Clinical efficacy and mechanisms of Astragalus membranaceus, active components, and herbal formulas for chronic atrophic gastritis

Abstract

Chronic atrophic gastritis (CAG) is a gastric disease characterized by atrophy of the gastric mucosal glands and fibrosis of the lamina propria. Regarded as a recognized precancerous lesion preceding gastric cancer, CAG requires early intervention to prevent malignant progression. As a widely used herbal remedy in traditional Chinese medicine, Astragalus membranaceus (Huangqi) is abundant in a variety of bioactive compounds, such as polysaccharides, saponins, and flavonoids. Astragalus membranaceus-based herbal formulas have demonstrated remarkable clinical efficacy for CAG treatment. The underlying mechanisms primarily include eradicating Helicobacter pylori, modulating immunity, protecting the gastric mucosa, alleviating inflammatory responses, regulating gastrointestinal microbiota, and mitigating oxidative stress, thereby effectively delaying disease progression. This review systematically examined the classical records on Astragalus membranaceus and overviewed the recent therapeutic effects and pharmacological mechanisms of its formulas and active constituents in treating CAG. Based on this comprehensive analysis, it aims to establish a scientific basis and theoretical framework to support the clinical application of traditional Chinese medicine and the development of novel therapeutics strategies for CAG.

Key Words: Astragalus membranaceus; Traditional Chinese medicine formula; Chronic atrophic gastritis; Clinical efficacy; Mechanism of action

Core Tip: Chronic atrophic gastritis carries the risk of malignant transformation into gastric cancer, posing a severe threat to patient health. Astragalus membranaceus and its herbal formulas have demonstrated remarkable efficacy in the treatment of chronic atrophic gastritis. The underlying mechanisms primarily involve eradication of Helicobacter pylori, modulation of immunity, alleviation of inflammatory responses, mitigation of oxidative stress, and protection of the gastric mucosa.

INTRODUCTION

A defining feature of chronic atrophic gastritis (CAG) is the progressive loss of gastric mucosal glands accompanied by fibrosis within the lamina propria; this condition may also present with intestinal or pseudopyloric metaplasia. Among its various pathogenic triggers, Helicobacter pylori (H. pylori) infection stands out as the predominant cause of glandular atrophy[1]. Its pathogenesis involves immune dysregulation, gut microbiota dysbiosis, and oxidative stress[2]. In advanced stages, CAG can progress to intestinal metaplasia and atypical hyperplasia, ultimately leading to gastric cancer (GC) development, and is thus considered the initial step in the multistage gastric precancerous cascade[3]. Epidemiological surveys indicate that the annual incidence of GC among patients with CAG ranges from 0.1% to 0.25% globally and exceeds 1.5% in certain Asian countries[4]. Individuals suffering from CAG exhibit a 5-10 times greater susceptibility to GC than the general population, making early intervention crucial for cancer prevention[5]. Patients with CAG frequently experience upper gastrointestinal discomforts, including epigastric distension, dull epigastric pain, postprandial fullness, decreased appetite, belching, bitter taste, and weight loss[6]. Astragalus membranaceus, a well-known traditional Chinese medicinal herb, possesses the therapeutic properties of tonifying qi, raising yang, expelling toxins, promoting pus drainage, and facilitating tissue regeneration. It holds a crucial position in the management of CAG and is frequently used as a sovereign herb (Jun Yao) in traditional Chinese medicine (TCM) formulas. Owing to its remarkable therapeutic efficacy, it significantly alleviates clinical symptoms and delays disease progression in patients with CAG.

CLASSICAL RECORDS OF ASTRAGALUS MEMBRANACEUS AND ITS ACTIVE CONSTITUENTS

Classical records of Astragalus membranaceus

Astragalus membranaceus originates from the dried root of Astragalus membranaceus var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge., which belongs to the Fabaceae family[7]. It is also known as Huangqi, Jianhuangqi, Mianhuangqi, Dugen, Hongqi, Jinqi, and Chuanqi[8]. Astragalus membranaceus (Fisch.) Bge. is mainly distributed in Northeast, North, and Northwest China, whereas Astragalus membranaceus var. mongholicus is primarily produced in the Heilongjiang, Inner Mongolia, Hebei, and Shanxi provinces[9]. The medicinal use of Astragalus membranaceus was first documented in Volume III of Shen Nong Ben Cao Jing (The Divine Farmer’s Materia Medica), where it was classified as a superior-grade herb, “sweet in taste and slightly warm in property. It is indicated for chronic purulent sores, promoting pus drainage and relieving pain, severe leprosy, hemorrhoids, and scrofula. It also tonifies deficiencies and treats various pediatric diseases”. To the best of our knowledge, this is the first documentation of its medicinal properties, indications, and therapeutic effects. Subsequent herbal texts frequently cited this description and progressively expanded on its therapeutic efficacy and clinical indications[10].

