Targeting the Wnt/β-catenin pathway in inflammatory bowel disease: Mechanisms and challenges of traditional Chinese medicine treatment

Abstract

The Wnt/β-catenin pathway is a key regulator of intestinal mucosal repair and immune modulation in inflammatory bowel disease (IBD). Traditional Chinese medicine (TCM), including herbal formulas and acupuncture, has been reported to target this pathway; however, the mechanistic basis and therapeutic challenges remain unclear. This minireview synthesizes findings from preclinical and clinical studies investigating the effects of TCM interventions (herbal formulas, single compounds, acupuncture, moxibustion) on the Wnt/β-catenin pathway in IBD models and patients. Approximately 90% of colorectal cancers exhibit Wnt pathway abnormalities, and IBD patients face a 2- to 5-fold higher risk of colorectal cancer. In IBD-associated colorectal cancer (CRC), β-catenin nuclear expression is significantly higher than in sporadic CRC. TCM interventions—such as Huangqin-tang, Notoginsenoside R1, Indigo Naturalis, and electroacupuncture—have been shown to modulate key Wnt components and promote mucosal repair while limiting fibrosis. However, moderate activation of the pathway aids healing, whereas overactivation may lead to fibrosis and cancer, presenting a major therapeutic challenge. The bidirectional nature of Wnt/β-catenin signaling—beneficial for repair but harmful when overactivated—presents a therapeutic challenge. TCM offers multi-component, multi-target advantages but faces obstacles in mechanistic elucidation. Future efforts should integrate network pharmacology, multi-omics, and real-world data to construct ‘component-target-pathway-disease’ networks, while emerging platforms such as Chinese herbal medicine-derived extracellular vesicle-like particles and spatiotemporal regulation strategies may enable precision targeting of Wnt signaling in IBD.

Key Words: Wnt/β-catenin pathway; Inflammatory bowel disease; Traditional Chinese medicine; Mucosal repair; Acupuncture and moxibustion; Herbal formula; Precision medicine

Core Tip: This minireview discusses the Wnt/β-catenin pathway in traditional Chinese medicine for treating inflammatory bowel disease. Based on literature, it analyzes the pathway as a common target for herbal compounds and acupuncture-moxibustion, offering insights into treatment mechanisms and efficacy optimization. Understanding this pathway is crucial for advancing traditional Chinese medicine modernization and achieving precise inflammatory bowel disease therapy.

INTRODUCTION

Extracellular Wnt proteins are pivotal in initiating the Wnt signaling pathway, which is crucial for various biological processes including cell fate determination, proliferation, and differentiation. The seven-transmembrane receptor Frizzled, which is specific to the cell surface, acts as the primary receptor for Wnt signaling, facilitating the transduction of extracellular signals into intracellular responses[1]. Similar to GPCRs, upon binding to Wnt proteins, this protein initiates a series of intracellular signaling responses, including phosphorylation of Dishevelled, which subsequently activates the β-catenin signaling pathway[2]. By binding to both Frizzled and LDL receptor-related protein 6, Wnt3a activates specific intracellular signaling, thereby promoting cell growth and development. Cytoplasmic proteins, including glycogen synthase kinase 3β (GSK-3β), Axial protein, casein kinase 1 (CK1), and β-catenin, play particularly crucial roles in the Wnt signaling pathway. The abnormal accumulation of β-catenin in the cytoplasm and nucleus regulates the activity of T-cell factor/lymphotactic factor binding factor (TCF/LEF) as well as other genes, including cyclin D1 and the proto-oncogene c-myc[3-7]. Multiple phosphorylation sites for CK1 and GSK-3β are present in the N-terminal region of β-catenin[8-10]. In the absence of Wnt proteins, β-catenin binds to E-cadherin on the cell membrane, thereby maintaining intercellular adhesion and effectively preventing the invasion of harmful substances such as bacteria and endotoxins. In contrast, a small amount of cytoplasmic β-catenin is phosphorylated by the adenomatous polyposis coli (APC) complex. Within this complex, Axin acts as a crucial scaffold that facilitates the phosphorylation and degradation of β-catenin, thus inhibiting its nuclear accumulation and transcriptional activity[11]. CK1 phosphorylates the amino-terminal serine 45 site on β-catenin. Subsequently, GSK-3β sequentially phosphorylates the amino-terminal threonine 41 site, serine 37 site (Ser37), and serine 33 site (Ser33). The phosphorylated Ser37 and Ser33 sites are recognized by the U3 ubiquitin ligase β-transducer repeat protein (β-TRCP), which then ubiquitinates these sites, ultimately leading to β-catenin degradation via the ubiquitin-proteasome pathway[12,13]. Under normal conditions, β-catenin levels in the cytoplasm are low, and target genes remain inactive[14]. Disruption of the cellular equilibrium triggers the binding of Wnt proteins to their receptors, upon activation of Frizzled and low-density lipoprotein receptor-related protein 5/6, Dsh is activated, which inhibits GSK-3β activity and thereby maintains β-catenin stability[15,16]. As a result, the Ser37 and Ser33 residues of β-catenin are no longer phosphorylated, preventing their recognition by β-TRCP. As a result, β-catenin avoids degradation and accumulates in the cytoplasm. Once it reaches sufficient quantities, β-catenin translocates to the nucleus and binds to the nuclear transcription factor TCF/LEF. This complex regulates cellular biological activities by activating the transcription of downstream target genes[17].

Previous studies have reported that traditional Chinese medicine (TCM) can modulate the Wnt/β-catenin pathway in inflammatory bowel disease (IBD), but a systematic synthesis focusing on the bidirectional nature of this pathway - where moderate activation promotes mucosal repair while overactivation drives fibrosis and carcinogenesis - is lacking. Moreover, how TCM’s multi-component, multi-target characteristics can precisely address this duality and what therapeutic challenges and future directions exist for TCM modernization in this context remain underexplored. Therefore, this review aims to fill these gaps by integrating current preclinical and clinical evidence. Specifically, this minireview aims to: (1) Summarize the pathophysiological roles and bidirectional effects of the Wnt/β-catenin pathway in IBD; (2) Systematically review the evidence for TCM interventions (herbal formulas, single compounds, acupuncture, moxibustion) targeting this pathway; (3) Critically analyze the therapeutic challenges posed by pathway overactivation; and (4) Propose future directions - including network pharmacology, multi-omics, real-world research, and emerging platforms such as Chinese herbal medicine-derived extracellular vesicle-like particles (CHM-EVLPs) - to advance the scientific modernization of TCM for precision IBD therapy.

