1 Introduction

Angelica sinensis (Oliv.) Diels, also known as "Female Ginseng", is an medicinal material in traditional Chinese medicine, and has a long history of application (Kim et al., 2018; Nai et al., 2021; Shen et al., 2024). In traditional Chinese medicine, A. sinensis is used to treat gynecological diseases (e.g., irregular menstruation, dysmenorrhea), cardiovascular diseases (like hypertension, anemia), and serves as an immunomodulator (Hou et al., 2021; Shen et al., 2024). The title of "Female Ginseng", highlights its importance in women's health, but its benefits are not limited to this. It also involves systemic effects, such as hematopoietic function and anti-inflammatory effect (Kim et al., 2018; Nai et al., 2021).

The polysaccharides isolated from A. sinensis, are regarded as its main active components, endowing it with diverse pharmacological effects (Hou et al., 2021; Nai et al., 2021; Shen et al., 2024). These macromolecules exhibit properties, like immunomodulatory, anti-inflammatory, antioxidant and hematopoietic, and their structure-activity relationship, has always been the focus of research (Nai et al., 2021).

Inflammation is an important component of the immune response, which helps to eliminate pathogens and repair tissue damage. But, persistent or excessive inflammation is closely associated with the development of various chronic diseases, containing autoimmune diseases, cardiovascular diseases, and metabolic syndrome (Kim et al., 2018; Hou et al., 2020; Xue et al., 2023). Although non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, are the main drugs for current anti-inflammatory treatment, their long-term use is accompanied by serious side effects, like gastrointestinal damage, immunosuppression and increased cardiovascular risk (Hou et al., 2020; Ren et al., 2025). In contrast, natural polysaccharides, such as A. sinensis polysaccharides, are regarded as promising alternative options for their multi-target mechanisms, low toxicity and potential for long-term application (Hou et al., 2021; Ren et al., 2025).

This study explored the molecular mechanism of the anti-inflammatory activity of A. sinensis polysaccharides, with a focus on its effects on key signaling pathways, cytokine regulation and immune regulation. It clarifies the biological activity mechanism of A. sinensis polysaccharides, providing a scientific basis for the development of new anti-inflammatory drugs and functional foods, and promoting the integration of traditional herbal medicine and modern therapeutic strategies.

2 Chemical Composition and Structural Features of A. sinensis Polysaccharides

2.1 Extraction and separation methods

Angelica sinensis polysaccharides (ASPs), are mainly obtained through hot water extraction, and then the crude polysaccharides are often separated, with alcohol (ethanol) precipitation method. To improve the yield and purity, techniques, like ultrasonic-assisted extraction and membrane separation, were also adopted. The extraction conditions have a significant impact on the physicochemical properties, and biological activities of the obtained ASPs (Wang et al., 2019; Nai et al., 2021; Zou et al., 2022).

Further purification is usually accomplished by chromatographic methods, such as DEAE-Sepharose ion-exchange chromatography and gel filtration (like Sephadex G-50), which can separate polysaccharide components with different molecular weights and structural characteristics (Hou et al., 2021; Nai et al., 2021; Zou et al., 2022). High performance gel permeation chromatography (HPGPC), is often used to determine the molecular weight distribution, and obtain uniform polysaccharide components for structural analysis (Wang et al., 2016; Zhao et al., 2021).

2.2 Chemical composition and structural features

ASPs belong to heteropolysaccharides, composed of glucose, galactose, arabinose, rhamnose, fucose, xylose and galacturonic acid. Different components and extraction methods, leading to differences in their proportions (Liu et al., 2019; Nai et al., 2021; Zou et al., 2022; Tian et al., 2024). Structural analysis shows that, ASPs typically have homogalacturonan and rhamnogalacturonan main chains. The side chains are rich in β-1,6- and β-1,4- galactopyranoglycans, α-1,5- arabinoglycans, and arabinose and galactose residues with different connection patterns (Liu et al., 2019; Zhao et al., 2021; Tian et al., 2024). Its common glycosidic bonds include (1→3), (1→6), (1→4) and (1→2), and these connection methods increase the diversity of the structure.

