( [email protected] ); ORCID: 0000-0002-9256-5716 Tel/Fax numbers: Yunxia Li (+86) 28-8779-1296 Abstract Atherosclerosis (AS), recognized by the World Health Organization (WHO) as a critical global public health challenge, serves as the primary pathological basis of cardiovascular diseases. Its hallmark pathological features include lipid deposition in the vascular intima, formation of atheromatous plaques, and fibrous cap thickening. These changes reduce vascular compliance, cause luminal stenosis, and culminate in end-organ ischemia. The Wnt/β-catenin pathway, an evolutionarily conserved core transduction cascade, plays pivotal roles in the pathophysiology of diverse diseases by orchestrating critical biological processes such as cell proliferation, differentiation, and metabolic homeostasis. Recent studies have revealed its essential regulatory functions in multiple key stages of AS progression, including endothelial dysfunction, vascular inflammatory responses, and vascular remodeling. Traditional Chinese Medicine (TCM) demonstrates unique advantages in AS prevention and treatment through its holistic synergistic characteristics of ”multi-component, multi-target, multi-pathway” regulation. Current evidence indicates that active components of TCM and compound formulations can modulate the Wnt/β-catenin pathway to exert multiple biological effects, including anti-inflammatory and antioxidant actions, regulation of macrophage activation, inhibition of abnormal vascular smooth muscle cell proliferation and migration, and improvement of lipid metabolism disorders, thereby retarding AS progression. Therefore, this article analyzes the Wnt/β-catenin pathway’s molecular features and its regulatory role in AS progression, while reviewing recent TCM interventions targeting this pathway. By elucidating the Wnt/β-catenin pathway’s role, this study supports the rational design of clinical interventions and next-generation AS therapeutics. Additionally, the study discusses TCM toxicological principles in its conclusion, offering practical references to enhance TCM’s clinical efficacy in AS treatment. Keywords: Atherosclerosis, Traditional Chinese Medicine, Wnt/β-catenin, Toxicology, Cardiovascular diseases. Graphical Abstract : Active ingredients of traditional Chinese medicine and compound preparations regulate various pathological changes during the progression of atherosclerosis by targeting the Wnt/β-catenin pathway. CONTENTS 1. Introduction 5 2. Composition and Regulatory Mechanisms of the Wnt/β-catenin Pathway 7 3. The role of the Wnt/β-catenin pathway in the pathogenesis of AS 11 3.1 Lipid metabolism 11 3.2 Endothelial cell dysfunction and inflammatory reaction 13 3.3 Proliferation, migration, and apoptosis of vascular smooth muscle cells 14 3.4 Macrophage activation 17 4. Intervention of TCM in the Wnt/β-catenin pathway for the prevention and treatment of AS 18 4.1 TCM and its active ingredients 18 4.1.1 Vitexin 18 4.1.2 Moscatilin 19 4.1.3 Bavachin 19 4.1.4 Aralia armata (Wall.) Seem 20 4.1.5 Ziziphora clinopodioides Lam. 21 4.1.6 Echinacoside 22 4.1.7 Honokiol 22 4.1.8 Gentisic acid 23 4.1.9 Resveratrol 24 4.1.10 Cryptotanshinone 25 4.1.11 Paeoniflorin 25 4.1.12 Ursolic acid 26 4.1.13 Gypenosides 27 4.1.14 Semen ziziphi spinosae 27 4.1.15 Curcumin 28 4.2 Compound of TCM 31 4.2.1 Activating blood and resolving stasis therapy (ABRST) 31 4.2.2 Tongxinluo Capsule 32 4.2.3 Huxinkang 32 4.2.4 Changmaile capsule 33 4.2.5 Buyang Huanwu decoction 34 4.2.6 Yiqi Tongbi capsule 34 4.2.7 Guanxinning tablets 35 4.2.8 Wenxin Formula 36 4.2.9 Yindan Xinnaotong capsule 36 4.2.10 Compound Danshen Dripping Pills 37 4.2.11 Shexiang Baoxin Pill 38 5. Toxicology and adverse reactions 41 6. Conclusion and prospects 44 7. CRediT authorship contribution statement 46 References: 47 8. 1. Introduction Cardiovascular diseases (CVDs) refer to a series of diseases that affect the heart and blood vessels, including stroke, heart failure, arrhythmia, myocardial infarction, cardiac hypertrophy, hypertension, and angina pectoris. It dominates the composition of all-cause mortality in China (Soppert et al., 2020). Atherosclerosis (AS) represents a multifactorial pathological process characterized by chronic vascular wall inflammation, dysregulated lipid metabolism, atherosclerotic plaque formation, and vascular remodeling (Stone et al., 2022). Crucially, plaque instability may trigger thrombosis, leading to acute coronary syndromes, stroke, or peripheral ischemia (Cheng et al., 2023; Libby, 2021). Although current therapeutic strategies, including statin-mediated lipid modulation, PCSK9 monoclonal antibody-targeted therapies, and evidence-based lifestyle interventions, have improved patient outcomes to some extent, AS and its associated vascular complications remain formidable clinical challenges (Aili et al., 2024). This persistent burden underscores the critical need to explore novel preventive and therapeutic approaches (Porsch and Binder, 2024). The Wnt/β-catenin pathway, an evolutionarily conserved regulatory system, plays pivotal roles in embryonic development, tissue homeostasis maintenance, cell proliferation, differentiation, and stem cell biology (Carson and Nejak-Bowen, 2025; Liu et al., 2022b). Studies have shown that the abnormal activation of the Wnt/β-catenin pathway has a multi-dimensional association with the pathological process of AS (Oliveira-Paula et al., 2024; Tsutsumi et al., 2023; Xu et al., 2023a). This article, in combination with the pathogenesis of AS, elaborates the role of the Wnt/β-catenin pathway in AS from the perspectives of systemic lipid metabolism disorder, vascular endothelial dysfunction, and intensified inflammatory response, macrophage polarization and foaming process, as well as abnormal proliferation and migration of vascular smooth muscle cells. Traditional Chinese Medicine (TCM) demonstrates unique advantages in AS prevention and treatment through its multi-component, multi-target, multi-pathway regulatory characteristics (Chen et al., 2025; Wang et al., 2024b). Compared to Western pharmacotherapies, TCM interventions demonstrate superior safety profiles with fewer adverse effects in clinical practice (Zhang et al., 2024e). Emerging studies reveal that TCM can regulate the Wnt/β-catenin pathway to target multiple critical stages of AS progression, such as improving vascular endothelial dysfunction and inflammatory reactions, regulating macrophage activation, inhibiting abnormal vascular smooth muscle cell proliferation and migration, and correcting lipid metabolism disorders. However, this field lacks systematic consolidation of evidence. Therefore, this article will systematically review the mechanisms of the Wnt/β-catenin pathway in AS and summarize the effects of TCM monomers, extracts, and compound prescriptions on this pathway in AS treatment, aiming to provide a theoretical foundation for future research on the molecular mechanism and drug development of TCM. All pharmacologically active substances inherently carry potential toxicities. While investigating the therapeutic mechanisms of TCM, equal emphasis must be placed on characterizing its adverse drug reactions (ADRs) in clinical practice. At the end of this article, we discuss some aspects of research into the toxicology of TCM, highlighting the need for balanced evaluation of both efficacy and safety to optimize clinical outcomes. 2. Composition and Regulatory Mechanisms of the Wnt/β-catenin Pathway The Wnt gene family was first discovered in 1982, when researchers identified the integration1 (Int1) proto-oncogene in a mouse mammary tumor model. Subsequent studies demonstrated significant homology between Int1 and Drosophila’s segment polarity gene wingless (wg), prompting the combined nomenclature ‘Wnt’ (wingless-related integration site). This evolutionary conservation highlights Wnt’s crucial role in metazoan development and disease (Akoumianakis et al., 2022). β-catenin, a dual-function protein, serves as the central effector of canonical Wnt signaling. The Wnt/β-catenin pathway is an evolutionarily highly conserved cellular signal transduction pathway that critically regulates diverse biological processes, including cell proliferation, differentiation, migration, survival, and neurodevelopment (Tao et al., 2023; Xu et al., 2022). The core components of this pathway include the Wnt protein family, the Frizzled receptor family, the disheveled protein family, β-catenin, GSK-3β, Axin, APC, and a series of cofactors (Hao et al., 2022). Furthermore, Wnt signaling can be categorized based on its reliance on β-catenin (Huang et al., 2019b; Oh et al., 2024). The classical Wnt pathway operates in a β-catenin-dependent manner, whereas non-classical Wnt signaling encompasses alternative routes, such as the planar cell polarity (PCP) pathway and the Ca 2+ -mediated cascade (Niu et al., 2024). In the classical Wnt pathway, Wnt ligands bind to Frizzled (FZD) receptors, which activate the intracellular disheveled protein DVL (Huang et al., 2024). DVL inhibits the β-catenin degradation complex (e.g., GSK-3β), thereby stabilizing cytoplasmic β-catenin. Stabilized β-catenin translocates into the nucleus, where it forms a complex with the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors. This interaction activates the expression of downstream target genes, including C-myc and cyclin D1 (Chen et al., 2024c). In contrast, the non-classical Wnt signaling pathway operates independently of β-catenin and primarily encompasses two key mechanisms: the