This study is a narrative review that incorporates the principles of a systematic literature review. To enhance transparency and reproducibility, we established a clear search strategy and study selection process: The databases searched included PubMed, Web of Science, and the China National Knowledge Infrastructure. The search period spanned from January 2000 to June 2026, and the keyword combinations included “Wnt/β-catenin”, “inflammatory bowel disease”, “ulcerative colitis”, “Crohn’s disease”, “Traditional Chinese Medicine”, “Chinese herbal formulas”, “acupuncture”, “moxibustion”, and “traditional Chinese medicine”. Inclusion criteria included: (1) Animal and clinical studies investigating TCM interventions and the Wnt pathway in IBD models; (2) Studies evaluating TCM treatment for IBD that included Wnt-related outcome measures; and (3) Full-text articles published in English or Chinese. Two reviewers independently extracted data on TCM interventions, study models, Wnt-related targets, and biological effects.

PATHOPHYSIOLOGICAL CHARACTERISTICS OF IBD

IBD primarily includes ulcerative colitis (UC) and Crohn’s disease (CD), with pathophysiological features presenting as chronic intestinal mucosal inflammation, compromised barrier function, immune dysregulation, and abnormal tissue repair. In patients with UC, the colonic mucosa exhibits diffuse inflammation, characterized by the formation of crypt abscesses and a decrease in goblet cells, as evidenced by histological examination. In contrast, CD manifests with a range of clinical symptoms and pathological features, including abdominal pain, diarrhea, and weight loss. It is a chronic inflammatory process that can affect any part of the digestive tract from the mouth to the anus, with the small intestine and colon being the most commonly affected areas. CD manifests as transmural inflammation capable of affecting any segment of the gastrointestinal tract, frequently accompanied by fistulas and strictures. Elevated intestinal permeability is more prevalent among first-degree relatives of IBD patients, indicating that barrier dysfunction may represent an early defect[18]. Furthermore, a notable rise in immune cell infiltration within the mucosal lamina propria has been documented, with macrophages, neutrophils, and Th17 cells serving as the principal pro-inflammatory cell populations. In patients with UC, colonic mucosal interleukin (IL)-26 expression is markedly elevated, which activates pathways such as nuclear factor kappa-B (NF-κB) and activator protein 1 to induce the release of inflammatory mediators, including IL-6 and IL-8[19]. In CD patients, elevated levels of cytokines such as IL-1β and tumor necrosis factor-alpha (TNF-α) in the gut have been demonstrated to promote intestinal fibrosis and stricture formation, as evidenced by studies in chronic liver diseases and uterine myoma.

Changes in gut microbiota composition result in altered metabolites, which may potentially contribute to the pathogenesis of IBD. Metabolomics facilitates the identification of correlations between microbial composition and specific bacterial metabolic pathways. Comparative analysis of gut microbiota between healthy individuals and IBD patients reveals that 12% of metabolic pathways exhibit significant differences, as indicated by recent studies[20]. Studies have shown that compared to healthy individuals, patients with IBD typically exhibit an increase in certain bacteria, including Escherichia coli. The microbiota plays a pivotal pathogenic role in IBD, and chronic inflammation, in turn, promotes dysbiosis by altering the intestinal oxidative and metabolic environment. Although the microbiota plays a significant role as a trigger in IBD pathogenesis, it should be emphasized that studies to date have only discussed associations rather than causal relationships between them[21]. Lipopolysaccharide triggers the complement cascade in intestinal epithelial cells by engaging the toll-like receptor 4 (TLR4)-C3 axis, thereby amplifying the inflammatory response. During enteritis with mucosal barrier disruption, bacteria bind to TLR4, leading to an elevation in local C3 levels. Subsequent activation of bacterial C3b increases local C3a production, ultimately promoting the secretion of proinflammatory cytokines. Understanding the mechanisms underlying differential C3 expression in the intestines of CD and UC patients may contribute to better insight into the immune mechanisms that trigger distinct inflammatory patterns in these conditions[22].

The chronic persistence of IBD is significantly influenced by the body’s abnormal tissue repair mechanisms. The genes in the REG family (REG Iα, REG IV) are switched on in the intestinal mucosa of IBD patients, which aids in mucosal proliferation and repair. However, excessive activation of these factors can promote tumour growth. Studies demonstrate elevated levels of REG Iα, REG Iβ, and REG IV in CD, with REG IV being produced in greater quantities in the colon mucosa of UC patients. These findings support that REG family mRNA overexpression is linked to inflammation in autoimmune diseases like IBD[23]. At the same time, the Wnt/β-catenin pathway has dual roles: On one hand, it facilitates mucosal repair by promoting the growth and repair of intestinal stem cells (ISCs) and the epithelium; on the other hand, aberrant and prolonged activation can lead to fibrosis and carcinogenesis, as seen in approximately 90% of colorectal cancers (CRCs)[24]. M2 macrophages play a crucial role in regulating Wnt signaling, particularly in mucosal tissues that have undergone injury, where they contribute to the suppression of inflammation and promotion of tissue repair. M2 macrophages, a subtype of immune cells, can accelerate healing in the gastrointestinal tract by triggering the Wnt/β-catenin pathway. They achieve this through the secretion of signaling molecules such as Wnt2b and Wnt7b, which are known to play a role in cellular proliferation and regeneration. In chronic colitis, the Wnt pathway is excessively activated, leading to intestinal scarring. This is evidenced by an increase in collagen levels and the heightened activity of myofibroblast cells[25]. These studies illustrate the complexity of IBD and propose various treatment approaches.