The medicinal use of Hedysari Radix (Hongqi) was first documented in the entry of Astragali Radix (Huangqi) in Shen Nong Ben Cao Jing Ji Zhu (Notes on the Divine Farmer’s Materia Medica). Tao Hongjing stated, “(Huangqi) also has a red variety that can be used to make medicinal plasters. It is widely used in folk remedies, but is not required by Taoists”. The “red variety” mentioned here refers to Hedysari Radix. For a long time, it was considered a variety of Astragali Radix. However, with further research, it was discovered that although Hedysari Radix and Astragali Radix share the same meridian tropism and therapeutic indications, they differ in their chemical compositions and pharmacological effects. Consequently, they are not classified as the same TCM. Since the 1985 edition, Hedysari Radix has been listed as an independent entry in each subsequent edition of the Pharmacopeia of the People’s Republic of China[11].

Honey-fried Astragali Radix (Zhi Huang Qi) is a processed product of Astragali Radix. The Ming Dynasty text Pu Ji Fang (Formulas for Universal Relief) documented the method of “boiling with honey and wine”[12], which refers to processing Astragali Radix with a combination of honey and rice wine. During the Ming Dynasty, Li Zhongzi proposed that “Ancients mostly processed Astragali Radix by frying it with honey; however, I replaced this with wine processing. This approach not only helps it reach the body surface but also alleviates its stagnating nature. When used in kidney-tonifying formulas or for the treatment of leukorrhea and gonorrhea, it must be stir-fried in salt”. He maintained that processing Astragali Radix with wine could enhance its qi-regulating and blood-activating effects, thereby rendering it superior to honey-frying. Salt processing is another recognized method. Raw Astragali Radix functions to tonify qi, strengthen the exterior, and drain toxins to promote tissue regeneration, induce diuresis, and reduce swelling. It is commonly prescribed for spontaneous sweating and edema due to qi deficiency, purulent sores that fail to rupture, or chronic wounds that fail to heal. Honey-fried Astragali Radix, which is sweet, mild, warm, and moistening, enhances the effects of tonifying qi, raising yang, warming the lungs, and relieving dryness. It is frequently used for consumptive chronic cough, shortness of breath, fatigue, poor appetite, loose stools, qi deficiency, constipation, rectal prolapse, and bleeding conditions (such as metrorrhagia and hematochezia) because of the failure of qi to control blood. Wine-processed Astragali Radix, which capitalizes on the ascending nature of wine and its effects on activating blood, resolving stasis, and dispelling cold, is primarily indicated for cold-congealment syndromes resulting from lung qi deficiencies[13].

Main chemical constituents and pharmacological effects of Astragalus membranaceus

Recent studies demonstrated that the primary chemical constituents of Astragalus membranaceus include polysaccharides, flavonoids, and saponins. Polysaccharides are primarily Astragalus polysaccharides, which comprise glucans and heteropolysaccharides. Flavonoid constituents can be categorized into four classes: Flavones, isoflavones, isoflavanes, and pterocarpans. The principal saponins include astragaloside IV (AS-IV), astragalosides, and isoastragalosides[14,15]. These constituents exert effects including immunomodulatory, anti-inflammatory, cardioprotective, anti-hypertensive, anti-atherosclerotic, anti-tumor, and anti-aging. Furthermore, they play significant roles in regulating gut microbiota, modulating lipid metabolism, and improving insulin resistance[16,17]. The chemical composition of honey-fried Astragali Radix differs from that of the raw herb, which enhances its qi-tonifying efficacy. Specifically, honey frying reduced the molecular weight of Astragalus polysaccharides and increased the proportion of monosaccharides. Furthermore, AS-IV, astragaloside II, and azelaic acid contents decrease, whereas calycosin content increases[18,19].

