Saponins often exist in free forms and exhibit relative pharmacological effects and strong biological activity. Due to the difficulty in breakthroughs in purification and isolation techniques for Astragalus saponins, related research progress has been slow. Saponin compounds possess biological activities such as antiviral, antitumor, and immunomodulatory effects (Zhang et al., 2022). The main saponin metabolites of Astragalus include astragalosides I–VIII, isoastragalosides I, II, and IV, cycloastragenols E, F, and G, and astragaloside I–IV, among others (Luo et al., 2022; Nafti et al., 2022). Among these, astragaloside IV is a marker metabolites for quality control of Astragalus and one of the primary substances responsible for its antiviral pharmacological activities. Studies have found that it can induce tumor cell apoptosis, suppress tumor cell migration and invasion, inhibit epithelial-mesenchymal transition (EMT), regulate autophagy, modulate immune responses, reduce toxic side effects during tumor treatment, and enhance sensitivity to antitumor drugs (Yao et al., 2023; Ziyang et al., 2023).

The doses of astragaloside IV used in in vitro studies typically range from 1 to 50 μM, with treatment durations varying between 24 and 72 h. Both human cancer cell lines (e.g., MCF-7, A549) and animal models have been utilized to investigate its effects. Positive controls often include standard chemotherapeutic agents, while untreated cells or vehicle-treated groups serve as negative controls. These well-controlled designs ensure the observed effects are attributable to the saponins (Wang J. et al., 2021b; Zhao et al., 2020).

Astragalus polysaccharide (APS), a natural active metabolites extracted from Astragalus, is a macromolecular substance that plays a decisive role in its pharmacological effects. APS exhibits biological activities such as antiviral, immunomodulatory, antioxidant, anti-aging, anti-inflammatory, antitumor, and anti-atherosclerotic properties (Zhang Q. et al., 2024b; Li W. et al., 2020b; Zhong et al., 2022). Extensive research has proven that APS not only promotes tumor cell apoptosis but also enhances immunity to exert antitumor effects. Additionally, APS can improve the efficacy of chemotherapy drugs and reduce tumor cell drug resistance, making its antitumor role increasingly prominent in the field of oncology (Cao et al., 2024).

Typical APS doses in vitro range from 50 to 400 μg/mL, applied over 24–72 h, depending on the cell type and endpoint. In vivo models include murine tumor-bearing mice treated with APS doses from 50 to 200 mg/kg via intraperitoneal or oral administration for periods of 1–4 weeks. Controls include untreated and placebo groups, while some studies employ standard immunomodulators or chemotherapy drugs as positive controls. These parameters clarify the experimental contexts in which APS exerts its effects (Li et al., 2019; Chen et al., 2022a).

Flavonoids are one of the key active metabolites of Astragalus, with pharmacological effects including anti-inflammatory, antitumor, hypoglycemic, immunomodulatory, and antiviral activities (Yang et al., 2023). Over 50 flavonoid compounds have been purified from Astragalus, including flavonoid aglycones, isoflavones and their glycosides, isoflavans, and pterocarpans, with isoflavones and their glycosides being the most abundant (Sheng et al., 2021; Cui et al., 2022). Important active flavonoid metabolites in Astragalus include formononetin and calycosin-7-O-β-D-glucopyranoside (Xu et al., 2022; Li M. et al., 2022c; Liu F. et al., 2020a). The Astragalus isoflavone formononetin protects cardiomyocytes through antioxidant, anti-apoptotic, and autophagy-promoting effects, demonstrating excellent results in cardiovascular system protection (Chen Q. et al., 2024a). Furthermore, related studies have shown its beneficial protective effects in anti-atherosclerosis. Astragalus and its different metabolites inhibit tumorigenesis and progression by modulating multiple signaling pathways (Figure 1).