Wnt/planar cell polarity (PCP) pathway and the Wnt/Ca 2+ pathway. The Wnt/PCP pathway triggers the activation of c-Jun N-terminal kinase (JNK) via small G proteins, thereby facilitating cytoskeletal reorganization (Sun et al., 2024). Meanwhile, the Wnt/Ca 2+ pathway modulates cell adhesion and influences the expression of associated genes by releasing intracellular Ca 2+ ions (Astone et al., 2024). Dickkopf-related protein 1 (DKK1) and secreted frizzled-related proteins (sFRPs) are the primary endogenous inhibitors of the Wnt/β-catenin pathway (Penny et al., 2023). The Wnt/β-catenin pathway plays a complex, context-dependent role in both oncogenesis and cardiac development. Although it drives cancer progression in various malignancies, it is also essential for proper embryonic heart formation. Following myocardial infarction (MI), this pathway exerts contradictory effects—while reducing infarct size and improving ventricular function, it simultaneously promotes myocardial fibrosis and worsens cardiac performance (Shen et al., 2023; Yang et al., 2023a). Interestingly, recent studies have highlighted the role of the Wnt/β-catenin pathway in CVDs, including AS. Here, the active components of traditional Chinese medicine and Chinese herbal compound formulas reviewed in this study primarily prevent and treat AS by intervening in the classical Wnt/β-catenin pathway. Figure 1 illustrates the composition and transduction process of the classical Wnt/β-catenin signaling pathway. Additionally, this study provides a brief overview of the non-classical Wnt/β-catenin pathway, as shown in Figure 2. Figure 1: The canonical Wnt/β-catenin signaling pathway. (Left) In the absence of Wnt signaling, β-catenin associates with a cytoplasmic destruction complex containing CK1α, GSK-3β, Axin, and APC proteins. This facilitates the phosphorylation of β-catenin and its subsequent interaction with β-TRCP, leading to β-catenin ubiquitination and degradation by the proteasome. Within the nucleus prior to Wnt signal activation, transcription factors such as LEF and TCF bind to specific sequences in the promoter/enhancer regions of target genes and, together with Groucho, typically function to repress gene expression. (Right) Upon binding of Wnt ligands to their Frizzled receptors, Wnt signaling is initiated, resulting in the activation of DSH/DVL proteins. Activated DSH promotes the phosphorylation and consequent inhibition of GSK-3β. This inhibition disrupts the destruction complex, allowing the accumulation of free, unphosphorylated β-catenin in the cytoplasm, which then translocates to the nucleus. Increased nuclear β-catenin levels lead to its association with TCF/LEF, displacing corepressors and recruiting co-activators to alter the transcriptional machinery, thereby activating the expression of multiple target genes. CK1α, casein kinase 1α; GSK-3β, glycogen synthase kinase-3β; Axin, axis inhibition protein; APC, adenomatous polyposis coli; β-TRCP, β-transducin repeat-containing protein; LEF, lymphocyte enhancer factor-1; TCF, T cell factor; DSH/DVL, dishevelled. Figure 2: Non-canonical Wnt signaling pathways. (Left) In the Wnt/PCP pathway, Wnt proteins bind to Frizzled transmembrane receptors on the cell surface, which leads to the activation of Rho/Rac small GTPases and JNK via DSH. Subsequently, this pathway regulates cytoskeletal organization and gene expression. DSH connects to the downstream effectors Rho and ROCK through the adaptor protein Daam1. Rac is directly activated by DSH, which further activates JNK by sequentially activating MAP3Ks and MAP2Ks. (Right) In the Wnt/Ca 2+ pathway, Wnt ligands (primarily Wnt1, Wnt5A, and Wnt11) bind to Frizzled transmembrane receptors and participate in multiple cellular processes involving the stimulation of heterotrimeric G-proteins. This in turn activates PLC. PLC activation increases intracellular Ca 2+ release, decreases cGMP (cyclic guanosine monophosphate) levels, and triggers the activation of kinases such as CaMKII or calcineurin and PKC. These processes stimulate nuclear factors such as NFAT and other transcription factors. Thus, the Wnt/Ca 2+ pathway is likely a G‑protein‑dependent signaling cascade. PCP, planar cell polarity; Rho, ras homologous; Rac, ras-related C3 botulinum toxin substrate; JNK, c-Jun N-terminal Kinase; Daam1, dishevelled-associated activator of morphogenesis 1; ROCK, rho-associated coiled-coil containing protein kinase; MAP3Ks, mitogen-activated protein kinase kinase kinases; MAP2Ks, mitogen-activated protein kinase kinases; G-protein, heterotrimeric guanine nucleotide-binding protein; PLC, phospholipase C; CaMKII, Ca 2+ /calmodulin-dependent protein kinase II; PKC, protein kinase C; NFAT, nuclear factor of activated T-cells; TCF, T cell factor; CDC42, cell division control protein 42 homolog. 3. The role of the Wnt/β-catenin pathway in the pathogenesis of AS 3.1 Lipid metabolism AS involves profoundly disrupted lipoprotein particle flux across the arterial intima, manifested by three hallmark alterations: (a) hypertriglyceridemia, (b) attenuated High-Density Lipoprotein (HDL)-mediated atheroprotection, and (c) synergistic elevation of Low-Density Lipoprotein (LDL) and Total Cholesterol (TC) concentrations (Wen et al., 2024). Changes in these lipoprotein parameters and their dynamic ratios are independent predictors of AS progression (Senatus et al., 2023). Based on this pathophysiological mechanism, targeting hepatic lipid synthesis pathways now represents a key therapeutic strategy. As a negative regulator of lipid synthesis, the Wnt pathway plays a central role in homeostatic lipid metabolism, including adipogenesis, cholesterol transport, and secretion (Boucher et al., 2020). Studies demonstrate that the Wnt/β-catenin pathway regulates AS by inhibiting lipid synthesis (Wang et al., 2018). Glucocorticoid receptor agonists and other endocrine stimuli rapidly induce transient expression of C/EBPβ/δ, which (Yang et al., 2023a) subsequently activates Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) through a cascade. PPARγ then feeds back to regulate C/EBPα expression, forming a bidirectional regulatory network to drive preadipocyte differentiation. Notably, the Wnt/β-catenin pathway disrupts adipogenesis by both blocking initial PPARγ/C/EBPα activation and interfering with their feedback loop (Kawai et al., 2007). Low-density lipoprotein receptor-related protein (LRP), a key effector molecule downstream of the Wnt pathway, belongs to a family of lipid-binding transmembrane receptors (Xu et al., 2014). Furthermore, it binds to low-density lipoprotein to form functional complexes, critically regulating systemic lipid metabolism. It has been reported that specific LRP mutations are strongly correlated with altered serum lipid levels and may promote AS (Borrell-Pages et al., 2024; Brophy et al., 2019). Experiments involving LRP6 knockout models demonstrate that disrupted Wnt/β-catenin signaling induces hepatic metabolic dysregulation, characterized by accelerated lipogenesis and increased cholesterol synthesis (Kang, 2020), and treatment with exogenous Wnt3a significantly reverses this phenomenon, normalizing plasma triglyceride and LDL levels. Mechanistically, β-catenin binding to T Cell Factor/Lymphoid Enhancer Factor (TCF-LEF) enhances retinoic acid release and Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII)-mediated recruitment of the Silencing Mediator for Retinoid and Thyroid hormone receptors (SMRT). SMRT recruitment to the first intron of PPARγ gene suppresses intron acetylation and gene expression (Song et al., 2014), consequently inhibiting the expression of PPARγ. Since reduced synthesis of cholesterol, triglycerides, and LDL lowers AS risk, the Wnt/β-catenin pathway exerts anti-AS effects by suppressing lipid synthesis. 3.2 Endothelial cell dysfunction and inflammatory reaction AS is a chronic inflammatory disease characterized by endothelial dysfunction (Adkar and Leeper, 2024). Endothelial injury and dysfunction initiate AS development, upregulating adhesion molecule expression and promoting cytokine release, including tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). These cytokines mediate monocyte/macrophage infiltration, amplify inflammatory reactions, and enhance platelet activation and aggregation (Liang et al., 2022). Vascular endothelial cells express multiple key components of the Wnt pathway, including Wnt ligands (Wnt1, Wnt3a, Wnt5a), Frizzled receptors (Fzd1, Fzd4, Fzd6), and Low-Density Lipoprotein Receptor-Related Protein 5/6 (LRP5/6) co-receptors (Xie et al., 2023). Wnt-mediated activation of the β-catenin pathway enhances monocyte adhesion to endothelial cells and increases vascular permeability to both monocytes and pro-atherogenic macromolecules (e.g., LDL), thereby accelerating atherosclerotic plaque formation (Xu et al., 2023b). As an atypical secretory glycoprotein in the Wnt family, Wnt5a exhibits context-dependent modulation of the canonical β-catenin pathway, significantly influencing both endothelial dysfunction and immune reactions (Wan et al., 2023). Elevated Wnt5a expression has been demonstrated in macrophage-rich regions of atherosclerotic plaques in both human and rodent models. Mechanistic studies reveal that Wnt5a acts as a potent inflammatory mediator in AS by rapidly upregulating multiple pro-inflammatory cytokines in human aortic endothelial cells, including GM-CSF, IL-1α, IL-3, IL-5, IL-6, IL-7, and IL-8 (Christman et al., 2008). Interleukin-8 is a known angiogenic factor that has been