BIDIRECTIONAL EFFECTS OF THE WNT/Β-CATENIN SIGNALING PATHWAY IN IBD AND RISK PREDICTION

It has been demonstrated that inflammation in IBD disrupts the balance of the Wnt pathway: Inflammatory Factors like TNF-α have been shown to suppress the Wnt pathway, resulting in ISC dysfunction. However, moderate activation of the Wnt pathway has been demonstrated to promote ISC proliferation and expedite mucosal repair[26,27]. Research indicates that mutations in the Wnt pathway, especially within the APC gene, are responsible for initiating over 90% of CRCs. However, it is important to note that Wnt signalling is also essential for normal intestinal homeostasis, suggesting a bidirectional regulatory effect of the Wnt pathway on IBD. The bidirectional regulatory effect of the Wnt pathway on IBD can be summarised as follows: Moderate activation promotes mucosal repair, while excessive activation leads to inflammation and fibrosis. This bidirectional regulation constitutes a core pathophysiological feature of IBD. Genetic screening identified two inhibitory factors, namely Earthbound and Erect wing, which play crucial roles in Wnt-dependent control of ISC proliferation. The effects of these mutations are primarily observed in excessive Wnt signalling activation and epithelial hyperplasia progression caused by Apc1 inactivation[28]. The Wnt pathway plays a key role in accelerating tissue repair by promoting the proliferation and differentiation of ISCs. Studies have shown that Notoginseng saponin R1 promotes the regeneration of Lgr5+ stem cells and epithelial cells in colitis-affected mice by activating the Wnt/β-catenin signaling pathway, thereby alleviating dextran sulfate sodium (DSS)-induced colitis in mice by reducing mucosal inflammation and enhancing epithelial repair[27]. Activation of Wnt/β-catenin signaling and inhibition of Delta-like ligand 1-mediated Notch signaling in Lgr5-positive ISCs alleviates DSS-induced colonic mucosal inflammation by regulating colonic epithelial integrity and promoting mucosal barrier repair, while also upregulating the expression of E-cadherin, cytokeratin 20, chromogranin A, and Ki67 in organoids. Given that Lgr5-positive ISCs possess self-renewal and high proliferative potential, and are finely regulated by the cooperative actions of Wnt/β-catenin and Notch signaling pathways, multi-target intervention strategies targeting combined signaling pathways as well as Lgr5-positive ISC transplantation therapy offer new application prospects and therapeutic directions for the treatment of IBD[29]. Recent studies have demonstrated that the Wnt and Notch pathways play a crucial role in the differentiation of ISCs, maintaining a synergistic balance during the repair process. Research has shown that Notch inhibitors can promote the differentiation of secretory cells, and Wnt activators have been demonstrated to enhance the proliferation of ISCs. These findings suggest that Notch and Wnt signaling may have opposing roles in regulating ISC and cell fate[30]. The histone methyltransferase SETD2 exerts its influence over the function of ISCs by modulating the expression of Wnt pathway target genes[31].

The Wnt/β-catenin pathway plays a pivotal role in IBD, contributing to the repair of the intestinal mucosa following injury and to the progression of chronic inflammation. Studies have shown that this pathway is essential for the regulation of group 3 innate lymphoid cells, which are involved in intestinal inflammation, and for the proliferation and differentiation of ISCs, which are critical for mucosal repair. Furthermore, the pathway’s activation has been associated with improvements in IBD symptoms. Regarding mucosal repair, STAT6-deficient mice show delayed mucosal healing, along with reduced expression of ligands like Wnt2b, Wnt7b, and Wnt10a and in the TNBS-induced colitis model, there is a reduction in β-catenin nuclear translocation, which is associated with the progression of colitis. However, the infusion of IL-4-polarized M2 macrophages has been shown to restore Wnt pathway activity and accelerate the healing process[24]. In other diseases, IL-6 has been shown to activate the Wnt/β-catenin pathway, which in turn promotes the proliferation of endometrial mesenchymal stem cells. This suggests that a similar mechanism may be involved in the cyclic repair of the intestinal mucosa, as the Wnt/β-catenin pathway is known to play a critical role in tissue regeneration and repair processes[32]. In terms of inflammatory progression, expression of WNT1-induced signaling pathway protein 1 is significantly elevated in the colonic mucosa of patients with IBD, especially in neutrophils, CD4+ T cells, and CD8+ T cells, by activating the Wnt/β-catenin pathway to promote the inflammatory cascade response[33,34]. In a mouse model of TNBS-induced colitis, overexpression of miR-155 significantly exacerbated intestinal fibrosis; conversely, inhibition of miR-155 produced the opposite effect. In the CD-associated intestinal fibrosis model, miR-155 activated the Wnt pathway by targeting HBP1 and induced myofibroblast activation and collagen deposition, whereas inhibition of miR-155 alleviated fibrosis, i.e., the miR-155/HBP1 axis promotes colitis-associated intestinal fibrosis through the Wnt/β-streptavidin signaling pathway, and implicates miR-155 as a potential CD therapeutic target. IBD patients exhibit heightened expression of S100a9 within the intestinal lining, a factor that contributes to the promotion of inflammation and tumor development via its activation. The Wnt pathway, and antibodies targeting S100A9 have been shown to suppress inflammatory responses, inhibit tumor cell proliferation, and reduce immune cell infiltration in colonic tissues, as supported by research on CRC. Anti-S100a9 antibody inhibited DSS-induced colitis and Azoxymethane/DSS-induced colon cancer[35].

Different branches of the Wnt pathway play differential roles in IBD. The classical Wnt/β-catenin pathway mainly regulates cell proliferation and repair, whereas the nonclassical Wnt pathway is involved in the regulation of immune cell function. In a mouse model of DSS-induced colitis, elevated expression of Wnt5a in the intestinal tract leads to a pro-inflammatory phenotype characterized by increased secretion of interferon (IFN)-γ and reduced secretion of transforming growth factor (TGF)-β/IL-10 via the nonclassical pathway. Conversely, inhibition of Wnt5a or activation of the classical Wnt pathway can reverse these inflammatory effects[36]. R-spondin family proteins act as enhancers of the Wnt pathway in C. rodentium. However, the Wnt pathway can reverse this effect under certain conditions. R-spondin family proteins, as enhancers of the Wnt pathway, are dynamically expressed in C. rodentium infection and DSS colitis: Rspo3 is highly expressed in DSS colitis, whereas Rspo2 is elevated in susceptible mice infected with C. rodentium, suggesting that it may serve as a biomarker for disease subtypes[37]. Rspo3 was the most strongly induced R-spondin in DSS treatment, and the absolute expression level of the gene was significantly elevated, highlighting the role of Rspo3 as a potentially important mediator of intestinal Wnt signaling, findings that provide theoretical rationale for the precise targeting of the Wnt pathway for the treatment of IBD.