PATHOGENESIS AND INFLAMMATION-TO-CANCER TRANSFORMATION IN CAG

H. pylori infection

Studies have shown that > 80% of patients with CAG have H. pylori infections[20]. H. pylori can induce CAG development by producing various virulence factors, such as cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA), blood-group antigen-binding adhesin A, and urease. These virulence factors alter the intragastric pH, damage cellular structures, trigger inflammation, and exacerbate gastric mucosal injury and atrophy[21]. VacA and CagA are the primary virulence factors that mediate the pathogenic effects of H. pylori. CagA is recognized as an oncogenic protein that inhibits apoptosis of host epithelial cells and modulates multiple signaling pathways, ultimately leading to DNA damage and alterations in the immune microenvironment. It also induces cellular vacuolation and the release of cytochrome C from mitochondria, thereby provoking inflammatory responses and suppressing immune cell activation and proliferation. Both these virulence factors participate in GC development by regulating autophagy[22,23]. Furthermore, H. pylori releases inflammatory cytokines such as interleukin-8 (IL-8), which trigger the nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPK) as well as Janus kinase-signal transducer and activator of transcription signaling cascades and induce the expression of related factors such as miR-204 and miR-27a. These processes promote gastric mucosal and intestinal metaplasia and accelerate the progression of CAG to GC[23,24]. Evidence has demonstrated that H. pylori eradication may reverse atrophic gastritis and intestinal metaplasia, thereby reducing the incidence of GC[25].

Immune system dysfunction

Following immune system dysfunction, B lymphocytes produce anti-parietal cell antibodies targeting H⁺/K⁺-ATPase on the surface of gastric parietal cells. The subsequent immune response to these target antigens leads to elevated intragastric pH, decreased secretion of intrinsic factor, and destruction of parietal cells, ultimately causing gastric mucosal injury[26]. During H. pylori infection, T and B lymphocytes become excessively activated, releasing inflammatory mediators such as tumor necrosis factor-α and IL-6. This exacerbates the gastric mucosal inflammatory response and induces atrophy of the intrinsic glands[27]. Toll-like receptors residing on gastric mucosal epithelial cells can be persistently activated following H. pylori colonization. This signaling cascade promotes the secretion of pro-inflammatory cytokines and chemokines, thereby exacerbating immune reactions within gastric mucosa[28]. IL-17A can induce atrophy of acid-secreting parietal cells, triggering spasmolytic polypeptide-expressing metaplasia[29]. Furthermore, galectin-3 reduces bacterial adhesion and indirectly inhibits apoptosis, while promoting monocyte recruitment to the site of infection, which initiates persistent inflammation and serves as a critical foundation for inflammation-to-cancer transformation[30].

Chronic inflammation

Macrophages are among the first cells activated during infection or tissue injury. Excessive activation leads to the massive release of inflammatory cytokines, suppression of immune cell function, and parietal cell necrosis. This cascade results in a reduction in the intrinsic glands and gastric mucosal injury, ultimately triggering CAG[31]. Macrophages produce leucine-rich protein 1, proline, and glutamic acid via NF-κB transcription. Produce leucine-rich protein 1 upregulates the expression of granulocyte-macrophage colony-stimulating factor; the elevated granulocyte-macrophage colony-stimulating factor triggers epithelial-mesenchymal transition within gastric mucosa via paracrine signaling, accelerating tumor progression[32]. Furthermore, interferon-gamma can directly induce gastric epithelial cell death, serving as a major inducer of glandular atrophy and metaplasia[33]. During H. pylori infection, abnormal pathological changes occur in lymphoid tissues of the gastric mucosa, leading to chronic inflammation and fibrosis[34]. This disruption of mucosal homeostasis generates various inflammatory mediators that promote the progression of the Correa cascade, including the progression from chronic gastritis to atrophic gastritis, intestinal metaplasia, dysplasia, and ultimately GC, which elicit their effects through diverse mechanisms, including oxidative stress, regulation of cell proliferation and apoptosis, immune suppression and evasion, epithelial-mesenchymal transition, and tumor invasion[35,36].