identified as a transcriptional target for Wnt/β-catenin signaling in endothelial cells. The study by Masckauchán et al. (Masckauchán et al., 2005) suggests that Wnt/β-catenin signaling may promote endothelial cell proliferation and angiogenesis by inducing known angiogenesis regulators, such as interleukin-8. Recent studies demonstrate that Wnt5a upregulates cyclooxygenase-2 (COX-2) and pro-inflammatory cytokines, including TNF-α and IL-1β, via the non-classical Wnt/Ca 2+ /protein kinase C (PKC) axis (Ma et al., 2017). In human coronary artery endothelial cells (HCAECs), Wnt5a interacts with the receptor tyrosine kinase-like protein Ryk, activating the downstream ROCK/LIMK2/CFL1 pathway to increase vascular permeability (Wan et al., 2021). Under diabetic conditions, hypoxia and hyperglycemia enhance the nuclear β-catenin translocation in retinal endothelial cells, activating the Wnt/β-catenin pathway. Pretreatment with the Wnt inhibitor Dickkopf-1 (Dkk1) attenuates high glucose-induced retinal inflammation and reactive oxygen species (ROS) production (Chen et al., 2009). Together, these findings underscore the critical involvement of the Wnt/β-catenin pathway in vascular endothelial cells, promoting proliferation, inflammatory responses, and endothelial dysfunction—key mechanisms in the early pathogenesis of AS. 3.3 Proliferation, migration, and apoptosis of vascular smooth muscle cells Under physiological conditions, vascular smooth muscle cells (VSMCs) are predominantly found in the arterial media layer. They exhibit a characteristic contractile phenotype featuring extremely low proliferative activity and high expression of contraction-related proteins (Miano et al., 2021). However, during the development of AS, various pathological factors (such as the accumulation of oxidized low-density lipoprotein, endothelial cells activation, and the chronic inflammatory microenvironment) can trigger the phenotypic transformation of VSMCs, i.e., the transition from a contractile to a synthetic phenotype (Aherrahrou et al., 2020). During this process, VSMCs acquire the ability to migrate, moving from the middle membrane to the intima. They also exhibit significant proliferation and Extracellular Matrix (ECM) synthesis, leading to intima thickening and fibrous cap formation (Swiatlowska et al., 2024). Importantly, VSMCs in advanced or unstable plaques exhibit a significantly higher rate of apoptosis, which is a phenomenon closely associated with plaque vulnerability (Li et al., 2024c). Studies have shown that Wnt1 and Wnt3a play a key regulatory role in smooth muscle cell proliferation by activating the β-catenin pathway and upregulating Cyclin D1 (Uglow et al., 2003). Furthermore, Wnt4 has been shown to promote proliferation of VSMCs in AS, thereby contributing to pathological intimal thickening, suggesting its potential role in vascular remodeling and arterial diseases (Xu et al., 2024). In vitro experiments have confirmed that dickkopf-related protein 3 (Dkk-3) promotes the differentiation of Sca1 + vascular progenitors and fibroblasts into SMCs through coordinated activation of both TGF-β/ATF6 and Wnt signaling cascades. Compared with Dkk-3 +/+ /ApoE −/− controls, Dkk-3 −/− /ApoE −/− mice on a normal diet exhibited increased atherosclerotic plaque volume, reduced stability, elevated macrophage infiltration, and decreased SMC and ECM deposition. Notably, treatment with exogenous recombinant Dkk-3 protein significantly improved carotid artery plaque pathology in high-fat diet-fed Dkk-3 −/− /ApoE −/− mice, as evidenced by reduced intraplaque hemorrhage, fewer macrophages, increased SMC content, and enhanced ECM deposition (Karamariti et al., 2018). Over the past decade, research has elucidated the pivotal role of the Wnt/β-catenin system in regulating VSMC biology (Martínez-Moreno et al., 2012; Qin et al., 2022). This pathway mediates vascular remodeling through its effects on VSMC proliferation, migration, and apoptosis. Specifically, the β-catenin/TCF complex inhibits VSMC apoptosis while promoting their proliferation, thereby influencing neointima formation (Marinou et al., 2012). As an essential trace element, magnesium ions target Wnt/β-catenin to improve VSMC calcification phenotypes (Montes de Oca et al., 2014). Furthermore, Wnt/β-catenin participates in multiple atherosclerosis-related processes, including inflammatory cell infiltration, foam cell differentiation, pathological angiogenesis, and vascular calcification (Rong et al., 2014). In terms of plaque dynamics, the Wnt/β-catenin pathway not only maintains the survival of VSMCs but also reduces the stability of β-catenin by down-regulating the expression of Pin1 (Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) (Wang et al., 2002), a key factor in cell cycle regulation, thereby promoting the apoptotic process of VSMCs (Lv et al., 2010). Thus, Wnt/β-catenin pathway exhibits phase-specific influences during AS development: during early stages, it promotes VSMC proliferation and migration, contributing to intimal thickening and plaque formation. Conversely, in advanced stages, it exhibits atheroprotective properties by preventing VSMCs apoptosis and stabilizing vulnerable plaques. 3.4 Macrophage activation Macrophages, the most critical inflammatory effector cells in plaques, transform into foam cells via uptake of modified lipoproteins (Chen et al., 2022). Upon apoptosis, these cells release numerous pro-inflammatory factors that promote necrotic core formation in atherosclerotic lesions, and destabilize the fibrous cap by secreting matrix metalloproteinases (Koelwyn et al., 2018). This significantly increases the vulnerability of the plaque and the risk of acute cardiovascular events (Chen et al., 2021). LRP5, a key member of the low-density lipoprotein receptor (LDLR) family, mediates two critical pathological processes in AS: modified LDL endocytosis and macrophage migration (Pascual-Carreras et al., 2021). LRP5 deficiency promotes lipid accumulation in the mouse thoracic aorta, upregulates LRP6 expression, and enhances macrophage infiltration and inflammatory cytokine secretion. In high-cholesterol wild-type mice, LRP5 and Wnt/β-catenin pathway proteins are upregulated in the aorta; however, this effect is abolished upon LRP5 deletion. Furthermore, LRP5 deficiency exacerbates dyslipidemia by enhancing lipid and macrophage retention in the vascular wall and amplifying systemic inflammation (Badimon et al., 2021). Dickkopf-2 (Dkk2), a negative regulator of the Wnt/β-catenin pathway, remains incompletely understood in its mechanistic role in macrophage activation (Zhou et al., 2020). The latest research indicates that both bone marrow-derived macrophages (BMDMs) and peritoneal macrophages show marked upregulation of Dkk2 expression in ApoE −/− knockout mice exposed to ox-LDL (Zhang et al., 2021). Silencing Dkk2 promotes β-catenin nuclear translocation, activating the Wnt/β-catenin pathway. Notably, the β-catenin inhibitor XAV939 abolishes the macrophage activation state caused by Dkk2 silencing. These findings imply that Dkk2 sustains macrophage quiescence by suppressing the Wnt/β-catenin pathway, while its downregulation triggers macrophage activation. Collectively, these findings indicate that Wnt/β-catenin signaling may inhibit ox-LDL uptake in macrophages, consequently decreasing foam cell formation. This pathway appears to suppress necrotic core development and enhance fibrous cap stability, thereby exerting atheroprotective effects and promoting plaque stabilization. 4. Intervention of TCM in the Wnt/β-catenin pathway for the prevention and treatment of AS 4.1 TCM and its active ingredients 4.1.1 Vitexin Vitexin, a natural polyphenolic flavonoid abundant in medicinal plants, exhibits diverse pharmacological effects, including anti-tumor, antioxidant, and anti-inflammatory activities (Zhao et al., 2021a). Traditionally, it has been explored for treating diabetes, cancer, and CVDs (Chen et al., 2024d). Research shows that vitexin significantly reduces HG-induced apoptosis in HUVECs through specific suppression of Wnt/β-catenin signaling, an effect completely reversed by pharmacological inhibition of β-catenin using KYA1797K. Concurrently, vitexin reduces ROS and malondialdehyde (MDA) levels while enhancing superoxide dismutase (SOD) activity. Mechanistically, vitexin activates the Nrf2 pathway, a key mediator of its antioxidant effects (Zhang et al., 2024c). These findings suggest that vitexin protects against HG-induced endothelial injury via synergistic modulation of the Wnt/β-catenin and Nrf2 axes, highlighting its potential as a therapeutic agent for AS and diabetic cardiovascular complications. 4.1.2 Moscatilin Moscatilin, a natural bioactive ingredient isolated from Dendrobium loddigesii (DL), exhibits significant pharmacological effects, including anti-tumor, anti-inflammatory, and antipyretic properties (Huang et al., 2019a). Vascular calcification, a critical complication of atherosclerotic cardiovascular diseases and chronic kidney diseases, increases the risk of major adverse cardiovascular events and impairs vascular interventional therapy outcomes (Zeng et al., 2021). Studies demonstrate that moscatilin attenuates vascular calcification by modulating the Wnt/β-catenin signaling pathway. During osteogenic transdifferentiation of human aortic smooth muscle cells (HASMCs), interleukin-13 receptor subunit IL13RA2 is downregulated, which promotes pro-inflammatory factor secretion via the activation of the STAT3 axis. Mechanistically, moscatilin binds to and upregulates IL13RA2, effectively suppressing vascular calcification. Specifically, moscatilin can significantly weakenthe cross-talk between the Wnt3/β-catenin and IL13RA2/STAT3 signaling pathways, thereby inhibiting the differentiation of HASMCs into osteoblast-like cells (Zhang et al., 2025). 