The molecular weight range of ASPs is relatively wide, ranging from approximately 4.7 kDa to over 267 kDa, depending on the extraction and purification methods (Liu et al., 2019; Wang et al., 2019; Zou et al., 2022; Tian et al., 2024). Nuclear magnetic resonance (NMR), and Fourier transform infrared spectroscopy (FT-IR) studies, have shown that the structure of ASPs can be highly branched, with both linear and branched regions. Its conformational characteristics (degree of branching, the presence of "smooth regions" and "hairy regions", etc.), are closely related to its biological activity (Zhao et al., 2021; Zou et al., 2022).

2.3 Structure-activity relationships

The branching degree of ASPs, and the presence of their specific substituents, like arabinose, galactose, and aldehyde acid, are closely related to their biological activities (anti-inflammation, immune regulation, and hematopoiesis etc.) (Liu et al., 2019; Zhao et al., 2021; Tian et al., 2024). For instance, ASPs components with higher arabinose content, or more complex branched structures, exhibit stronger antioxidant and anti-inflammatory activities (Hou et al., 2021; Zou et al., 2022; Tian et al., 2024).

Structural modifications, like changes in molecular weight and branching degree, or the introduction of metal ions (such as cerium), can all affect the anti-inflammatory and antioxidant properties of ASPs. Polysaccharide components with specific conformational characteristics, or higher branching degrees exhibit stronger effects in reducing inflammatory markers, and resisting oxidative stress in cell and animal models (Wang et al., 2019; Li et al., 2023; Tian et al., 2024).

3 Regulation of Inflammatory Signaling Pathways by A. sinensis Polysaccharides

3.1 Modulation of the NF-κB pathway

Studies have shown that, A. sinensis polysaccharides (ASPs) can block the activation of the NF-κB pathway, by inhibiting the degradation of IκBα, thereby reducing the nuclear translocation of the NF-κB p65 subunit. This effect reduces the transcriptional activity of NF-κB, and subsequently inhibits the inflammatory response in various cell and animal models (Zhou et al., 2019; Tian et al., 2021; Zou et al., 2023). In LPS-induced and ischemia-reperfusion injury models, ASPs treatment can reduce the phosphorylation levels of IκBα and p65, which are key steps in NF-κB activation (Tian et al., 2021; Ye et al., 2023).

By inhibiting NF-κB activation, ASPs can down-regulate the expression of various inflammatory mediators, like TNF-α, IL-1β, IL-6, iNOS, and chemokines (e.g., CCL2, CXCL8) (Tian et al., 2021; Ye et al., 2023; Zou et al., 2023). This mechanism is manifested as a reduction in pro-inflammatory cytokines, and relief of tissue inflammation in models such as colitis, arthritis and myocardial injury (Zhou et al., 2019).

3.2 Mechanisms of MAPK pathway regulation

ASPs regulate the MAPK pathway, through inhibiting the phosphorylation of key kinases, like p38, ERK and JNK. This negative regulation reduces the activation level of MAPK-dependent transcription factors, thereby reducing the expression of inflammation-related genes (Xue et al., 2023). In fibroblast-like synovial cells and primary skin cells, ASPs inhibit MAPK signaling, exerting anti-inflammatory effects (Tian et al., 2021).

Through the inhibition of the MAPK pathway, ASPs reduced the transcription of inflammation-related genes, and further restricted the production of cytokines and chemokines in the inflammatory response (Tian et al., 2021; Xue et al., 2023). This mechanism has been demonstrated in both in vivo and in vitro experiments, manifested as a reduction in tissue damage and inflammatory cell infiltration.