The Wnt pathway is a key component in the pathogenesis of IBD, contributing to the onset and progression of the disease. It also serves as a significant predictor of disease complications, offering valuable molecular markers that aid in clinical risk stratification. Abnormal activation of the Wnt/β-catenin pathway is closely associated with the risk of IBD and disease progression[38]. The expression of key molecules in the Wnt signaling pathway in the intestinal mucosa of patients with IBD is positively correlated with disease activity, and the levels of promoter methylation in the Wnt signaling pathway-inhibiting genes MGMT-B and SFRP2 are significantly elevated. A study found that the expression level of ETV1 in the intestinal mucosa of IBD patients was significantly correlated with disease activity, suggesting that ETV1 may play a role in the pathogenesis of IBD. Additionally, the gut mucosal barrier’s role in IBD is significant, and genes like MGMT-B and SFRP2, which are involved in the Wnt pathway, may contribute to the development of IBD through their impact on the mucosal barrier. Methylation of MGMT-B and in patients with IBD, SFRP2 may offer a method for the early detection of IBD-associated tumors[39]. The rs3731257 polymorphism of CDKN2A/CDKN2B, identified in a genome-wide association study, was associated with the risk of IBD in the Korean population, and it has an important role in small bowel-specific gene regulation[40]. A transcriptome-based analysis was conducted by comparing 31 tumor samples with corresponding normal tissue samples from patients with IBD-associated CRC. The analysis of tumor subtypes in IBD-associated CRC has shown a complete absence of the classical epithelial subtype linked to the WNT signaling pathway, which is typically associated with β-catenin accumulation and APC gene mutations. Instead, there is a prevalence of the mesenchymal stroma-rich subtype, indicating a different molecular profile in the context of chronic inflammation. A distinct dysregulation mechanism of the WNT pathway, which is frequently observed in CRC, predisposes individuals with IBD to mesenchymal tumor subtypes. This dysregulation may influence the prognosis and the selection of therapeutic strategies. Enhanced Oncostatin-M-specific receptor subunit beta signaling may promote mesenchymal tumor formation in IBD patients. Molecular mechanisms suggesting that genetic and epigenetic factors influence IBD pathogenesis through the Wnt pathway[41].

Activation of the Wnt pathway is closely linked to the development of CRC, as well as the risk of extraintestinal manifestations and other complications in patients with IBD. Research indicates that approximately 90% of CRC patients exhibit abnormalities in the Wnt pathway, and the risk of CRC in IBD patients is significantly higher than that of the general population. Patients with IBD face a significantly elevated risk of CRC, ranging from 2 times to 5 times higher than that of the general population. This heightened risk is attributed to the aberrant activation of the Wnt/β-catenin pathway, which is a critical factor in the development of the disease. β-catenin nuclear expression is significantly higher in patients with IBD-associated CRC than in sporadic CRC[42]. Arthritis represents the most common extraintestinal manifestation of IBD and may precede, coincide with, or follow a diagnosis of overt IBD. IBD-associated spondyloarthritis (SpA/IBD) is classified as SpA. Arthritis contributes to the early diagnosis of IBD, and Wnt pathway inhibitors serum sclerostin (SOST), levels are reduced and anti-sclerostin-immunoglobulin G (anti-SOST-IgG) levels are elevated and show a positive correlation with the duration of joint symptoms[43]. Serum levels of Wnt2 are significantly elevated in patients with IBD, showing a positive correlation with disease activity. Moreover, CD patients exhibit significantly higher serum Wnt2 concentrations compared to healthy controls[44]. CASC11 was pathologically upregulated in CRC cells and tissues. Through gene set enrichment analysis, it was found that the Wnt/β-catenin signaling pathway is correlated with CASC11 expression, which promotes tumor progression through the activation of the Wnt pathway, and the upregulation of CASC11 in patients with CRC was associated with tumor size, plasma membrane invasion, lymphatic metastasis, and TNM classification[45].