Gut microbiota imbalance

According to existing studies, CAG is associated with a gut microbial imbalance marked by the depletion of commensal bacteria, notably Firmicutes and Bacteroidetes, and the proliferation of pathogenic taxa, among which are Proteobacteria, Campylobacter, and Streptococcus[37]. Notably, Streptococcus can induce atrophy, mucous metaplasia, and dysplasia in gastric parietal cells[38]. Gut microbial dysbiosis interferes with the synthesis and metabolic processes of bile acids, further inducing bile reflux. Retrograde flow of bile acids into the gastric cavity elevates the intragastric pH, which not only facilitates the colonization of certain pathogenic bacteria but also compromises the gastric mucosal barrier[39], thereby promoting the development of CAG. Patients infected with H. pylori exhibit reduced the richness and community diversity of intestinal microbiota[40]. Metabolic dysbiosis of the gut microbiota disrupts the gastric mucosa and promotes the development of precancerous lesions by modulating immune responses, interfering with metabolic pathways, and directly interacting with gastric tumor cells[41].

Oxidative stress

Oxidative stress refers to an imbalance between oxidation and antioxidant defense mechanisms in organisms. In chronic gastritis, the continuous release of reactive oxygen species (ROS) by neutrophils disrupts the cellular structure and causes gastric mucosal injury[42]. Oxidative stress promotes upregulation of oxidases and activation of the NF-κB signaling cascade, thereby generating harmful substances such as malondialdehyde and nitric oxide (NO). This process exacerbates the gastric mucosal injury and worsens pathological changes, ultimately increasing the risk of carcinogenesis[43]. H. pylori infection stimulates ROS production. Through redox signaling mechanisms, this process accelerates the proliferation and metastasis of GC cells[44]. On the contrary, excessive accumulation of ROS triggers oxidative injury and GC cell death. Accordingly, oxidative stress represents a promising therapeutic target for GC[45].

CLINICAL EFFICACY AND MECHANISMS OF ACTION OF ASTRAGALUS-BASED COMPOUND FORMULATION FOR CAG TREATMENT

Clinical efficacy of Astragalus-based compound formulations in the treatment of CAG

Yan et al[46] conducted a systematic search for clinical trials evaluating Huangqi Jianzhong Decoction in the management of CAG according to the PRISMA guidelines. They evaluated the methodological rigor and potential sources of bias within the selected literature, subsequently carrying out a meta-analysis with the aid of RevMan 5.4 software. The results demonstrated that Huangqi Jianzhong Decoction can alleviate multiple symptoms in patients with CAG, yielding a higher overall efficacy rate, an improved H. pylori eradication rate, greater relief from stomach pain and acid reflux, and a reduced recurrence rate.

Zhang et al[47] enrolled 98 patients diagnosed with CAG and allocated these subjects to intervention group and conventional treatment group via simple random number table, with 49 participants assigned to each group. The conventional treatment group received oral omeprazole, whereas the intervention group received oral omeprazole combined with the modified Huangqi Sijun Decoction. The outcomes revealed that the overall response rate in the intervention group was markedly higher relative to the conventional treatment group. The TCM syndrome scores and IL-6 levels were considerably lower, whereas the serum gastrin-17 and pepsinogen I levels were significantly increased in the intervention group compared with the conventional treatment group. The modified Huangqi Sijun Decoction exhibited significant clinical efficacy in the treatment of CAG and effectively improved serological parameters.

Li[48] enrolled 72 patients with CAG who met the inclusion and exclusion criteria and randomly divided them into trial and control groups (n = 36 each). The control arm received standard Western medical therapy consisting of teprenone and folic acid, whereas those in the trial group received a modified Huangqi Guizhi Decoction in addition to the conventional treatment. The therapeutic efficacy was compared between the two groups. The results demonstrated that the modified Huangqi Guizhi Decoction exhibited significant therapeutic efficacy in treating CAG in the spleen-stomach deficiency pattern. It effectively alleviated clinical symptoms, improved endoscopic and pathological findings, and enhanced serological gastric function and immune-related parameters, indicating a therapeutic advantage over the use of conventional Western medicine by itself.

Zheng et al[49] enrolled 90 patients with chronic CAG diagnosed with qi deficiency and blood stasis pattern who satisfied the enrollment criteria, and subsequently allocated them into control and TCM groups. The control group received oral teprenone and folic acid tablets, whereas the TCM group was administered an orally modified Huangqi Renshen Decoction. After 12 weeks of treatment, the clinical symptoms in both groups improved significantly, accompanied by a marked decrease in TCM syndrome scores. Notably, the improvements and total efficacy rates in the TCM group surpassed those documented in the control group (P < 0.05). They found that modified Huangqi Renshen Decoction can effectively alleviate clinical symptoms and restore gastric mucosal function among individuals suffering from CAG accompanied by qi deficiency and blood stasis pattern.