3.3 Other relevant pathways

ASPs also exert anti-inflammatory effects, by inhibiting the JAK/STAT pathway, especially the JAK2/STAT3 signaling pathway. This inhibition reduces the expression of pro-inflammatory cytokines and mediators, which has been verified in models of rheumatoid arthritis, liver fibrosis and adjuvant arthritis (Zhou et al., 2019; Li et al., 2020; Wang et al., 2020a; Xue et al., 2023). In some cases, JAK2/STAT3 can act as an upstream of MAPK, suggesting its synergistic regulatory effect (Xue et al., 2023).

Besides, ASPs can activate the Nrf2/HO-1 pathway, enhancing the body's antioxidant defense, and promoting anti-inflammatory effects. This dual regulation helps alleviate oxidative stress and inflammation, protect tissues and promote recovery (Wang et al., 2016; Xiao et al., 2023). ASPs promotes the expression of antioxidant enzymes, and reduces oxidative damage by activating Nrf2/HO-1 (Xiao et al., 2023).

4 Immunomodulatory Effects of A. sinensis Polysaccharides

4.1 Regulation of innate immunity

ASPs can stimulate innate immune responses, especially in enhancing the proliferation and phagocytic activity of macrophages, as well as the release of inflammatory mediators. In vitro and in vivo studies have shown that, ASPs promote macrophage proliferation, enhance their phagocytic function, and increase the production of cytokines such as IL-1β and IL-12p70, as well as the expression of inducible nitric oxide synthase (iNOS) and lysozyme (Shen et al., 2022). ASPs can also upregulate the levels of surface molecules, liek ICAM-1 and TLR4, further promoting the activation of macrophages and pathogen recognition.

And ASPs can activate natural killer (NK) cells, and increase the ratio of monocytes/macrophages in peripheral blood and spleen, enhancing non-specific immunity (Liu et al., 2019; Shen et al., 2022). In aquatic animal models (such as white shrimp), ASPs can increase survival rate and enhance the activities of phenol oxidase, superoxide dismutase and glutathione peroxidase, indicating that its immunostimulative effect is conserved across species (Pan et al., 2018).

ASPs also can promote the maturation of dendritic cells (DCS), and this effect is manifested by the increased expression of major histocompatibility complex class II molecules (MHCII) and CD86, which are crucial for effective antigen presentation (Gu et al., 2019). Mature DCS can better activate T cells and initiate adaptive immune responses, demonstrating the potential of ASPs as immune enhancers and even vaccine adjuvants. If ASPs are encapsulated in a nanoparticle delivery system, their ability to activate antigen-presenting cells and enhance immune responses is stronger.

4.2 Influence on adaptive immunity

ASPs regulate adaptive immunity by promoting the proliferation of total spleen cells and T cells, manifested as an increase in the proportion of CD4⁺ T cells, and a slight decrease in the proportion of CD8⁺ T cells. Meanwhile, ASPs upregulates TH1-type cytokines (IL-2, IFN-γ), and downregulates Th2-type cytokines (IL-4), suggesting that it can promote Th1-dominant immune response, and thereby improve immune balance (Wang et al., 2020b) (Figure 1). In tumor models, ASPs have been found to restore the Th1/Th2 balance in the tumor microenvironment, further verifying their immunotherapeutic potential (Wang et al., 2020b; Zhang et al., 2021).

Figure 1 Proposed schematic diagram of AP-PP-DOX (Angelica polysaccharide-peptide-doxorubicin) nanoparticles for antitumor drug delivery (Adopted from Wang et al., 2020b)

In terms of B cells, ASPs can promote the recovery of pre-B cells (pro-B) and early B cells (pre-B) in the bone marrow, increase the number of B cells in the spleen and periphery, and enhance the production of immunoglobulins (Xiao et al., 2023). These effects are achieved, by promoting the production of IL-7 and activating the IL-7R signaling pathway, which is crucial for the survival and differentiation of B cells. In some studies, ASPs have also been reported, to be able to suppress excessive humoral immunity, suggesting that they have regulatory functions and can help prevent the occurrence of autoimmune reactions.