4.1.3 Bavachin Bavachin, a flavonoid derived from the seeds and fruits of Rubia spp. (Rubiaceae), is widely used in traditional Asian medicine (Wei et al., 2023b). It exhibits multiple pharmacological activities, including estrogen-like and anti-inflammatory effects (Jin et al., 2021). Autophagy, a key regulator of cellular homeostasis, significantly contributes to the AS process (Francis and Razani, 2022). In β-glycerophosphate (β-GP)-stimulated HASMCs, intracellular Ca 2+ concentration increases, accompanied by upregulated expression of calcification-related proteins (e.g., OPG, OPN, Runx2, and BMP2), which triggers autophagy and apoptosis. Mechanistically, β-GP activates the Wnt/β-catenin pathway to promote osteogenic differentiation and apoptosis. Notably, bavachin dose-dependently reduces Ca 2+ levels and downregulates expressions of OPG, OPN, Runx2, and BMP2, thereby suppressing apoptosis. Furthermore, bavachin upregulates LC3-II and Beclin1, and induces punctate LC3-II aggregation, an Atg7-dependent process negatively regulated by mTOR. When autophagy is inhibited by wortmannin (WM), the protective effects of bavachin against β-GP-induced HASMCs calcification and apoptosis are significantly attenuated (He et al., 2019). These findings demonstrate that bavachin attenuates apoptosis and calcification in HASMCs by activating the Atg7/mTOR-autophagy axis and inhibiting the Wnt/β-catenin pathway, suggesting its therapeutic potential for AS. 4.1.4 Aralia armata (Wall.) Seem Aralia armata (Wall.) Seem (AAS) is a medicinal and edible plant widely distributed in Guangxi Zhuang Autonomous Region, China. Its tender buds and stems are consumed as a specialty vegetable with a unique aromatic flavour (Clement and Clement, 2015). It has been reported that AAS exhibits hepatoprotective and growth-promoting effects, as well as therapeutic potential against acute and chronic inflammatory diseases and neurasthenia syndrome (Kim et al., 2017; Kwon et al., 2019). In traditional medicine, AAS root bark extract is used to treat CVDs, chronic nephritis, prostatitis, edema, and rheumatoid arthritis. Modern studies indicate that saponins from this plant possess multiple bioactivities, including anti-inflammatory (Lyu et al., 2011; Woo et al., 2019), anti-tumor (Li et al., 2021a), anti-AS (Zhou et al., 2018), and hypoglycemic effects (Li et al., 2017). Notably, AAS significantly inhibits abnormal proliferation and migration of vascular endothelial cells, potentially via modulation of the Wnt/β-catenin pathway. Specifically, it suppresses Fetal Bovine Serum (FBS)-induced β-catenin activation and downregulates pathway-related proteins (e.g., Wnt3α, Dvl-1, GSK-3β, β-catenin, Cyclin D1) (Zhao et al., 2021b), suggesting its role in mitigating post-injury endothelial hyperproliferation. 4.1.5 Ziziphora clinopodioides Lam. Ziziphora clinopodioides Lam. (ZcL), known as ”New Tower Flower” in TCM, is a semi-shrub of the Lamiaceae family. It exhibits mint-like aromatic properties and is colloquially termed ”lip herb” or ”small-leaf mint” (Taheri et al., 2022). Traditional applications have documented the pharmacological activities of ZcL, including sedative, tonic, and vasodilatory effects, with clinical use as an adjunctive therapy for insomnia, hypertension, and CVDs (Yang et al., 2014). Modern studies demonstrate that ZcL delays weight gain in AS mice, ameliorates dyslipidemia, stabilizes plaques, and repairs endothelial injury (Taheri et al., 2023). Mechanistically, ZcL targets dual pathways: (1) It downregulates aortic expression of TLR4, NF-κB, Wnt1, Wnt3a, and β-catenin; (2) It reduces serum pro-inflammatory factors (TNF-α, IL-1β, IL-6) while elevating anti-inflammatory mediators (Zhang，H., 2019). These data imply that the anti-AS effects of ZcL involve coordinated modulation of TLR4/NF-κB and Wnt/β-catenin pathways and their downstream inflammatory networks. However, additional mechanisms (e.g., oxidative stress regulation or endothelial function improvement)—along with potential pathway crosstalk may underlie the effects of ZcL, highlighting the need to explore its multi-target anti-atherosclerotic properties. 4.1.6 Echinacoside Echinacoside (ECH), an active phenethyl glycoside isolated from Cistanche tubulosa (Orobanchaceae family), exhibits potent antioxidant, anti-apoptotic, and anti-inflammatory activities (Thida et al., 2021). Growing evidence highlights its therapeutic potential in CVDs, attributed to free radical scavenging, immunomodulation, and anti-inflammatory effects (Ding et al., 2023). The Wnt pathway, a critical regulator of vascular calcification, mediates cell proliferation, differentiation, and migration (Zhou et al., 2019). Notably, Wnt3a, LRP5, and β-catenin are upregulated in calcified aortic valves (Caira et al., 2006). Recent studies demonstrate that ECH attenuates vascular calcification dose-dependently by inhibiting the Wnt3a/LRP5/β-catenin axis and BMP-2 expression (Yuan et al., 2024). Structural and functional analyses reveal that ECH acts as a competitive antagonist of Wnt3a-LRP5 interaction, effectively abrogating canonical Wnt signaling. These results position ECH as a pleiotropic Wnt pathway inhibitor, offering a rational framework for targeting vascular calcification. 4.1.7 Honokiol Honokiol (HNK), a major bioactive ingredient derived from Magnolia officinalis, exhibits diverse pharmacological properties including anti-inflammatory, antioxidant, and glycolipid metabolism-regulating activities (Hu et al., 2023). These characteristics indicate HNK’s potential efficacy against AS. Experimental studies demonstrate that HNK significantly suppresses pathological angiogenesis and neointima formation in ApoE −/− mice, while reducing abnormal proliferation of VSMCs and excessive ECM deposition (Zhu et al., 2014). In vitro studies further revealed that HNK could protect endothelial cells from ox-LDL-induced damage by alleviating oxidative stress (Wang et al., 2022a). Both in vivo and in vitro AS model studies have shown that HNK downregulates Wnt3a and β-catenin expression, inhibits migration of HA-VSMCs, and inhibits media thickening and vascular wall thickness (Zhan et al., 2022). Intriguingly, when co-treated with PNU-74654 (a specific Wnt inhibitor blocking TCF/β-catenin interaction), the atheroprotective efficacy of HNK was only partially attenuated (Leal et al., 2015), implying involvement of additional pathways. These results establish HNK as a polypharmacological agent capable of concurrent Wnt pathway regulation, offering a structural blueprint for the rational design of next-generation anti-AS therapeutics. 4.1.8 Gentisic acid Gentisic acid (GA), a polyphenolic ingredient abundant in Olea europaea, Cynara scolymus, and Aloe vera (Razliqi et al., 2023), exhibits diverse pharmacological activities including anti-inflammatory, antioxidant, hepatoprotective, and neuroprotective effects (Kim et al., 2020). The sorting nexin (SNX) family, characterized by phosphoinositide-binding PX domains, mediates endosomal protein sorting (Wang et al., 2021). Among them, SNX10 (the structurally simplest member) plays a pivotal role in endosomal-lysosomal trafficking (Lee et al., 2022; Trachsel-Moncho et al., 2025). Intriguingly, SNX10 knockout in ApoE −/− mice markedly attenuates atherogenesis by suppressing CD36-mediated ox-LDL uptake (You et al., 2020). The latest research reveals that GA-mediated targeting of SNX10 induces conformational changes that prevent its association with LRP6, ultimately promoting lysosomal clearance of LRP6 and downstream pathway regulation. Meanwhile, down-regulation of the LRP6 level can effectively inhibit activation of the Wnt/β-catenin pathway, thereby reducing macrophage apoptosis (Chen et al., 2024b). 4.1.9 Resveratrol Resveratrol is a naturally occurring diphenyl polyphenol ingredient widely distributed in plant-based foods such as grapes (Vitis vinifera), red wine, peanuts (Arachis hypogaea), and blueberries (Vaccinium spp.) (Zheng et al., 2023). In addition, it is also the main active component of TCM such as Polygonum cuspidatum, Atractylodes macrocephala, and white peony root. Studies have shown that resveratrol has multiple significant protective effects on the cardiovascular system, including endothelial protection, anti-AS activity, and antioxidant properties, in rat models of hypercholesterolemia (Pannu and Bhatnagar, 2019). A study found that abnormal activation of the Wnt/β-catenin pathway in endothelial cells is closely related to increased NOX-4 protein expression. This molecular alteration can promote atherosclerotic lesions and oxidative stress injury. Notably, resveratrol was shown to potently augment the vascular reparative capacity of endothelial progenitor cells (EPCs) through selective modulation of the Wnt/β-catenin/NOX-4 signaling axis, as evidenced by (Elgeziry et al., 2024). This mechanism not only elucidates a novel molecular intervention strategy but also highlights the potential of resveratrol for targeted therapy of dyslipidemia-related endothelial dysfunction. 