Tang[50] enrolled 68 outpatients with CAG, spleen deficiency and qi stagnation pattern. They were randomized into a conventional treatment group and an intervention group, with 34 patients in each group. The intervention group received the Huangqi Yujin Decoction, whereas the conventional treatment group received Weifuchun tablets. After 12 weeks of treatment, the results demonstrate that the intervention group exhibited superior efficacy relative to the conventional treatment group. The treatment not only alleviated the patients’ symptoms but also improved the endoscopic manifestations and histopathological findings. To some extent, it slowed the progression of atrophic gastritis to precancerous lesions and reduced the risk of GC.

Lin[51] analyzed 80 patients hospitalized for CAG. In accordance with adopted interventions, all participants were separated into a control group consisting of 40 patients with single Western medicine therapy and a research group with 40 patients receiving Western medicine plus Huangqi Yiqi Decoction. Comparisons of therapeutic efficacy were conducted across the two groups. The findings indicated that the overall effective rate reached 90% in the research group, a value markedly superior to the 65% recorded in the control group (P < 0.05). Upon completion of therapy, the symptom scores recorded in the experimental group were markedly reduced in comparison with those of the control group (P < 0.05). They concluded that Huangqi Yiqi Decoction can enhance the therapeutic efficacy of CAG treatment and is suitable as an adjunct to conventional Western medicine (Table 1).

Table 1 Clinical efficacy of Astragalus-based compound formulations.

Ref.	Research contents	Composition of the compound formulation	Control group regimen	Clinical efficacy
Yan et al[46]	Therapeutic efficacy of Huangqi Jianzhong Decoction in treating CAG	Astragalus membranaceus, Ramulus Cinnamomi, Radix Paeoniae Alba, Rhizoma Zingiberis Recens, Fructus Jujubae, Radix Glycyrrhizae	None	Amelioration of multiple symptoms in patients with chronic atrophic gastritis
Zhang et al[47]	Therapeutic efficacy of Huangqi Sijun Decoction in treating CAG	Astragalus membranaceus, Pseudostellariae Radix, Rhizoma Atractylodis Macrocephalae, Poria, Ramulus Cinnamomi, Taraxaci Herba, etc.	Omeprazole	Amelioration of clinical symptoms and serum markers in patients
Li[48]	Therapeutic efficacy of modified Huangqi Guizhi Decoction combined with Western medicine in treating CAG of the spleen-stomach deficiency pattern	Astragalus membranaceus, Ramulus Cinnamomi, Radix Paeoniae Alba, Codonopsis Radix, Rhizoma Atractylodis Macrocephalae, Radix Saposhnikoviae, Pericarpium Citri Reticulatae, Radix Glycyrrhizae, etc.	Teprenone and folic acid	Enhancement of immune function and amelioration of clinical symptoms in patients
Zheng et al[49]	Clinical efficacy of Jiawei Huangqi Renshen Decoction in treating CAG with qi deficiency and blood stasis syndrome	Astragalus membranaceus, Codonopsis Radix, Rhizoma Atractylodis Macrocephalae, Radix Ophiopogonis, Angelicae Sinensis Radix, Pericarpium Citri Reticulatae etc.	Teprenone and folic acid tablets	Amelioration of clinical symptoms and repair of the gastric mucosa
Tang[50]	Clinical efficacy and medication safety of Huangqi Yujin Decoction in treating CAG	Astragalus membranaceus, Curcumae Radix, Poria, Rhizoma Atractylodis Macrocephalae, Radix Glycyrrhizae, Radix Paeoniae Alba, Radix Bupleuri, Fructus Aurantii, Semen Raphani Tostum etc.	Weifuchun Tablets	Alleviation of symptoms and delay of the inflammation-to-cancer sequence
Lin[51]	Therapeutic efficacy of Huangqi Yiqi Decoction combined with Western medicine in treating CAG	Honey-fried Astragali Radix, Aurantii Fructus Immaturus, Magnoliae Officinalis Cortex, Hedyotidis Diffusae Herba, Taraxaci Herba, Curcumae Rhizoma, Codonopsis Radix etc.	Omeprazole, Colloidal Bismuth Subcitrate, and Amoxicillin	Combination with Western medicine can enhance therapeutic efficacy

CAG: Chronic atrophic gastritis.