4.3 Cross-talk between inflammation and immunity

ASPs help maintain the balance between immune tolerance and inflammatory response, through regulating the activity of myelogenic suppressor cells (MDSCs) and the Th1/Th2 cytokine profile (Wang et al., 2020b; Shen et al., 2022). Although ASPs usually show enhanced immune function, they can promote the proliferation and immunosuppressive function of MDSCs, by the STAT1/STAT3 signaling pathway. This effect helps control excessive inflammation, but if not regulated properly, it may also bring the risk of immunosuppression (Shen et al., 2022).

ASPs also can regulate a wide range of cytokine networks, enhance the secretion of IL-2, IFN-γ, IL-6 and TNF-α, while reducing the levels of IL-4 and, in some cases, IL-10 (Wang et al., 2020a). This comprehensive regulatory mechanism serves as the foundation for its immunomodulatory and anti-inflammatory effects, helping to enhance the body's resistance to infections, tumor growth, and immune-related diseases. ASPs can simultaneously regulate pro-inflammatory and anti-inflammatory factors, highlighting its potential as a balanced immunomodulator (Wang et al., 2016; Gu et al., 2019; Zhang et al., 2021).

5 Cellular and Molecular Evidence of A. sinensis Polysaccharides

5.1 In vitro cell studies

ASPs have been widely studied in various in vitro inflammatory models, like LPS-induced macrophage models. The results show that, ASPs can enhance the phagocytic activity of macrophages, promote their proliferation, and regulate the release of inflammatory mediators, including IL-1β, IL-6 and TNF-α (Wang et al., 2016). Furthermore, in models induced by hydrogen peroxide or tert-butyl hydrogen peroxide, ASPs can protect chondrocytes from oxidative stress, and apoptosis damage by reducing ROS levels, and improving mitochondrial function (Zhuang et al., 2016; Ni et al., 2023).

Commonly used molecular markers, like iNOS, COX-2 and various pro-inflammatory cytokines, can be detected by qRT-PCR and western blotting to evaluate the anti-inflammatory effect of ASPs. Studies have shown that, ASPs can up-regulate antioxidant enzymes (e.g., SOD2), down-regulate the expression of inflammatory mediators, and restore the levels of extracellular matrix proteins in chondrocytes (Zhuang et al., 2016; Ni et al., 2023). Flow cytometry and apoptosis experiments, further verified the protective and regulatory effects of ASPs in immune cells and non-immune cells.

5.2 Animal model research

ASPs has been validated in a variety of animal models, including acute and chronic inflammation, osteoarthritis, liver fibrosis, and tumor models. In osteoarthritis models, administration of ASPs can improve cartilage degeneration, enhance mitochondrial metabolic function, and reduce chondrocyte apoptosis (Ni et al., 2023). In liver fibrosis and chemotherapy-induced injury models, ASPs reduce tissue damage, improve hematopoietic function, and promote immune cell recovery (Wang et al., 2020a; Du et al., 2023; Xiao et al., 2023; Sun et al., 2024).

Serum cytokine detection showed that, ASPs could reduce pro-inflammatory factors (TNF-α, IL-1β, etc.) and increase the levels of anti-inflammatory or regulatory factors (e.g., IL-22, IFN-γ) (Wang et al., 2016; 2020a; Du et al., 2023). Histopathological analysis indicated that, the inflammatory infiltration of animal tissues treated with ASPs was reduced, the tissue structure was protected, and the burden of fibrosis or tumor was alleviated (Wang et al., 2020a; Zhao et al., 2021; Ni et al., 2023).

5.3 Molecular target verification

Western blotting, is often used to verify the regulatory effects of ASPs on signaling pathways, like the PPARγ/SOD2/ROS pathway in chondrocytes, the IL-22/STAT3 pathway in the liver, and the PI3K/AKT pathway in the spleen and bone marrow (Wang et al., 2020a; Du et al., 2023; Ni et al., 2023). Immunofluorescence and immunohistochemical experiments, further confirmed the regulation of ASPs on the localization and expression levels of key proteins in tissues and cells (Ni et al., 2023).