4.1.10 Cryptotanshinone Cryptotanshinone (CTS), an active ingredient isolated from the traditional Chinese medicine Salvia miltiorrhiza Bunge, exhibits significant anti-inflammatory and cardioprotective effects (Wang et al., 2024a). Studies have found that CTS inhibits β-catenin-dependent transcriptional activity in a dose-dependent manner. Additionally, it significantly reduces the expression levels of vascular endothelial growth factor (VEGF) and cyclin D, thus inhibiting endothelial cell viability, migration, invasion, and in vitro angiogenesis (Chen et al., 2014). These findings demonstrate that CTS inhibits pathological angiogenesis by regulating the Wnt/β-catenin pathway. 4.1.11 Paeoniflorin Paeoniflorin, a characteristic ingredient of Paeoniaceae plants, is widely distributed in roots, stems, and leaves, with the highest accumulation in roots (Ren et al., 2023). Studies demonstrate its diverse pharmacological activities, including anti-tumor, anti-inflammatory, lipid-modulating, and anti-thrombotic (Gao et al., 2023; Ji et al., 2016; Zhi et al., 2024). Recent evidence highlights its cardiovascular protective effects, such as ameliorating myocardial ischemia-reperfusion injury, hypertension, and stroke (Han et al., 2016; Tang et al., 2021; Yu et al., 2020). These benefits are mediated through inhibition of pro-inflammatory factors, suppression of programmed cell death, and promotion of VSMCs proliferation, thereby attenuating AS progression (Guo et al., 2017). Specifically, paeoniflorin inhibits ox-LDL-induced apoptosis and inflammation in HCAECs by blocking the Wnt/β-catenin pathway, supporting its potential for AS therapy. Animal experiments have also confirmed that paeoniflorin can significantly alleviate aortic pathological injury and macrophage infiltration while improving the lipid profile by reducing blood levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) and increasing blood levels of high-density lipoprotein cholesterol (HDL-C) (Liu et al., 2023). Collectively, paeoniflorin exerts anti-AS effects through Wnt/β-catenin regulation and lipid metabolism modulation, positioning it as a promising anti-AS drug candidate. 4.1.12 Ursolic acid Ursolic acid (UA), a pentacyclic triterpenoid, is abundantly present in vegetables, fruits, and medicinal plants (Zheng et al., 2024). Structurally, UA exists as a positional isomer of oleanolic acid. Two decades of rigorous investigation have elucidated its multifaceted pharmacological profile, encompassing potent anti-inflammatory, antimicrobial, antioxidant, and anti-proliferative activities (Chen et al., 2024a; Qiu et al., 2023). At the molecular level, UA exerts its atheroprotective effects through targeted regulation of the Wnt/β-catenin signaling cascade. Secreted frizzled-related protein 4 (SFRP4), a tumor suppressor, inhibits canonical Wnt signaling by competitively binding to frizzled receptors, thereby reducing β-catenin nuclear translocation and suppressing cell proliferation (Chen et al., 2023). UA upregulates SFRP4 expression, which subsequently enhances transcription factors Foxo3a and p27. This cascade inhibits the proliferation of VSMCs, ultimately attenuating AS progression (Sun, 2016). 4.1.13 Gypenosides Gypenosides (GPs), bioactive compounds extracted from the traditional Chinese herb Gynostemma pentaphyllum, are clinically used to treat hyperlipidemia (Zhou et al., 2023b). Notably, GPs proved to have significant anti-inflammatory, hepatoprotective, and cardiovascular regulatory activities (Guo et al., 2024; Liu et al., 2021). In AS models, GPs attenuate aortic inflammation by downregulating the expression of PPAR-γ, Wnt3a, and β-catenin, thereby slowing AS progression (Shou et al., 2024). Molecular docking studies further reveal that GP constituents, namely baicalin, cholesterol, campesterol, sitosterol, and 3’-methylrhamnosin, bind strongly to the PPAR-γ receptor, suggesting PPAR-γ pathway regulation as an additional therapeutic mechanism. 4.1.14 Semen ziziphi spinosae Semen Ziziphi Spinosae (SZS), the dried mature seed of Ziziphus jujuba var. spinosa (Rhamnaceae), is a traditional sedative listed in the Chinese Pharmacopoeia. Clinically, it is used to treat insomnia, palpitations, night sweats, and thirst associated with Yin deficiency, functioning to nourish the heart, calm the mind, and consolidate Yin (Ren et al., 2024). Modern pharmacological studies have revealed that SZS and its active ingredient have therapeutic potential in the treatment of sleep disorders, fatigue, hypertension, and post-stroke rehabilitation (Bi et al., 2025; Li et al., 2023b; Liu et al., 2022a). Notably, SZS significantly reduces serum TC, TG, and MDA levels in hyperlipidemic rats, indicating potent lipid-lowering and antioxidant effects (Xiao et al., 2022). Mechanistic studies demonstrate that SZS extract attenuates arterial lipid plaque deposition by downregulating catenin delta-1 (CTNND1) protein expression and suppressing transcriptional activity of Wnt-related genes (WNT5A/9A, CTNNB1, CD44) (Li et al., 2024b). These findings suggest that SZS exerts an anti-AS effect by regulating the Wnt/β-catenin pathway. 4.1.15 Curcumin Curcumin, a polyphenolic ingredient derived from the rhizomes of Curcuma longa, is characterized by its distinct orange-yellow pigmentation (Nunes et al., 2024). As the main active ingredient in the traditional Asian condiment curry, it has been proven to possess significant anti-inflammatory and antioxidant properties (Yeung et al., 2019). Experimental studies demonstrate that curcumin intervention can effectively alleviate HUVECs dysfunction induced by ox-LDL, and manifested by a significantly increased HUVECs proliferation rate, enhanced migration ability, and improved angiogenic activity. Research into the mechanism reveals that this protective effect may be achieved by inhibiting the excessive activation of the Wnt/β-catenin pathway induced by ox-LDL (Wu et al., 2024). Another study found that long non-coding RNA H19 (LncRNA H19) could counteract the protective effect of curcumin on the carotid balloon injury model in rats by activating the Wnt/β-catenin pathway (Zhou et al., 2021). These findings suggest that curcumin may prevent AS by regulating the Wnt/β-catenin signaling axis. Some related content will be presented in a tabular format, as shown in Table 1. The effects of TCM and its active components on preventing and treating AS by intervening in the Wnt/β-catenin pathway are summarized in Figure 3. Table1 The active ingredients of TCM prevent and treat AS by targeting the Wnt/β-catenin-related signaling pathway. Flavonoid compound Vitexin Wnt/β-catenin and Nrf2 signaling pathway HUVECs induced by high glucose Inhibits the apoptosis and oxidative stress induced by high glucose in endothelial cells (Zhang et al., 2024c) Dendrobium loddigesii Moscatilin Wnt3/β-catenin and IL13RA2/STAT3 signaling pathway Male C57BL/6J mice， Osteogenesis of HASMCs under phosphate conditions Inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating the WNT3/β-catenin signaling pathway (Zhang et al., 2025) Rubiaceae Bavachin Wnt/β-catenin signaling pathway and Atg7/mTOR-autophagy axis β-glycerophosphate (β-GP)-stimulated HASMCs Protects HASMCs against apoptosis and calcification by activation of the Atg7/mTOR-autophagy pathway and suppression of the β-catenin signaling (He et al., 2019) Tropaeolum majus L. AAS Wnt3α/Dvl-1/β-catenin Pathway Rats with femoral artery injury Improves intimal hyperplasia after vascular injury by downregulating the Wnt3α/Dvl-1/β-catenin pathway (Zhao et al., 2021b) Lamiaceae ZcL TLR4/NF-κB and Wnt/β-catenin signaling pathway ApoE − / − mice Inhibits the protein levels and downstream factor contents related to the TLR4/NF-κb and Wnt/β -catenin signaling pathways, and reduces inflammatory reactions (Zhang，H., 2019) Cistanche tubulosa ECH Wnt/β-catenin signaling pathway ApoE − / − mice Inhibits vascular calcification by preventing the binding of β-catenin, Wnt3a, and LRP5 within the Wnt signaling pathway (Yuan et al., 2024) Magnolia officinalis HNK Wnt/β-catenin signaling pathway SD rats, Ox-LDL-induced HA-VSMCs, and HUVECs Reduces the area of the aortic medium and the thickness of the vascular wall by down-regulating the expression of Wnt and β-catenin and inhibiting the migration of HA-VSMCs (Zhan et al., 2022) Polyphenolic compound GA Wnt/β-catenin signaling pathway LRP6-mediated macrophage Prevents the development of atherosclerotic lesions by inhibiting SNX10-mediated stabilization of LRP6 (Chen et al., 2024b) Diphenyl polyphenol compound Resveratrol Wnt/β-catenin/NOX-4 signaling pathway Wistar rats Inhibits atherosclerotic lesions and oxidative stress damage by preventing the abnormal activation of the Wnt/β-catenin/NOX-4 signaling pathway in ECs. (Elgeziry et al., 2024) Salvia miltiorrhiza Bunge CTS Wnt/β-catenin signaling pathway HUVECs Inhibits angiogenesis by blocking the activation of the Wnt/β-catenin signaling pathway (Chen et al., 2014) Paeoniaceae family Paeoniflorin Wnt/β-catenin signaling pathway Ox-LDL-induced HCAECs Inhibits ox-LDL-induced HCAECs apoptosis and inflammation via the Wnt/β-catenin pathway and alleviates CAD (Liu et al., 2023) Burdock root UA SFRP4/Wnt/β-catenin/Foxo3a/p27 signaling pathway SD rats, AngⅡ-induced VSMCs Inhibits the proliferation of VSMCs by up-regulating the expression of SFRP4, suppresses the activation of Wnt/β-catenin, and up-regulates the expression of transcription factors Foxo3a and p27 (Sun, 2016) Gynostemma pentaphyllum GPs PPAR-γ and Wnt/β-catenin signaling pathway SD rats Inhibits the progression of AS by down-regulating the expression of PPAR-γ, Wnt3a, and β-catenin proteins to alleviate aortic inflammation (Shou et al., 2024) Ziziphus jujuba var. spinosa SZS Wnt/β-catenin signaling pathway ApoE − / − mice Reduces the deposition of arterial lipid plaques by down-regulating the expression of catenin delta-1 (CTNND1) protein and inhibiting the expression of WNT-related genes (Li et al., 2024b) Curcuma longa Curcumin Wnt/β-catenin signaling pathway Ox-LDL-induced HUVECs Promotes the proliferation, migration, and angiogenesis of HUVECs to improve AS by inhibiting the excessive activation of the Wnt/β-catenin signaling pathway induced by ox-LDL. (Wu et al., 2024) Figure 3: Active ingredients of traditional Chinese medicine intervene in the Wnt/β-catenin pathway to prevent and treat atherosclerosis. The schematic diagram illustrates that TCM and its active components can exert protective effects against AS by intervening in the Wnt/β-catenin pathway, including alleviating endothelial cell damage, inhibiting vascular calcification, and reducing smooth muscle cell apoptosis, among others. 