REGULATION OF IBD AND WNT/Β-CATENIN PATHWAY BY CHINESE MEDICINE

Huangqin-tang ameliorated DSS-induced colitis in mice by inhibiting the NF-κB and Wnt pathways, resulting in mice with a reduced disease activity index (DAI), increased colon length, and decreased apoptosis of Intestinal epithelial cells play a pivotal role in regulating intestinal epithelial cell homeostasis, inflammation, and immune responses[18]. Histological analysis revealed that Zhikang capsule (ZKC) mitigated DSS-induced inflammatory responses, cuprocyte loss, and submucosal edema. ZKC markedly inhibited pro-inflammatory cytokines, promoted the production of anti-inflammatory mediators, effectively prevented oxidative stress, and selectively down-regulated MyD88-dependent TLR4 signaling pathway. It is suggested that comfrey extract exerts a protective effect against DSS-induced colitis, combining the advantages of high therapeutic efficacy and low toxicity, and shows significant superiority over western drugs in the treatment of IBD[46]. Indigo Naturalis demonstrated potent anti-colitis effects in mice with experimental colitis by inhibiting Th1/Th17 cell differentiation through suppression of oxidative stress in the colon and by inhibiting the induction of Th1/Th17 responses in the colon to alleviate DSS-induced colitis in mice. Activation of AMPK/Nrf-2 signaling and inhibition of STAT1/STAT3 signaling led to decreased levels of IFN-γ and IL-17, as well as reduced β-catenin expression in mouse colon tissues[47]. DIREN exhibited significant protective effects in a DSS-induced UC mouse model. Its main effects included significantly reducing the DAI, promoting colon length recovery, and showing effects at the histopathological level, attenuating cuprocyte loss, maintaining intestinal mucosal barrier integrity, and inhibiting colonic fibrosis and type I collagen deposition. Additionally, DIREN inhibited apoptosis of colonic epithelial cells and down-regulated the expression of genes, for instance, CDH2, ITGA1 and TGF-β2. Through gene set enrichment analysis, it was shown that the differentially expressed genes were significantly concentrated in the “focal adhesion” pathway. At the protein level, DIREN down-regulated the expression of the pro-apoptotic protein BAX, along with N-calmodulin, β-catenin, integrin A1, and neuregulin, were down-regulated; whereas the anti-apoptotic protein BCL2 was up-regulated, and the co-expression of N-calmodulin and α-SMA was promoted. Taken together, DIREN may exert a therapeutic effect on UC by modulating focal adhesion and the WNT/β-catenin signaling pathway, inhibiting fibroblast migration and collagen secretion, and thereby attenuating colonic fibrosis[48]. A survey on the current status of the use of complementary and A study on alternative medicine (herbs, massage, and other therapies) for patients with IBD in Chile showed that when patients reduced their use of alternative medicine, they reported fewer disease flare-ups, improved IBD symptoms, and better overall health. Fifty-four percent of former or current CAM users reported an improvement in gastrointestinal symptoms. Additionally, 5% of former CAM users and 12% of current CAM users successfully reduced the intensity of their medication (CMT) due to CAM. use, which further reveals the effectiveness of complementary and alternative medicine therapies in enhancing treatment efficacy and reducing medication toxicity in IBD[49]. The survey also revealed that patients with IBD experienced fewer disease flares, alleviated IBD symptoms, and enhanced overall health.

Acupuncture has been demonstrated to mitigate inflammatory disease by boosting vagal activity. Acupuncture moxibustion and other external Chinese medical treatments have also been shown to be is effective in treating IBD. Acupuncture has been shown to effectively regulate intestinal dysbiosis, enhance intestinal barrier function, alleviate visceral hypersensitivity, improve intestinal motility dysfunction, and reduce symptoms of depression/anxiety and pain. These effects contribute to a significant improvement in the quality of life for patients with IBD[50]. Compartmentalized moxibustion works by stimulating the “zhongwan” (RN12), “tianshu” (ST25), and “qihai” (RN6) acupoints, thereby alleviating the patient’s systemic symptoms, intestinal symptoms, and social and emotional capabilities were enhanced. After the treatment, endoscopy revealed that the mucosa was nearly healed, with improvements in mucosal edema and congestion, and the Mayo score and Barron’s score decreased compared with the pre-treatment period. It is indicated that this therapy ameliorated the pathological changes in the colonic mucosa and rectified intestinal immune dysfunction, while also controlling the inflammatory response and tissue damage, and the patients maintained the remission period with no side effects for 3 months, and the symptoms of UC patients were controlled[51]. Randomized controlled trials have confirmed that patients with CD Activity Index (CDAI) experienced a significantly greater decrease in their CDAI scores after 4 weeks of acupuncture treatment compared to those who did not receive acupuncture., and A study on the combination of moxibustion and acupuncture has also demonstrated that a 12-week course of treatment can lead to significant reductions in patients’ CDAI scores and enhancements in their quality of life[52,53].

Electroacupuncture improves the integrity and function of the colonic mucosal barrier by activating the Wnt/β-catenin pathway, inhibiting NF-κB signaling, and modulating the excessive activation of enteric glial cells, thereby alleviating the inflammatory response[54]. Animal studies suggested that rats carrying After herbal segmented moxibustion and electroacupuncture therapeutic interventions, the overall condition of the DSS-induced UC gene showed gradual improvement. Following moxibustion and electroacupuncture treatments, the ulcerated colon tissues in rats showed slight injury, reduced bleeding, and decreased fecal output. The histopathologic features of the colon tissues encompassed healing of the ulcerated surface, proliferation and coverage of the mucosal epithelium, and a reduction in lymphocyte and plasma cell infiltration. It Studies have demonstrated that both moxibustion and electroacupuncture exert a protective effect on the colon of rats with colitis, preventing damage induced by DSS and modulating abnormal gene combinations, such as the NF-κB signaling pathway downstream of Wnt, to alleviate symptoms[55]. Acupuncture may also act as a complementary approach to facilitate the postoperative recovery of patients at risk of potential colorectal carcinogenesis following the sustained progression of IBD. Studies have confirmed that laparoscopic colorectal surgery is associated with better short-term clinical outcomes, including faster recovery of gastrointestinal function, than open surgery. Patients undergoing elective laparoscopic surgery for colon and upper rectal cancers who received electroacupuncture therapy experienced shorter durations of postoperative paresthesia and shorter hospital stays. Acupoint electroacupuncture therapy promotes early recovery of bowel function after laparoscopic colorectal surgery and reduces the need for postoperative analgesia more than no acupuncture and sham acupuncture[56]. Figure 1 visually summarizes the regulatory effects of TCM, acupuncture, and moxibustion on the Wnt/β-catenin signaling pathway when used to treat IBD. The main TCM interventions and their effects on the Wnt/β-catenin pathway are summarized in Table 1.

Figure 1 Schematic diagram of herbal acupuncture and moxibustion intervention in inflammatory bowel disease through Wnt signaling pathway. The left panel illustrates three representative traditional Chinese medicine interventions—herbal medicine, acupuncture, and moxibustion—which target the intestinal tract. The enlarged view of the intestinal microenvironment on the right shows that, in the pathological states of colorectal cancer (CRC) and inflammatory bowel disease (IBD), tumor tissues abnormally activate the Wnt signaling pathway: Wnt ligands inhibit the degradation of β-catenin by the Axin/GSK3β complex, promoting the entry of β-catenin into the cell nucleus and activating the T-cell factor transcription factor; simultaneously, dysregulation of this pathway modulates immune cells such as Th17, Treg, and ILC3, mediating the secretion of cytokines including interleukin (IL)-17A, IL-10, and IL-22 via RORγt, thereby influencing intestinal inflammation and tumor progression. The schematic diagram illustrates how traditional Chinese medicine can improve the intestinal pathological microenvironment by targeting the Wnt pathway and immune networks, thereby demonstrating its potential for the prevention and treatment of CRC and IBD. CRC: Colorectal cancer; IBD: Inflammatory bowel disease; TCF: T-cell factor; IL: Interleukin. Adapted from WPS Docer Image Library, by Kingsoft Office (Supplementary material).