In vitro experiments with formononetin typically utilize concentrations ranging from 5 to 40 μM, with treatment durations of 24–72 h on various tumor and normal cell lines. In vivo studies administer doses of 10–50 mg/kg via oral or intravenous routes, over time frames from several days to weeks. Controls include vehicle treatment and known pathway inhibitors. Such detailed experimental setups validate the flavonoids’ multifaceted biological effects (Zhang et al., 2021; Liu J. et al., 2020b).

Tumor cells are characterized by uncontrolled proliferation, infinite growth, and invasive metastasis. Reducing tumor spread and improving therapeutic efficacy remain hot topics in medical research worldwide. During tumor migration and invasion, EMT plays a critical role. Chen et al. found that Astragalus-Curcuma combination inhibits NETs expression by suppressing the Complement C5a/C5aR pathway, gradually ameliorating the hypercoagulable state of the body, thereby inhibiting tumor growth (Chen et al., 2003). Formononetin extracted from Astragalus root plays a significant role in inhibiting cancer cell proliferation, and metastasis by targeting key signaling pathways at interconnected junctions. It regulates cell cycle arrest and mediator protein-induced apoptosis, and promotes the upregulation of key regulatory factors (e.g., p-AKT and p53), while effectively inhibiting signaling pathways such as NF-κB. In addition, it can inhibit the expression of ERK1/2 pathway, which can further inhibit the signaling of lamin A/C, and ultimately regulate the tumor microenvironment (TME) to further inhibit tumor proliferation (Liu et al., 2025). Current studies have shown that formononetin can effectively inhibit the transduction of JAK/STAT signaling pathway and induce the inactivation of PKB/AKT pathway and MAPK pathway, which in turn can effectively inhibit the migration and invasion of cancer cells (Aliya et al., 2023). Jiang and colleagues et al. found that AS-IV inhibited the proliferative activity and invasiveness of breast cancer cells. Further studies revealed that AS-IV inhibited the activation of two key signaling molecules, ERK1/2 and JNK, members of the MAPK family, and downregulated the matrix metalloproteinases MMP-2 and MMP-9, which ultimately inhibited the invasive function of tumor cells. Furthermore, AS-IV mediates the downregulation of guanine nucleotide exchange factor Vav3 and inhibits activated Rac1 expression, ultimately suppressing tumor cell proliferation (Jiang et al., 2017).

Critical Evaluation: While these studies collectively suggest inhibitory effects of Astragalus metabolites on tumor proliferation and migration, most experiments were conducted exclusively in vitro using a limited range of tumor cell lines, often without inclusion of non-tumorigenic controls. The majority lacked dose–response analyses within clinically achievable concentration ranges, and in vivo validation remains scarce. Furthermore, mechanistic conclusions often rely on correlative signaling pathway changes without direct causality testing (e.g., gene knockdown or rescue experiments). These limitations reduce the strength of translational claims and highlight the need for standardized, multi-model validation approaches.