4.2 Compound of TCM 4.2.1 Activating blood and resolving stasis therapy （ABRST） Traditional Chinese medicines with blood-activating and stasis-resolving effects demonstrate multi-target regulatory mechanisms against AS. Their mechanisms involve lipid regulation, anti-inflammatory effects, oxidative stress reduction, and endothelial protection (Zhang et al., 2024a). Emerging research demonstrates that ABRST induces marked upregulation of the Wnt/β-catenin signaling cascade, as indicated by enhanced expression levels of key pathway components including Wnt1, Frizzled-1 receptor, Axin scaffolding protein, and β-catenin. This regulation further enhances VEGF mRNA transcription, ameliorating vascular endothelial dysfunction in carotid atherosclerosis models (Yu et al., 2016). These findings demonstrate that ABRST exerts vascular protection via the Wnt/β-catenin-VEGF axis. 4.2.2 Tongxinluo Capsule Tongxinluo Capsule is a multi-component TCM formulation developed based on meridian disease theory. Its formula comprises 12 herbal and animal-derived components, such as ginseng, leeches, scorpions, and red peony root. This insect-plant combination embodies the TCM principle of ’meridian unblocking’ (Ouyang et al., 2025). It shows significant clinical efficacy against AS-related cerebrovascular disorders (Dong et al., 2024). Studies demonstrate that Tongxinluo capsule decreases aortic atherosclerotic plaque size while lowering serum pro-inflammatory factors (e.g., TNF-α, IL-6) and downregulating Wnt pathway proteins (Wnt1, Wnt3a, β-catenin) at both mRNA and protein levels in aortic tissues (Jiang et al., 2023). It is suggested that Tongxinluo capsule may delay the progression of AS by inhibiting the inflammatory reaction mediated by the Wnt/β-catenin pathway. 4.2.3 Huxinkang Huxinkang is a TCM compound containing Trichosanthes kirilowii bark, Allium chinense, dried tangerine peel, Polygonum multiflorum, and Pinellia ternata. It exerts therapeutic effects by resolving phlegm, dispersing nodules, activating blood circulation, and removing stasis (He et al., 2024). Studies confirm that phlegm-resolving and blood-activating TCM significantly alleviate AS (He et al., 2025). In TLR4 -/- mice with AS, β-catenin expression is markedly upregulated (Dong et al., 2018). The Huxinkang treatment demonstrates lipid-lowering effects and downregulates the expression of β-catenin, Wnt1, and Wnt5a in atherosclerotic plaques, thereby suppressing the progression of AS (Ding et al., 2019; Dong et al., 2019). It is suggested that Huxinkang inhibits AS by blocking Wnt pathway activation and downstream inflammatory signaling. However, the exact mechanism by which Huxinkang regulates Wnt signaling remains unclear, necessitating further proteomic and signaling pathway analyses. 4.2.4 Changmaile capsule The Changmaile capsule is a compound herbal preparation composed of six herbs: Hirudo (leech), Salviae Miltiorrhizae Radix et Rhizoma (danshen), Curcumae Radix (yujin), Polygoni Multiflori Radix Praeparata (processed fleeceflower root), Astragali Radix (huangqi), and Puerariae Lobatae Radix (gegen). It follows the therapeutic principle of ”promoting blood circulation without impairing vital qi, while eliminating stasis and reinforcing healthy qi” (Weng et al., 2022). Through the rational combination of blood-activating and tonifying herbs, this formula reflects the holistic treatment concept of ”removing stasis to regenerate new tissues and replenishing qi to unblock meridians” (Zhang et al., 2024b). Clinical studies have demonstrated that the Changmaile capsule significantly improves vascular endothelial function and promotes the regression of carotid atherosclerotic plaques (Lin et al., 2015). Specifically, this formulation potently inhibits the expression of key Wnt pathway components (including β-catenin, Dishevelled-1, and Wnt1) in ECs and VSMCs. By targeting the Dvl-1-mediated signaling cascade, it effectively suppresses the disease progression of carotid AS (Xie and Chen, 2020). 4.2.5 Buyang Huanwu decoction As a well-established blood-activating and stasis-resolving formula, Buyang Huanwu decoction (BYHWD) has been confirmed to exert anti-AS effects through multiple mechanisms, such as inhibiting inflammatory reactions, regulating lipid metabolism, protecting vascular endothelial function, alleviating oxidative stress, and regulating VSMC phenotypic transformation (Feng et al., 2023; You et al., 2021). Experimental studies have demonstrated that BYHWD significantly reduced aortic lipid deposition, with dose-dependent effects observed. The high-dose group showed the most pronounced therapeutic efficacy. Mechanistically, BYHWD downregulates pro-inflammatory serum factors (e.g., IL-6, TNF-α, IL-1β, and MCP-1) and suppresses key molecules of the Wnt/β-catenin pathway in aortic tissue (Fan and Yuan, 2024). These findings suggest that BYHWD inhibits pathological phenotypic transformation of VSMCs by blocking the aberrant Wnt/β-catenin pathway, thereby attenuating AS progression. 4.2.6 Yiqi Tongbi capsule The Yiqi Tongbi capsule has demonstrated significant clinical efficacy in treating carotid atherosclerosis, primarily by promoting plaque regression and restoring vascular endothelial function (Lin et al., 2024). Mechanistic studies indicate this preparation regulates the Wnt pathway via multiple targets, notably by downregulating key effector molecules including β-catenin, glycogen synthase kinase-3β (GSK-3β), and vascular endothelial growth factor (VEGF). Experimental evidence shows this regulation effectively reduces atherosclerotic lesion area and suppresses pathological angiogenesis in rat models (Chen, 2023). Nevertheless, the exact molecular targets and systems-level mechanisms through which Yiqi Tongbi capsule orchestrates Wnt pathway modulation require comprehensive characterization. 4.2.7 Guanxinning tablets Guanxinning tablets (GXN), a traditional Chinese medicine compound containing Salvia miltiorrhiza and Ligusticum chuanxiong (Wang et al., 2024d), have shown clinical efficacy in coronary atherosclerosis when combined with standard therapies (clopidogrel and aspirin) (Yang et al., 2022). Mechanistic studies reveal that GXN dose-dependently downregulates Wnt3a and β-catenin expression in the carotid arteries of AS model rats. Crucially, this effect is pharmacologically reversed by lithium chloride (LiCl), a Wnt/β-catenin pathway activator, which fully antagonizes the therapeutic effects of GXN suppression of oxidative stress and inflammation. These findings directly confirm that GXN exerts anti-AS effects via Wnt/β-catenin pathway inhibition (Zhang et al., 2024d), providing a robust pharmacological basis for its development as a targeted anti-AS therapy. 4.2.8 Wenxin Formula The Wenxin Formula (WXF) is a traditional herbal remedy comprising Ginseng, Cinnamon twigs, Allium victorialis, Trichosanthes kirilowii, Pinellia ternata, and Ligusticum chuanxiong. It has been widely used in the treatment of cardiovascular diseases (Jiang et al., 2022; Yang et al., 2025). Clinical studies have demonstrated its efficacy in reducing coronary artery plaque burden and improving ST-segment recovery on electrocardiograms (Wang et al., 2022b). Experimental evidence indicates that WXF exerts anti-AS effects through dual-pathway regulation: (1) inhibition of the PI3K/Akt/mTOR pathway to attenuate inflammatory injury in ECs, and (2) suppression of VSMCs proliferation via downregulation of β-catenin and cyclin D1 in the Wnt/β-catenin pathway (Li et al., 2021b). Importantly, WXF promotes ECs to secrete miR-145-enriched exosomes, which enhance miR-145 expression in VSMCs through intercellular communication, preventing their phenotypic switch from contractile to synthetic (Li et al., 2023a). Furthermore, recent research has revealed that WXF-treated HUVEC exosomes target Wnt2B via miR-145. This inhibits β-catenin nuclear translocation, which subsequently reprograms VSMCs and alleviates intimal hyperplasia (Li et al., 2025). 