Gene knockout and overexpression studies have revealed that, the molecular mechanism of action of ASPs. For example, in liver fibrosis models, blocking IL-22 or STAT3 eliminates the anti-fibrotic effect of ASPs, thereby confirming the key role of these pathways (Wang et al., 2020a). In the tumor model, by manipulating the expression of miRNA and its target genes, the regulatory axis of ASPs exerting anti-tumor effects was further demonstrated (Cai et al., 2024).

6 Case Studies

6.1 Anti-inflammatory roles in arthritis models

In collagen-induced and adjuvant induced arthritis models, ASPs reduce joint swelling, inhibit the production of anti-type II collagen antibodies, and lower the levels of pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β (Li et al., 2020; Hu et al., 2022; Xue et al., 2023). Xue et al. (2023) explored the anti-inflammatory mechanism of ASPs in rheumatoid arthritis (RA) in rats with collagen-induced arthritis (CIA). The results showed that, ASPs can inhibit the proliferation, migration and invasion of synovial fibroblast-like cells (FLS) induced by tumor necrosis factor -α (TNF-α) in vitro, promote cell apoptosis and arrest the cell cycle at the G0/G1 phase. ASPs also reduced the expression levels of inflammatory factors, like IL-6, IL-1β, iNOS and MMPs, indicating that it has multi-target anti-inflammatory effects.

Mechanism studies further revealed that, ASPs exert effect by inhibiting the phosphorylation activity of the JAK2/STAT3 and MAPK signaling pathways, among which the JAK2/STAT3 pathway may be located upstream of MAPK (Xue et al., 2023). By blocking signal transduction and reducing the secretion of inflammatory factors, the joint inflammatory response can be alleviated (Figure 2).

Figure 2 Schematic diagram of the mechanism by which ASP inhibits inflammation of rat CIA-FLS through the JAK2/STAT3 and MAPK signaling pathways (Adopted from Xue et al., 2023)

6.2 Application in ulcerative colitis models

In the ulcerative colitis (UC) model, ASPs exhibit a good anti-inflammatory effect. In the colitis model, which induced by sodium dextran sulfate (DSS) and 2, 4-dinitrobenzenesulfonic acid (DNBS), ASPs can reduce the expression of pro-inflammatory factors, such as IL-6, IL-1β and TNF-α, and inhibit myeloperoxidase activity in colon tissue (Cheng et al., 2020; Zou et al., 2023). ASPs can alleviate oxidative stress, with the help of restoring glutathione levels, and reducing malondialdehyde content, thereby resisting tissue damage mediated by neutrophils. Mechanically, ASPs further weakens inflammatory signaling by inhibiting the TLR4/MyD88/NF-κB pathway (Zou et al., 2023).

ASPs also improve intestinal barrier function through up-regulating tight junction proteins (e.g., zona occludens 1, occludin, claudin-1), and reducing epithelial cell apoptosis (Cheng et al., 2020; Zou et al., 2023). Its nanoparticle formulation can enhance colon-targeted delivery, improve mucosal healing, prolong colon length, and restore intestinal microbiota homeostasis and short-chain fatty acid levels (Xu et al., 2023).

7 Clinical Implications of A. sinensis Polysaccharides

7.1 Progress in preclinical research

Existing preclinical studies have shown that, ASPs have multiple activities, such as anti-inflammatory, immunomodulatory, liver-protective, anti-fibrotic, anti-tumor and antioxidant (Bi et al., 2021; Liu et al., 2021; Zhang et al., 2021). These effects are closely related to the regulation of inflammatory response, oxidative stress and fibrosis-related signaling pathways, and have been verified in cell and animal models of various diseases, like colitis, arthritis, liver fibrosis and metabolic syndrome etc. (Luo et al., 2023; Xu et al., 2023; Zou et al., 2023).