Table 1 Summary of traditional Chinese medicine interventions targeting the Wnt/β-catenin pathway in experimental inflammatory bowel disease models.

TCM intervention	Experimental model	Specific molecular targets on Wnt/β-catenin pathway	Biological effects on IBD
Huangqin-tang (herbal formula)	DSS-induced colitis mice	↓ β-catenin protein expression (colon tissue)	Reduced DAI, increased colon length, decreased IEC apoptosis
ZKC (herbal formula)	DSS-induced colitis mice	↓ MyD88/TLR4 → downstream suppression of Wnt pathway (indirect)	↓ Pro-inflammatory cytokines, ↓ oxidative stress, attenuated crypt loss and submucosal edema
Indigo Naturalis (single herbal extract)	DSS-induced colitis mice	↓ β-catenin expression in colon tissue; ↓ STAT1/STAT3 signaling	Suppressed Th1/Th17 responses, ↓ IFN-γ and IL-17, reduced oxidative stress
DIREN (herbal formula)	DSS-induced UC mice	↓ β-catenin, ↓ N-cadherin, ↓ integrin A1; inhibition of focal adhesion pathway	Attenuated colonic fibrosis, ↓ collagen deposition, ↓ apoptosis, ↑ BCL2
NGR1 (single compound)	DSS-induced colitis mice	↑ Wnt/β-catenin activation, ↑ Lgr5+ ISC proliferation	Promoted intestinal epithelial renewal, mucosal repair (reversed by Wnt inhibitors)
Acupuncture (manual)	DSS-induced UC rats	Modulation of NF-κB (downstream of Wnt) and inflammatory genes (genome-wide regulation)	Improved mucosal healing, reduced bleeding, ↓ lymphocyte/plasma cell infiltration
Electroacupuncture	DSS-induced UC rats; laparoscopic colorectal surgery (clinical)	Not fully defined, but regulates Wnt/NF-κB signaling axis	Reduced postoperative ileus, shorter hospital stay, enhanced bowel function recovery
Herbs-partitioned moxibustion (at RN12, ST25, RN6)	DSS-induced UC rats; UC patients (case study)	↓ β-catenin nuclear translocation (inferred from pathology)	Mucosal healing, reduced Mayo score, improved immune dysfunction, sustained remission
Moxibustion + acupuncture	DSS-induced UC rats; Active Crohn’s disease patients (RCT)	Regulation of downstream inflammatory effectors (NF-κB, cytokines) via Wnt pathway	↓ CDAI scores, improved quality of life, reduced endoscopic inflammation

TCM: Traditional Chinese medicine; IBD: Inflammatory bowel disease; DSS: Dextran sulfate sodium; DAI: Disease activity index; ZKC: Zhikang capsule; TLR4: Toll-like receptor 4; IFN: Interferon; IL: Interleukin; UC: Ulcerative colitis; NGR1: Notoginsenoside R1; ISC: Intestinal stem cell; NF-κB: Nuclear factor kappa B; RCT: Randomized clinical trial; CDAI: Crohn's Disease Activity Index; IEC: Intestinal epithelial cells.

QUESTIONING THE SCIENTIFICITY OF CHINESE MEDICINE IN THE TREATMENT OF IBD

Chinese medicine has accumulated a wealth of clinical experience in the treatment of IBD. However, owing to the differences in understanding perspectives, treatment methods, and validation criteria between Chinese and Western medicine, the scientific validity of TCM in treating IBD has faced numerous questions from modern medical circles community. These questions pertain to technology, mechanism of action, clinical evidence, safety, as well as profound differences in scientific concepts. TCM theory emphasizes the “holistic view” and “evidence-based treatment”, and suggests that IBD is associated with spleen and kidney deficiencies. This pathological model, primarily focused on symptom and sign summaries, does not encompass the comprehensive anatomical, pathophysiological, and molecular biological insights that are integral to the modern medical approach to IBD. In the field of modern pharmacology, there are still many unknowns regarding the identification of active ingredients and their targets of action in traditional Chinese medicine formulations, and this remains a significant unresolved issue. Chinese medicine prescriptions typically combine multiple herbs and hundreds of chemical components, and research has shown that these components can interact in various ways, including synergistically, additively, or in a counteracting manner. This complexity is a departure from the precise treatment approach of modern medicine.

Regarding efficacy evaluation, most current TCM studies primarily rely on symptom scores, such as the frequency of diarrhea, the degree of abdominal pain and the TCM evidence score serve as the primary endpoints; these are more subjective and prone to the placebo effect and researcher bias. In contrast, modern IBD research often focuses on key endpoints that include objective biomarkers such as mucosal healing observed during endoscopic procedures, histopathologic improvements, and the presence of fecal calreticulin. There also exists a contradiction between TCM’s emphasis on “evidence-based treatment” and standardized clinical research. TCM underscores individualized treatment; even for the same disease, the medications employed may vary depending on different symptom types; however, modern clinical studies usually require consistent treatment protocols, otherwise, it becomes difficult to standardize comparisons. The traditional understanding of toxicity in Chinese medicine mainly comes from the “eighteen anti nineteen dangers”, “contraindications” and other empirical summaries, which are mostly derived from ancient clinical practices observations. Further modern toxicological studies are required to ascertain the safety profile of TCM in the context of IBD treatment, as evidenced by the development of specific TCM formulations for IBD and the use of herbal compounds for related gastrointestinal conditions.

POTENTIAL PATHS TOWARD THE SCIENTIFIC MODERNIZATION OF TCM FOR IBD

Despite these doubts, there remain feasible approaches to the modernization of TCM for IBD. The emergence of network pharmacology and systems biology has revolutionized the understanding of TCM compounding by elucidating its multi-component, multi-target, and multi-pathway interactions. By leveraging the construction of a multidimensional network that integrates components, targets, pathways, and diseases, the multi-target action of TCM can be characterized in a more comprehensive manner.