In summary, Astragalus membranaceus serves as the sovereign herb (Jun Yao) in this compound formula. As a primary therapeutic agent targeting this disease, it exerts potent pharmacological effects. It is frequently combined with Atractylodes macrocephala, Paeonia lactiflora, Codonopsis pilosula, Pseudostellaria heterophylla, and Ramulus Cinnamomi. These herbs work synergistically to invigorate the spleen, replenish qi, expel toxins, and consolidate the exterior, thereby improving their clinical efficacy in CAG.

Experimental studies and mechanisms of action of Huangqi compound formulas in treating CAG

By analyzing the gut microbiota in the cecal contents of rats, Zhang et al[52] identified ten metabolites related to gut microbiota. The therapeutic efficacy of Astragalus membranaceus and Huangqi Jianzhong Decoction was superior to that of the non-Astragalus membranaceus group, demonstrating the crucial role of Astragalus membranaceus in treating CAG through the regulation of gut microbiota.

Xia et al[53] established a rat model of CAG and treated it with high-, medium-, and low-dose Jiawei Huangqi Guizhi Decoctions. Hematoxylin and eosin (HE) staining was applied to assess pathological alterations of the gastric mucosa, while enzyme-linked immunosorbent assay was adopted to quantify serum gastrin, phosphoinositide 3-kinases (PI3K), protein kinase B (Akt), and mTORC2 concentrations. The findings demonstrated that the decoction effectively ameliorated gastric mucosal damage, reduced inflammation, and restored epithelial cell structure. Furthermore, it regulated the mRNA and protein expression of PI3K, Akt, and mTORC2, which may help prevent CAG progression.

Liu et al[54] evaluated the therapeutic efficacy of the Huangqi Jianzhong Decoction in CAG rats. The results showed that Huangqi Jianzhong Decoction exerted a modulatory influence on urinary metabolic disturbances in CAG rats, with 14 out of 32 urinary metabolites significantly modulated by treatment. They concluded that the primary mechanism of Huangqi Jianzhong Decoction in CAG treatment may be associated with the regulation of energy metabolism, inhibition of inflammation, improvement of immune function, and alleviation of oxidative stress.

Yu et al[55] established a rat model of gastric mucosal injury induced by H. pylori infection. The rats were randomly divided into the model group, low-, medium-, and high-dose Huangqi Jianzhong Decoction groups, and quadruple therapy group (omeprazole + amoxicillin + clarithromycin + colloidal bismuth pectin capsules). Pathological changes in the gastric mucosa were observed using HE staining, and serum expression of inflammatory factors, gastrin-17, and key signaling pathway proteins was detected. The results indicated that Huangqi Jianzhong Decoction could alleviate H. pylori-induced gastric mucosal injury in rats by inhibiting the inflammatory response through suppression of the interferon regulatory factor 8/interferon-gamma signaling pathway.

Huang et al[56] randomly divided 80 SPF-grade SD rats into eight groups: A blank control group; a blank control plus Qiling Formula group; a model group; high-, medium-, and low-dose Qiling Formulation groups; a folic acid group; and a Moluodan group. The expression levels of inflammatory factors and related proteins were detected using HE staining. Their research indicated that Qiling formulation is capable of blocking pro-inflammatory factor release and gastric epithelial cell apoptosis through downregulating the PI3K/Akt pathway, thereby partially reversing intestinal metaplasia and delaying the inflammation-cancer transformation (Table 2).

Table 2 Mechanisms of action of Astragalus compound formulas in the treatment of chronic atrophic gastritis.

Ref.	Research contents	Experimental model	Mechanism of action
Zhang et al[52]	Therapeutic efficacy of Astragalus membranaceus in CAG rats: Insights from Huangqi Jianzhong Decoction	CAG rat model (cecal contents analysis)	Astragalus membranaceus treats CAG by regulating gut microbiota
Xia et al[53]	Mechanisms of action of modified Huangqi Guizhi Decoction in the treatment of CAG	CAG rat model	Mitigation of gastric mucosal injury and inflammation and restoration of epithelial cell structure
Liu et al[54]	Therapeutic efficacy of Huangqi Jianzhong decoction in established CAG rats	Rat model of CAG	Inhibition of inflammation, and amelioration of immunity and oxidative stress
Yu et al[55]	Therapeutic effects and mechanisms of Huangqi Jianzhong Decoction on H. pylori infection-induced gastric mucosal injury in rats	H. pylori infection-induced rat model	Inhibition of inflammatory response and amelioration of H. pylori-induced gastric mucosal injury
Huang et al[56]	Potential mechanisms of Qiling Formula in intervening in CAG with intestinal metaplasia	Rat model of CAG with intestinal metaplasia	Inhibition of pro-inflammatory factor release and gastric mucosal epithelial cell apoptosis, and delay of the inflammation-to-cancer transformation