In tumor cells, the regulatory mechanisms of apoptosis are disrupted, leading to abnormal proliferation and survival. Key apoptotic regulators include Bcl-2 family proteins (Bcl-2, Bax) and caspase family proteins (caspase-3). Li et al. found that APS-mediated macrophages accelerate 4T1 cell apoptosis primarily via the mitochondrial apoptotic pathway without causing cytotoxicity (Li W. et al., 2020b; Jia et al., 2019). However, APS-mediated macrophages significantly inhibit 4T1 cell growth by inducing cell cycle arrest (G2 phase) and apoptosis. Other studies demonstrate that astragaloside IV enhances the Bax/Bcl-2 ratio, triggering endogenous apoptosis in various cancers, including breast, lung, colorectal (Zheng et al., 2019; Zhao Y. et al., 2019a; Cui et al., 2020). In liver cancer, breast cancer and bladder cancer cells, APS can significantly reduce mitochondrial membrane potential, increase the Bax/Bcl-2 ratio and cleave PARP. Simultaneously inhibit PI3K-p110β and p-AKT, promote FoxO1 translocation, thereby amplifying cisplatin-induced DNA damage, and increase the apoptosis rate from 12% to more than 40% (Chen et al., 2025). In cisplatin-refractory bladder cancer xenograft mice, APS combined with chemotherapy could reduce tumor volume by 55%, and no obvious systemic toxicity was observed. In the osteosarcoma model, APS inhibits JNK/c-Jun by upregulating miR-133a, significantly increasing the proportion of early and late apoptotic cells and inhibiting the metastasis trend (Chu et al., 2018). Astragalus saponin IV also exhibited broad-spectrum pro-apoptotic activity. In cells such AS colorectal cancer and non-small cell lung cancer, AS-IV can dose-dependently enhance the Bax/Bcl-2 ratio and activate caspase-3, and simultaneously downregulate Mcl-1 and NF-κB by blocking the IL-6/JAK2/STAT3 axis, thereby inhibiting anti-apoptotic signals. More importantly, AS-IV can upregulate Fas/FasL and DR5, enhance the sensitivity of tumor cells to TRAIL and radiotherapy, thereby overcoming the inherent tolerance of the exogenous death receptor pathway (Ran et al., 2025). In the breast cancer stem cell model, AS-IV also increased the paclitaxel-induced apoptosis rate by more than twice by inhibiting the Akt/GSK-3β/β-catenin signaling, significantly reducing the tumor burden of the stem cell subpopulation (Yang et al., 2024; Sun et al., 2023).

Critical Evaluation: Although apoptosis-related findings are promising, most studies rely on single cancer cell lines and short-term assays, making it difficult to assess long-term effects or off-target cytotoxicity. Concentrations of active compounds are often much higher than those achievable in human plasma, raising concerns about clinical relevance. In vivo evidence is limited, with few studies incorporating pharmacokinetic or biodistribution assessments. Moreover, mechanistic claims are often based on pathway inhibition or activation without definitive causal confirmation (e.g., knockdown/overexpression experiments or use of specific inhibitors). Future work should focus on multi-cell line validation, integration of physiological dosing, and comprehensive in vivo mechanistic testing.

Cell cycle arrest helps maintain genomic stability. Mutations in cell cycle regulatory genes play a significant role in tumorigenesis. Under normal conditions, DNA damage triggers cell cycle arrest at checkpoints, providing time for repair to minimize mutations and prevent tumor formation. Yang et al. studied Astragalus injection’s effects on proliferation, apoptosis, and cell cycle arrest in human nasopharyngeal carcinoma CNE-1 cells (Yang et al., 2021). CNE-1 cells were divided into Astragalus injection groups (50 g/L, 100 g/L, 200 g/L, 400 g/L, 800 g/L) and a control group. CCK-8 assays revealed dose- and time-dependent inhibition of proliferation. Flow cytometry showed cell cycle arrest at G0/G1 phase and increased apoptosis after 72 h, correlated with downregulated caspase-3 protein expression. Zhou et al. demonstrated that Astragalus injection inhibits CNE-2 cell proliferation via G0/G1 phase arrest and apoptosis induction, as confirmed by ATP-bioluminescence assays and flow cytometry (Zhou et al., 2017). Duan et al. found that Astragalus injection suppresses MCF-7 breast cancer cell growth by arresting the cell cycle at G1 phase (Duan et al., 2022). Deng and colleagues reported that miR-149 can inhibit the expression of EphB3 and downregulate the expression of PI3K/AKT signaling pathway, and then inhibit the function of STAT3 pathway, and ultimately induce G0/G1 stagnation in colorectal cancer cells, and inhibit the proliferation and invasion of colorectal cancer cells (Deng et al., 2021).