ASPs are a type of natural water-soluble polysaccharides, that have long been applied in traditional medicine and diet. Research generally holds that its toxicity is extremely low, and its safety is relatively high. Due to its stable source and good tolerance, it not only has the potential to be used as a therapeutic drug, but is also highly regarded as a drug carrier. But, there is still a lack of large-scale, standardized clinical trials and systematic safety evaluations at present (Nai et al., 2021; Shen et al., 2024; Tian et al., 2024; Ren et al., 2025).

7.2 Clinical application potential

ASPs show promising application prospects, in a variety of chronic inflammation-related diseases, including ulcerative colitis, rheumatoid arthritis, non-alcoholic fatty liver disease and some hematopoietic system diseases (Wang et al., 2020a; Hu et al., 2022; Luo et al., 2023). Studies found that ASPs often function through multiple pathways and multiple links, such as regulating the gut microbiota, restoring immune balance and maintaining tissue integrity (Bi et al., 2021; Zou et al., 2023; Ren et al., 2025). This multi-target mechanism precisely aligns with the complex, and multi-factorial characteristics of chronic diseases.

Its immunomodulatory and anti-inflammatory properties, make ASPs a very promising adjuvant treatment option. It can be used in combination with traditional medicines, or with the help of a nanoparticle delivery system to enhance therapeutic effects and reduce side effects. Existing experimental results have shown that, ASPs can improve the targeting of drugs, promote the recovery of hematopoietic function after chemotherapy, and also produce synergistic effects with other active substances (Zhang et al., 2019; Nai et al., 2021; Xiao et al., 2023; Sun et al., 2024).

7.3 Development of functional foods and health products

In recent years, the progress made in the extraction, purification and structural characterization of ASPs has laid a foundation, for their application in the fields of drugs and functional foods. The design of nanoparticles and dual-responsive delivery systems has improved their bioavailability, targeting and therapeutic effects, especially showing application potential in gastrointestinal and liver diseases (Nai et al., 2021; Xu et al., 2023; Sun et al., 2024).

ASPs is increasingly being applied in health products and dietary supplements, like immune support, blood replenishment and metabolic regulation (Luo et al., 2023; Tian et al., 2024; Ren et al., 2025). Its safety has been verified. Its natural origin and multi-functional biological activities, make it have broad application prospects in the health industry.

8 Concluding Remarks

ASPs have shown obvious potential in anti-inflammation and immune regulation. It can function through multiple molecular mechanisms, including regulating inflammatory mediators, reducing oxidative stress and regulating the activity of immune cells. The target sites of ASPs are quite broad, covering cytokines, signaling molecules and antioxidant enzymes, and they play regulatory roles in key pathways, like NF-κB, TLR4/MyD88 and STAT3. These mechanisms make it stand out in aspects, including hematopoietic support, immune regulation and tissue protection.

But, most of the existing evidence remains at the level of in vitro experiments and animal models, and clinical verification is still insufficient. At present, there is still a lack of standardized large-scale clinical trials to confirm the efficacy, and safety of ASPs in humans. Data on pharmacokinetics, bioavailability and the optimal dosing regimen are also limited. In addition, the differences in extraction methods and structural heterogeneity, have also increased the difficulty of dose standardization and clinical application.

Future research needs to introduce multi-omics technologies, such as genomics, proteomics and metabolomics, to further analyze the action targets and molecular pathways of ASPs and deepen the understanding of the structure-activity relationship. Meanwhile, attempts can be made to develop derivatives, or carry out structural modifications, and with the aid of novel delivery systems, like nanoparticles, its activity and targeting can be enhanced. With the advancement of these directions, ASPs are expected to gradually evolve from laboratory achievements to effective drugs and functional health products, providing new options for clinical treatment and the health industry.

Acknowledgments

The authors sincerely thank Ms. Wang for reviewing the manuscript and providing valuable suggestions, which contributed to its improvement. Additionally, heartfelt gratitude is extended to the two anonymous peer reviewers for their comprehensive evaluation of the manuscript.

Conflict of Interest Disclosure

The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

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