Systems biology: Multi-omics integration decodes holistic TCM regulation

Systems biology offers a robust framework for comprehending the integrative effects of herbal medicines. Systems biology aims to quantitatively characterize and interpret the response of biological systems to pharmacological interventions by integrating transcriptomic, proteomic, and metabolomic data. This approach allows for a comprehensive understanding of the complex interactions within biological systems, as it considers the differences and complementarity between these data types, which is crucial for accurately interpreting the effects of pharmacological interventions. Taking the Wnt/β-catenin pathway as an example, three types of signaling abnormalities are closely related to the occurrence and development of human cancer. Therapeutic selection can be categorized based on the following: (1) Cancers with APC/CTNNB1 mutations and activation of the WNT/β-catenin signaling pathway; (2) Cancers with RNF43/ZNRF3/RSPO2/RSPO3 mutations; and (3) Cancers with up-regulated ROR1, which are characterized by activation of the WNT/PCP and WNT/RTK signaling pathways. Corresponding therapeutic regimens targeting WNT signaling need to be selected based on different signaling pathways. Therefore, genome sequencing, transcriptomics and/or immunohistochemical assays are essential for identifying and subtyping WNT signaling-driven cancers before and during treatment. To ensure the efficacy and safety of WNT signaling-targeted therapeutic agents, it is imperative to conduct comprehensive histological monitoring, encompassing genome sequencing, transcriptomic profiling, immunohistochemical analysis, and organoid-based assays[57]. When applied to the study of TCMs, this solution is particularly feasible: Firstly, through high-throughput histological analysis of serum, tissues, and other biological samples before and after Through TCM interventions, comprehensive gene, protein, and metabolic profiles are obtained. This generates comprehensive global change data for genes, proteins, and metabolites. Subsequently, bioinformatics methods were employed to conduct differential expression analysis, GO and KEGG functional enrichment analysis, as well as pathway perturbation analysis, thereby identify the core biological pathways regulated by TCM as a whole. Metabolomics analyses revealed that after TCM compounding interventions, endogenous metabolic networks underwent overall remodeling, which was associated with specific physiopathological processes such as energy metabolism and inflammatory responses. This approach shifts the research focus from targeting individual components to understanding the network pathways, thereby revealing the dynamic landscape of the synergistic interactions among TCM ingredients. and providing robust and systematic evidence for mechanism elucidation[58].

Network pharmacology: From single targets to network modules

At the core of network pharmacology is the construction and resolution of multilevel biological network models. The methodology offers a step-by-step approach, progressing from “network” to “module” and then to “node”. Leveraging the TCM chemical composition database and drug target prediction algorithms, the active ingredient groups in TCM formulas and their potential target proteins were systematically screened. Secondly, a heterogeneous network of “TCM active ingredients - predicted targets - known disease targets” is constructed by utilizing the protein-protein interaction database and disease-related gene database. Through the calculation of the network’s topological parameters, key targets and core sub-network modules can be identified. Further pathway enrichment analysis of core target groups enables the hypothesis of key biological processes intervened by TCM. A study on the synergistic mechanism of Gegen Qinlian decoction on Wnt signaling pathway provides a good example[59]. By integrating network pharmacological prediction and experimental validation, the study firstly targeted gegenin, glycyrrhizic acid, hanhuangqin, and berberine as the key active ingredients, and further found that gegenin and glycyrrhizic acid had a significant synergistic effect in the inhibition of CRC cells. Glycyrrhizic acid not only plays the role of an active ingredient by down-regulating CTNNB1, but also significantly enhances the intracellular accumulation of puerarin by regulating cell adhesion molecules such as CDH1, CADM1 and other membrane proteins such as integrins ITGB2, ITGA1, etc. Studies have systematically elucidated the molecular mechanisms underlying glycyrrhizic acid’s role as an active ingredient in CRC inhibition, demonstrating its synergistic effect on suppressing cancer cell proliferation and migration. This article systematically explains the molecular basis of glycyrrhizic acid, particularly its role in inhibiting tumor cell proliferation and inducing apoptosis through the suppression of pathways such as SIRT3, ROS, and AKT. Glycyrrhizic acid plays dual roles in the formula, acting both as an active ingredient and a delivery guide. The multi-level “component-target-pathway-compatibility” analysis dynamically integrates traditional pharmacological properties with modern molecular pathways, thereby clearly elucidating the therapeutic mechanism of the compound preparation. This study clearly demonstrated the networked mode of action of the compound by synergistically regulating the Wnt signaling pathway, as evidenced by the intricate mechanisms detailed in recent research. multi-targets. This study reveals that integrating network pharmacology with multi-omics technology enables the conversion of discrete components, targets, and pathway information of TCM compounds into a visualized ‘compounding-efficacy’ regulatory network. This approach facilitates the logical deduction and experimental verification of the biological basis underlying the synergistic effects of compounding at the systemic level, thereby contributing to the elucidation of the scientific principles of TCM compounding theory. This provides a convincing research methodology and a coherent chain of evidence to interpret the scientific connotation of Chinese medicine compounding theory. Research indicates that the methodological development of network pharmacology in TCM should focus on four areas: Integrating multimodal data with artificial intelligence; constructing tissue/cell-specific networks to elucidate hierarchical relationships between phenotypes and molecules; designing quantitative metrics and AI models to enable precise identification of network targets and dose-response navigation; and developing deeply interpretable frameworks for inferring network relationships, leveraging language models to overcome the limitations of traditional black-box approaches, thereby systematically enhancing the interpretability and generalizability of TCM network pharmacology[60,61].

Real-world research and precision medicine: An evidence-based path for personalized TCM

Integrating real-world research with precision medicine could potentially mitigate the contradiction between the individualized nature of TCM and the standardized requirements of research. Large-scale, prospective patient registration studies have been instrumental in collecting detailed data on the efficacy of TCM in treating IBD, including the use of Atractylodes macrocephala and other herbal remedies. When integrated with genomic, metabolomic, and other multi-omics analyses, such studies leverage the power of metabolomics to uncover metabolic changes and biomarkers in diseases, and to evaluate the efficacy of treatments. It is expected that these approaches will identify patient populations that respond well to specific TCM formulations, thus promoting the precision application of TCM.