CAG: Chronic atrophic gastritis; H. pylori: Helicobacter pylori.

The Astragalus membranaceus-based compound formula exerts therapeutic effects on CAG through multiple mechanisms, including protection of the gastric mucosa and alleviation of inflammatory injury. The sovereign herb, Astragalus membranaceus, plays a prominent role in this therapeutic effect, which is closely associated with its diverse active constituents. The underlying mechanisms are discussed in the following sections.

MECHANISMS OF ACTION OF ASTRAGALUS MEMBRANACEUS AND ITS ACTIVE CONSTITUENTS IN CAG TREATMENT

Anti-H. pylori activity and prevention of inflammation-to-cancer transformation

AS-IV mitigates gastric mucosal injury by reducing the release of proinflammatory cytokines. It also indirectly inhibits H. pylori infection by suppressing the survival microenvironment, thereby preventing inflammation-to-cancer transformation[57]. H. pylori infection is a major pathological factor that contributes to the development of CAG. Astragalus membranaceus exhibits a significant inhibitory effect on H. pylori VacA activity in a concentration-dependent manner[58]. AS-IV attenuates H. pylori colonization by inhibiting urease activity and the expression of related genes (ureA and ureB)[59].

Immunomodulation and restoration of immune tolerance

Both raw and honey-fried Astragalus membranaceus promote propionic acid synthesis, enhance anti-inflammatory factor activity, and suppress the production of pro-inflammatory cytokines. They also significantly regulate the serum expression of immune factors, thereby enhancing immunomodulatory capacity[60]. Total Astragalus saponins can inhibit mucosal injury, improve mucosal blood flow, enhance systemic immune function, and suppress lipid peroxidation[61]. Astragalus polysaccharides exert immunomodulatory effects by activating the NF-κB p65/MAPK signaling pathway[62]. Astragalus membranaceus and its active ingredients reconstruct gastrointestinal immune tolerance by regulating the Th1/Th2 and Treg/Th17 immune axes, modulating immune cell function, and remodeling the composition of gut microbiota[63].

Alleviation of inflammatory responses and protection of the gastric mucosa

AS-IV exerts its anti-inflammatory properties by downregulating NF-κB activity and curtailing pro-inflammatory cytokine secretion, thereby blocking the transformation of inflammation into cancer via regulation of CXCL5-CXCR2 axis-driven epithelial-mesenchymal transition[64,65]. Furthermore, Astragalus membranaceus modulates the PI3K/Akt, Wnt/β-catenin, and Janus kinase-signal transducer and activator of transcription 3 signaling pathways[66]. It protects the gastric mucosa through multiple mechanisms, including alleviating inflammatory injury, enhancing antioxidant capacity, regulating cell apoptosis and proliferation, and improving gastric mucosal microcirculation[67]. AS-IV can also regulate the thrombin/PAR-1 signaling pathway and inhibit the p53 and MAPK signaling pathways, thereby increasing gastric acid secretion, protecting the gastric mucosa, and exerting therapeutic effects against CAG[68,69]. Additionally, Astragalus polysaccharides exert beneficial effects on the gastric mucosa by regulating cyclooxygenase-2 and metalloproteinases-2, which are downstream effector proteins of the epidermal growth factor receptor gene[70].

Regulation of gastrointestinal microbiota and alleviation of metabolic disorders

Both raw and honey-fried Astragalus membranaceus can exert therapeutic effects on CAG by regulating the gastric mucosal microbiota[71] and alleviating CAG-induced metabolic disorders of the intestinal microflora. Among these, Acetobacter and Escherichia coli, as well as hydroxyalkanoic and deoxycholic acids, may serve as potential targets for Astragalus membranaceus[72]. AS-IV enhances the abundance of Bifidobacterium in the gut and regulates serum metabolite levels via the Wnt3a/β-catenin signaling pathway, thereby exerting antitumor effects[73].