4.2.9 Yindan Xinnaotong capsule The Yindan Xinnaotong capsule is a combination of eight traditional Chinese medicines, including Ginkgo biloba, Salvia miltiorrhiza, and Erigeron breviscapus. It exhibits multiple pharmacological effects, such as immunomodulation, anti-inflammatory activity, vascular endothelial protection, and antiplatelet aggregation (Pang et al., 2019). Clinically, it is primarily used to treat coronary heart disease, angina pectoris, hyperlipidemia, cerebral arteriosclerosis, stroke, and its sequelae (Pang et al., 2022). Ginkgo biloba improves microcirculation, inhibits calcium influx, and reduces platelet aggregation, thereby lowering thrombosis risk (Pfuhlmann et al., 2025). Salvia miltiorrhiza exerts anti-inflammatory and anti-AS effects through mechanisms including antioxidant activity, oxygen free radical scavenging, and Ca 2+ metabolism regulation (Jia et al., 2019). Erigeron breviscapus regulates vascular endothelial function, inhibits inflammatory factor release, reduces platelet aggregation, and improves hemodynamics (Wang et al., 2024c). Studies have demonstrated that this capsule can improve balloon injury-induced carotid intimal hyperplasia in rats by inhibiting the Wnt3a/β-catenin pathway, attenuating inflammatory responses, suppressing VSMC proliferation and migration, and promoting apoptosis (Ding, 2022). 4.2.10 Compound Danshen Dripping Pills Compound Danshen Dripping Pills (CDDP) is a modern pharmaceutical preparation derived from traditional Chinese medicines, including Salvia miltiorrhiza and Panax notoginseng. It is widely used in clinical practice for the prevention and treatment of CVDs, including myocardial ischemia (Yang et al., 2023b). Vascular calcification (VC), an independent risk factor for cardiovascular events, is characterized by abnormal calcium-phosphate crystal deposition in the vascular wall and is closely associated with AS, diabetic vascular lesions, and other pathologies (Chen et al., 2020). Studies demonstrate that CDDP inhibits aberrant LRP6/β-catenin signaling by upregulating DKK1 expression and decreasing calcification-related proteins (e.g., Runx2, BMP2) in ECs and VSMCs. Furthermore, CDDP suppresses cellular senescence markers (p16, p21) through Sirt1 deacetylase activation, thereby delaying EC/VSMC senescence (Yang et al., 2024). 4.2.11 Shexiang Baoxin Pill Shexiang Baoxin Pill (SBP), a TCM derived from the classical formulation Suhexiang Pill (recorded in Taiping Huimin Heji Jufang), is clinically used to treat cardiovascular and cerebrovascular diseases, including cardiac insufficiency and CAD (Guo et al., 2021). Experimental evidence indicates that SBP has multifaceted therapeutic effects, including improving myocardial remodeling, dilating coronary arteries, alleviating fibrosis, relieving vasospasm, enhancing ischemic myocardial microcirculation, and protecting vascular endothelial cells (Li et al., 2024a; Wei et al., 2023a). Notably, it reduces myocardial oxidative stress and inhibits Wnt/β-catenin pathway via downregulation of LRP6, GSK-3β, and β-catenin, thereby attenuating remodeling, apoptosis, and mitochondrial dysfunction (Huang et al., 2021). While the cardioprotective properties of SBP are well-documented, its potential regulation of AS progression through similar mechanisms requires further investigation. Some related content will be presented in a tabular format, as shown in Table 2. The effects of TCM compound prescriptions on preventing and treating AS by intervening in the Wnt/β-catenin pathway are summarized in Figure 4. Table2 The compound of TCM prevents and treats AS by targeting the Wnt/β-catenin-related signaling pathway. ABRST Peach kernels, Safflower, Angelica sinensis, Rehmannia glutinosa, Achyranthes bidentata, Ligusticum chuanxiong Wnt/β-catenin-VEGF axis SD rats Improves vascular endothelial dysfunction by up-regulating the Wnt/β-catenin signaling pathway and promoting the expression of VEGF genes (Yu et al., 2016) Tongxinluo Capsule Ginseng, Leeches, Scorpions, and Red peony root Wnt/β-catenin signaling pathway ApoE − / − mice Inhibits the inflammatory reaction of AS by reducing the size of atherosclerotic plaques and the levels of TNF-α and IL-6 in serum, while simultaneously lowering the protein expressions of Wnt1, Wnt3a, and β-catenin in aortic tissue (Jiang et al., 2023) Huxinkang Trichosanthes kirilowii bark, Allium chinense, Dried tangerine peel, Polygonum multiflorum, and Pinellia ternata Wnt5a TLR4 − / − mice Alleviates the formation of AS by reducing the expression of blood lipids and Wnt5a in AS (Dong et al., 2019) Changmaile capsule Hirudo, Salviae Miltiorrhizae Radix et Rhizoma, Curcumae Radix, Polygoni Multiflori Radix Praeparata, Astragali Radix, and Puerariae Lobatae Radix Wnt1/β-catenin/dvl-1 Wistar rats Reduces the degree of carotid artery AS by inhibiting the expression of Wnt1, β-catenin, and dvl-1 in the Wnt signaling pathway of rats (Xie and Chen, 2020) BYHWD Astragalus membranaceus, Angelica sinensis tail, Red Peony Root, Ligusticum chuanxiong Wnt/β-catenin signaling pathway ApoE − / − mice Inhibits the inflammatory reaction by reducing the lipid content and OPN expression in the aortic sinus of mice, simultaneously lowering the levels of serum IL-6, TNF-α, IL-1β, and MCP-1, and down-regulating the expression of Wnt1 and β-catenin proteins in the aorta (Fan and Yuan, 2024) Yiqi Tongbi capsule Ma Qianzi, White-flowered snake, Centipede, Gastrodia elata Wnt/β-catenin/GSK-3β/VEGF Wistar rats Inhibits angiogenesis in AS rats and reduces the severity of carotid artery AS in rats by suppressing the expression of β-catenin, GSK-3β, and VEGF genes in the Wnt signaling pathway (Chen, 2023) GXN Salvia miltiorrhiza and Ligusticum chuanxiong Wnt/β-catenin signaling pathway SD rats Inhibits the formation of AS plaques in rats by down-regulating the expression of Wnt3a and β-catenin in the carotid arteries of rats (Zhang et al., 2024d) WXF Ginseng, Cinnamon twigs, Allium victorialis, Trichosanthes kirilowii, Pinellia ternata, and Ligusticum chuanxiong WNT2B and Wnt/β-catenin signaling pathway SD rats, HUVECs, HAVSMCs Alleviates vascular endothelial hyperplasia by upregulating the expression of miR-145 in HAVSMCs, targeting WNT2B, inhibiting the Wnt/β-catenin signaling pathway, regulating the transformation of HAVSMCs to the contractile type, and inhibiting their proliferation and migration. (Li et al., 2025) Yindan Xinnaotong capsule Ginkgo biloba, Salvia miltiorrhiza, and Erigeron breviscapus Wnt/β-catenin and CaN/NFAT signaling pathway SD rats Improves carotid intimal hyperplasia in rats caused by balloon injury by inhibiting the Wnt3a/β-catenin and CaN/NFAT signaling pathway (Ding, 2022) CDDP Salvia miltiorrhiza and Panax notoginseng DKK1/LRP6/β-catenin signaling pathway ApoE − / − mice, HASMCs, HUVECs Reduces vascular calcification by regulating the DKK1/LRP6/β-catenin signaling pathway in ECs/VSMCs and interactions with the crosstalk of ECs and VSMCs. (Yang et al., 2024) SBP Musk, Ginseng, Bezoar, Cinnamon Wnt/β-catenin signaling pathway SD rats Reduces myocardial oxidative stress and suppresses Wnt/β-catenin pathway activation by downregulating LRP6, GSK-3β, and β-catenin mRNA expression, thereby inhibiting myocardial remodeling, attenuating apoptosis, and preserving mitochondrial function (Huang et al., 2021) Figure 4: Traditional Chinese medicine compound intervenes in the Wnt/β-catenin pathway to prevent and treat atherosclerosis. The schematic diagram illustrates that TCM compound prescriptions can exert protective effects against AS by intervening in the Wnt/β-catenin pathway, including improving endothelial dysfunction, inhibiting inflammatory responses, and reducing blood lipid levels, among others. 5. Toxicology and adverse reactions As a key component of China’s traditional medical system, TCM has expanded beyond clinical treatment into health food, cosmetics, and other fields, driven by growing health demands and the Over-The-Counter (OTC) market. However, public perception of TCM safety remains problematic (Liao et al., 2022). Many assume that TCM exhibits negligible toxicity, poses minimal side effects, is generally regarded as safe, and contains exclusively natural-origin components. Due to the underestimation of the toxicity and side effects of TCM and the neglect of its pharmacological toxicity, there has been an increase in the reporting of adverse reactions related to TCM in recent years. Tripterygium wilfordii, a TCM, exhibits potent anti-inflammatory, immunomodulatory, and cardiovascular protective effects. Its primary active ingredient, triptolide, regulates signaling pathways (e.g., NF-κB and MAPK), conferring therapeutic benefits such as blood circulation promotion and meridian regulation. Clinically, it is widely used to treat autoimmune diseases, including rheumatoid arthritis and nephrotic syndrome (Gao et al., 2019; Guo et al., 2023; Wang et al., 2023b). However, long-term or high-dose administration of Tripterygium wilfordii preparations is associated with severe hepatotoxicity. The predominant pathological manifestation is cholestatic liver injury, characterized by interlobular bile duct damage (with inflammatory infiltration on histology), hepatocyte ballooning degeneration, and spotty necrosis. Clinical symptoms include jaundice, dark urine, and pruritus (Zhou et al., 2023a). Additionally, Tripterygium glycoside tablets and related formulations have been linked to abnormal liver function tests, such as elevated serum ALT, AST, total bilirubin, and total bile acids. Adverse effects may also involve gastrointestinal disturbances (e.g., nausea, vomiting, loss of appetite) and hepatic complications (e.g., hepatomegaly, fatty liver, cholesterol crystal deposition, and even cirrhosis) (Fu et al., 2025). Aristolochia manshuriensis, a traditional diuretic and dampness-eliminating herb, contains aristolochic acids (AAs), known as potent nephrotoxins. Studies demonstrate that AA-I, the principal nephrotoxic constituent, undergoes renal metabolic activation to form DNA adducts, which initiate apoptotic cascades in proximal tubular epithelial cells. Chronic AA-I exposure culminates