International quality standards and safety monitoring: From experience to evidence

The establishment of internationalized quality standards, as seen in the European Union and the United States, is crucial for TCM to achieve global recognition and acceptance. Drawing on relevant experience from the European Union’s traditional herbal medicine registration and the United States Food and Drug Administration’s botanical medicine guidelines, a multi-dimensional quality control system encompassing fingerprinting and bioefficacy testing can be established to enhance the consistency of product batches. In addition, the safety monitoring of herbal medicines should be strengthened, a perfect pharmacovigilance system should be established, and the benefits and risks of herbal therapy should be further characterized.

Emerging directions: CHM-EVLPs

A variety of extracellular vesicle-like particles derived from traditional medicinal plants (CHM-EVLPs) have shown significant therapeutic potential in experimental models of colitis[62]. These naturally occurring nanoparticles carry bioactive molecules and exhibit intrinsic tissue-targeting properties. Although direct evidence linking CHM-EVLPs to the Wnt/β-catenin pathway in IBD remains limited, several lines of indirect evidence suggest potential crosstalk. For instance, plant-derived exosome-like particles have been shown to modulate colonic inflammation and epithelial regeneration, processes tightly regulated by Wnt signaling. It is plausible that CHM-EVLPs may deliver specific Wnt modulators to ISC niches, thereby influencing β-catenin nuclear translocation or GSK-3β activity. Future studies employing high-throughput sequencing of EVLPs cargo and organoid-based functional assays are warranted to dissect their mechanism of action. The high compatibility of CHM-EVLPs with the core principles of TCM - multi-component synergy and holistic regulation - opens new avenues for developing targeted biologics with reduced systemic side effects for IBD therapy.

Other innovative platforms: Bacteria-based therapeutic strategies

In parallel, bacteria-based therapeutic platforms have emerged as a novel strategy for IBD management, offering advantages in targeted drug delivery and modulation of the gut microenvironment[63]. While their direct interaction with the Wnt pathway remains unexplored, bacterial metabolites have been reported to influence ISC homeostasis, suggesting potential indirect regulation. These approaches complement TCM therapies and may be integrated with herbal compounds in future precision medicine frameworks.

Specifically, we have explicitly contrasted the comprehensive findings of this study with major existing reviews on Wnt signaling in IBD, emphasizing that while previous studies have focused on chemical inhibitors, the novelty of this review lies in its systematic analysis of how the multi-component, multi-target nature of TCM uniquely addresses the bidirectional nature of Wnt pathway regulation. We also highlight emerging platforms such as CHM-EVLPs as forward-looking contributions to this field that have not yet been comprehensively explored. This study also has certain limitations: (1) Current research is primarily preclinical in nature, and there is a lack of large-scale randomized controlled trials that directly measure Wnt activity in patients with IBD receiving TCM treatment; (2) The mechanisms by which complex Chinese herbal formulas achieve pathway-specific effects and non-targeted regulation are not yet fully understood; (3) Indirect evidence regarding CHM-EVLPs and bacterial platforms requires further mechanistic validation; and (4) Potential publication bias.

CONCLUSION

The Wnt/β-catenin pathway is a common molecular target for TCM interventions in IBD. TCM exerts its therapeutic effects through multi-component, multi-target regulation of this pathway, promoting mucosal repair and modulating the immune response. However, the bidirectional nature of Wnt signaling - which is beneficial for healing but can be harmful when overactivated - presents unique challenges for treatment. Preclinical evidence indicates that various TCM modalities (herbal formulas, single herbs, acupuncture, and moxibustion) can modulate Wnt activity, as shown in Figure 2. Future research must integrate network pharmacology, multi-omics technologies, and rigorous clinical trial designs to move beyond descriptive correlations toward a mechanistic understanding. Emerging platforms such as CHM-EVLPs and bacterial-based systems represent highly promising directions but require further validation. The complexity of TCM is not an obstacle to modernization; rather, it necessitates the adoption of sophisticated systems-level approaches to unlock its potential in the precision treatment of IBD.

Figure 2 The role of the Wnt/β-catenin signaling pathway in maintaining intestinal homeostasis and repairing damage, and the regulatory mechanisms of traditional Chinese medicine interventions. The left panel shows the normal intestinal crypt structure. Under physiological conditions, the Wnt/β-catenin pathway maintains the proliferation of Lgr5+ intestinal stem cells, drives the renewal of intestinal epithelial cells (including intestinal epithelial cells, goblet cells, and cluster cells), and ensures the integrity of the intestinal mucosal barrier. When the intestine is damaged, this pathway becomes overactivated, which can induce fibrosis and carcinogenesis. The right panel illustrates the molecular mechanism of the Wnt/β-catenin pathway: Β-catenin is ubiquitinated by a degradation complex composed of casein kinase 1, GSK3β, adenomatous polyposis coli, and Axin, and subsequently degraded by the proteasome; When Wnt ligands bind to the lipoprotein receptor-related protein 5/6 receptors on the cell membrane, DVL is activated and inhibits the activity of the degradation complex, allowing β-catenin to accumulate in the cytoplasm and translocate into the nucleus, where it binds to T-cell factor/Lymphotactic factor binding factor transcription factors to regulate the expression of target genes. Traditional Chinese medicine interventions can target this pathway to regulate intestinal stem cell proliferation and epithelial repair, reverse abnormal activation in damaged states, and restore intestinal physiological homeostasis. ISC: Intestinal Stem Cell; LRP5/6: Lipoprotein receptor-related protein 5/6; CK1: Casein Kinase 1; APC: Adenomatous polyposis coli; TCF: T-cell factor; LEF: Lymphotactic factor binding factor.

ACKNOWLEDGEMENTS

We thank Shandong University of Traditional Chinese Medicine and Linyi Hospital of Traditional Chinese Medicine for supporting this study.