Anti-oxidative stress and amelioration of gastric mucosal pathological lesions

A hydrogel composed of Astragalus membranaceus polysaccharides and glycyrrhizic acid mitigates oxidative stress-related gastric mucosal injury through ROS scavenging and anti-apoptotic mechanisms[74]. AS-IV exerts antioxidant and anticancer effects by modulating the activity of ROS-scavenging enzymes and participating in the induction of apoptosis and autophagy[75]. Furthermore, it suppresses serum NO and inducible NO synthase levels while enhancing superoxide dismutase activity to ameliorate pathological gastric mucosal lesions[76]. In addition, it regulates mitochondrial energy metabolism, thereby exerting therapeutic effects on CAG[77] (Table 3).

Table 3 Experimental studies and mechanisms of action of Astragalus and its active components in the chronic atrophic gastritis treatment.

Research contents	Action targets	Outcomes	Ref.
Astragalus membranaceus	H. pylori vacuolating cytotoxin A	Inhibition of H. pylori activity	Wang et al[58]
	Inflammatory factors	Suppression of pro-inflammatory cytokines and immunomodulation	Liu et al[60]
	Th1/Th2 and Treg/Th17 immune axes	Enhancing immune tolerance	Chang et al[63]
	PI3K/Akt, Wnt/β-catenin, and Janus kinase-signal transducer and activator of transcription 3 pathways	Protecting the gastric mucosa	Liu et al[66]; Yan and Zhang[67]
	Acetobacter and Escherichia coli	Alleviating gut microbial metabolic disorders	Liu[71]; Liu et al[72]
Astragaloside IV	H. pylori urease and related genes (ureA, ureB)	Attenuating the colonization ability of H. pylori	Wang et al[59]
	CXCL5-CXCR2 axis and the NF-κB pathway	Anti-inflammatory effects and inhibition of inflammation-to-cancer transformation	Pei et al[64]; Tian et al[65]
	Thrombin/PAR-1, p53, and MAPK signaling pathways	Increasing gastric acid secretion and protecting the gastric mucosa	Shen et al[68]; Duan et al[69]
	Bifidobacterium and the Wnt3a/β-catenin signaling pathway	Regulation of serum metabolite levels and anti-tumor effects	Wen et al[73]
	Reactive oxygen species, serum nitric oxide, and inducible nitric oxide synthase	Antioxidant and anticancer effects and improvement of clinical efficacy in CAG	Xia et al[75]; Li et al[76]
Astragalus polysaccharides	NF-κB p65/MAPK signaling pathway	Enhancement of immunomodulatory effects	Feng et al[62]
	Epidermal growth factor receptor downstream effector proteins cyclooxygenase-2 and metalloproteinases-2	Protection of the gastric mucosa	Zhu et al[70]
Total astragalosides	Immune factors	Enhancement of immunomodulatory capacity	Zhang et al[61]

CAG: Chronic atrophic gastritis; H. pylori: Helicobacter pylori; PI3K: Phosphoinositide 3-kinases; Akt: Protein kinase B; NF-κB: Nuclear factor-κB; MAPK: Mitogen-activated protein kinases.

CONCLUSION

CAG is a gastric disease and is a critical stage in the pathological progression of GC, posing a severe threat to patient health. Early intervention is crucial to delay disease progression and prevent inflammation-to-cancer transformation. As a commonly used traditional Chinese medicinal material, Astragalus membranaceus possesses diverse biological activities and pharmacological properties, showing promising prospects for clinical application in the management of CAG. Astragalus membranaceus and its active ingredients exert therapeutic effects through multi-level and multi-target mechanisms, primarily by eradicating H. pylori, modulating immunity, alleviating inflammatory responses, regulating the gastrointestinal microbiota, and mitigating oxidative stress. However, the current research is predominantly limited to animal and cellular studies. Future studies should further elucidate their therapeutic effects and underlying mechanisms, promote the standardized and personalized diagnosis and treatment of Astragalus membranaceus-based formulas, and explore integrated Chinese and Western medicine models. These efforts aim to enhance the clinical efficacy, prevent inflammation-to-cancer transformation, and provide scientific evidence and theoretical guidance for clinical treatment and novel drug development.