in renal interstitial fibrosis and tubular atrophy, histologically manifested as oligocellular fibrosis. Following the 2003 ”Longdan Xiegan Wan Incident”, which highlighted AA-I-induced nephropathy, the China Food and Drug Administration (CFDA) banned Aristolochia manshuriensis and removed it from the Chinese Pharmacopoeia. Consequently, all related Chinese patent medicines now substitute it with Akebia quinata (Lardizabalaceae), a safer alternative (Wu et al., 2016). Fuzi (Aconitum spp.) is a cornerstone herb in TCM, primarily used for emergency treatment and Yang energy restoration. Its processed forms, namely Hei Shun Pian and Bai Fu Pian, exhibit cardioprotective, anti-inflammatory, analgesic, antitumor, and immunomodulatory properties (Tu et al., 2023). However, Fuzi’s narrow therapeutic window (where the effective dose approaches toxic levels) has led to frequent poisoning incidents. Studies identify the heart and nervous system as primary targets of its toxicity, though hepatotoxicity and nephrotoxicity are also documented. Chronic use may further induce metabolic disturbances and endocrine dysfunction (Wang et al., 2023a). A comprehensive analysis indicates that, when evaluating the efficacy of drugs, their safety must be carefully considered. TCM has long been considered safe for treating CVDs, particularly when used at conventional doses. However, studies on the systematic toxicity assessment of traditional Chinese medicinal compounds, extracts, and active ingredients are still relatively limited, as is evidence-based research into their adverse reactions. Toxicology research into TCM faces many challenges (Jiashuo et al., 2022). Firstly, TCM compound prescriptions typically comprise multiple active ingredients that can interact with each other in various ways (e.g., synergistically, antagonistically, or additively) once inside the body. This makes it difficult to predict toxicity based only on the content of a single ingredient. Secondly, once in the human body, the ingredients of TCM can affect multiple organs and pathways. Their toxic manifestations often involve multiple levels, including metabolism, immunity, and the neuroendocrine system. This makes it difficult to attribute the toxic mechanism simply to a specific ingredient or target. Finally, even at a cellular level, the toxicity assessment of TCM extracts can be affected by various factors, such as solvent effects, cell culture conditions, and impurities. Therefore, a strict quality control system must be implemented to eliminate nonspecific cytotoxicity interference. Given the above challenges, future research should focus on strengthening aspects such as compatibility and toxicity, and the relationships between toxicity regulatory elements, toxicity, and the toxicity of prescriptions, drugs, and diseases. 6. Conclusion and prospects Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid deposition in the arterial intima, vascular wall hardening, and the formation of vulnerable plaques. As the underlying cause of cardiovascular and cerebrovascular diseases, AS leads to progressive lumen stenosis and triggers severe clinical events due to plaque instability. Epidemiological data indicate that AS-related morbidity and mortality rates are rising globally, with approximately 20 million annual deaths and a trend toward younger onset. This imposes a heavy socio-economic burden, threatening both public health and societal stability. The Wnt/β-catenin pathway, an evolutionarily conserved signaling system, regulates cell proliferation, differentiation, and homeostasis. While its role in tumorigenesis is well-studied, recent research has increasingly focused on its pathophysiological implications in cardiovascular diseases (CVDs). This article systematically reviews the molecular mechanisms of the Wnt/β-catenin pathway in AS development, emphasizing lipid metabolism disorders, endothelial dysfunction, inflammation, vascular smooth muscle cell proliferation, and macrophage activation. Traditional Chinese medicine (TCM), with over two millennia of clinical practice, represents a unique repository of medical knowledge in China. It is characterized by syndrome differentiation and natural product-based therapies, empirically linked to disease phenotypes and informing modern medicine. Recent studies have highlighted the advantages of TCM in the treatment of AS. On the one hand, it can intervene in the AS process by regulating key molecular pathways, such as the Wnt/β-catenin pathway. On the other hand, compared with chemical drugs, it shows fewer adverse reactions and exhibits multi-component synergy and multi-link intervention characteristics. Multiple active ingredients of TCM and compound formulations exert therapeutic effects by targeting the Wnt/β-catenin pathway and regulating its upstream/downstream effector molecules. These mechanisms include anti-inflammatory and antioxidative stress actions, regulation of autophagy processes, suppression of pathological apoptosis, influence on macrophage polarization phenotype switching, improvement of lipid metabolism disorders, and inhibition of abnormal vascular smooth muscle cell proliferation and migration. Such multi-target, multi-level regulatory effects not only effectively delay the progression of AS but also demonstrate significant cardiovascular protective properties. Significant progress has recently been made in this field of research, resulting in new intervention strategies for preventing and treating AS. However, urgent solutions are needed to address several issues in the research on the regulation of the Wnt/β-catenin pathway by TCM for the prevention and treatment of AS: Firstly, the application of active ingredients and compound prescriptions of TCM deviates from the principle of syndrome differentiation and treatment under the guidance of TCM theory. Secondly, research into the intervention of TCM in the Wnt/β-catenin pathway for the treatment of AS is currently mainly limited to basic research and lacks sufficient clinical empirical support. Finally, the Wnt/β-catenin pathway exhibits intricate crosstalk with numerous other pathways. Current mechanistic studies predominantly focus on isolated single-pathway analyses. Future research should use data mining technologies and bioinformatics approaches to systematically study pathway interactions. This will clarify the mechanisms of action and treatment methods of AS and promote the development of TCM. Furthermore, this article examines the impact of TCM toxicology and adverse drug reactions (ADRs) on disease treatment, offering critical insights to advance targeted TCM therapy for AS. By elucidating these factors, we aim to strengthen the evidence base for safer and more effective clinical applications of TCM in AS management. 7. CRediT authorship contribution statement Chaoyang Zhang: Conceptualization, Review methodology, Investigation, Writing – original draft preparation. Yujie Yu and Shu Dai: Software, Writing – original draft preparation. Dong Liu and Mengling Zhou: Writing – review & editing. Jianlan Zhang: Data curation. Yunxia Li: Supervision, Visualization. All the authors have read and approved the final manuscript. Ethics approval This manuscript does not involve any study on animals or humans. Funding This work was supported by the National Natural Science Foundation of China (No: U24A20790), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (No: ZYYCXTD-D-202209), Sichuan TCM Science and Technology Industry Innovation Team (No: 2022C001). Declaration of competing interest The authors declare no conflict of interest. Data availability No data was used for the research described in the article. 8. References: Adkar, S.S., Leeper, N.J., 2024. Efferocytosis in atherosclerosis. Nature reviews. Cardiology 21(11), 762-779. Aherrahrou, R., Guo, L., Nagraj, V.P., Aguhob, A., Hinkle, J., Chen, L., Yuhl Soh, J., Lue, D., Alencar, G.F., Boltjes, A., van der Laan, S.W., Farber, E., Fuller, D., Anane-Wae, R., Akingbesote, N., Manichaikul, A.W., Ma, L., Kaikkonen, M.U., Björkegren, J.L.M., Önengüt-Gümüşcü, S., Pasterkamp, G., Miller, C.L., Owens, G.K., Finn, A., Navab, M., Fogelman, A.M., Berliner, J.A., Civelek, M., 2020. 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Information & Authors Information Version history V1 Version 1 26 March 2026 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Chaoyang Zhang Chengdu University of Traditional Chinese Medicine View all articles by this author Yujie Yu Chengdu University of Traditional Chinese Medicine View all articles by this author Shu Dai Chengdu University of Traditional Chinese Medicine View all articles by this author Dong Liu Chengdu University of Traditional Chinese Medicine View all articles by this author Mengling Zhou Chengdu University of Traditional Chinese Medicine View all articles by this author Jianlan Zhang Chengdu University of Traditional Chinese Medicine View all articles by this author Yunxia Li [email protected] Chengdu University of Traditional Chinese Medicine View all articles by this author Metrics & Citations Metrics Article Usage 162 views 90 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Chaoyang Zhang, Yujie Yu, Shu Dai, et al. Therapeutic Regulation of the Wnt/β-catenin Pathway by Traditional Chinese Medicine: Emerging Strategies in Atherosclerosis Management. Authorea . 26 March 2026. DOI: https://doi.org/10.22541/au.177452357.77869690/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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