Critical Evaluation: Although related studies suggest that Astragalus injection and its active metabolites can induce tumor cell cycle arrest and promote apoptosis, most experiments are limited to in vitro cell models with small sample sizes and lack validation across diverse tumor types. Additionally, there is considerable variation in dosage ranges and exposure times, with a lack of in vivo or clinically relevant dosing validation, which limits the generalizability of the findings. Future studies should incorporate in vivo models and mechanistic investigations to improve reliability.

Autophagy, a lysosome-mediated self-digestion process, recycles damaged organelles and long-lived proteins, playing dual roles in tumorigenesis. Early-stage autophagy suppresses tumors, while late-stage autophagy promotes tumor growth and metastasis by sustaining energy supply under stress (e.g., nutrient deprivation, TME) (Chen et al., 2023). Wang et al. found that astragaloside IV inhibits autophagy by modulating P62 and LC3 expression, suppresses MMP-2/MMP-9, enhances A549 cell adhesion, and reduces metastasis (Wang et al., 2018). Wang et al. showed that APS inhibits gastric cancer BGC823 cell proliferation, migration, and invasion, while increasing Beclin-1, Bax, and LC3-II/LC3-I ratios and decreasing p62 and Bcl-2, suggesting autophagy induction (Wang et al., 2017).

Critical Evaluation: Current literature shows some controversy regarding the role of Astragalus metabolites in regulating autophagy. Some studies report autophagy promotion, while others indicate inhibition, suggesting stage-specific and cell-type specific effects. Most studies lack in vivo validation and employ incomplete autophagy detection markers. There is a need to establish standardized and multi-dimensional evaluation systems.

The tumor microenvironment (TME), comprising diverse cells and biomolecules, is closely linked to tumor initiation, progression, and metastasis. Traditional therapies focus on tumor cells, but emerging strategies target tumor-host interactions. APS enhances immunity, modulates TME metabolites (cells, cytokines, extracellular matrix), suppresses inflammation, induces apoptosis, and reverses chemoresistance (Li Q. et al., 2024a). Bamodu et al. demonstrated that APS promotes dendritic cell maturation and M1 macrophage polarization in lung cancer TME, downregulating IL-10 (Bamodu et al., 2019). Lee et al. found APS inhibits VEGF and upregulates PD-1/PD-L1, aiding tumor immune escape (Lee et al., 2020). Elham et al. revealed APS boosts anti-tumor immunity in HeLa-PBMC co-cultures by inhibiting IL-10 and TGF-β (Elham et al., 2021).

Critical Evaluation: Research is generally limited to in vitro co-culture or isolated immune cell models, with a lack of systematic animal experiments and clinical data support. Immune regulatory mechanisms involve complex multi-layered signaling pathways, and most existing studies provide correlative observations without in-depth causal verification. Moreover, studies on dosage, safety, and long-term effects are insufficient.

VEGF-driven angiogenesis is critical for tumor vascularization. HUANG et al. showed APS normalizes tumor vasculature by blocking VEGF signaling, enhancing anti-cancer therapy efficacy (Huang et al., 2012). Zhao et al. found APS suppresses Lewis lung cancer growth/metastasis by downregulating VEGF and EGFR (Zhao L. et al., 2019b). Zhang et al. reported Astragalus flavonoids reduce VEGF and VEGFR-2 in tumor-bearing mice (Zhang Y. M. et al., 2024b). Law et al. demonstrated that Astragalus saponins inhibit mTOR signaling, downregulate VEGF, and suppress angiogenesis/metastasis (Law et al., 2012). Auyeung et al. revealed APS inhibits LoVo cell lymphangiogenesis via VEGF-C suppression (Auyeung et al., 2014). Astragaloside IV downregulates COX-2/PGE2/VEGF in SGC7901 and A549/U251 cells, curbing tumor growth (Chen et al., 2021).

Critical Evaluation: Although numerous in vitro and small animal model studies support the inhibitory effects of Astragalus metabolites on tumor angiogenesis, issues remain regarding inconsistent dosage standards, large variability among models, and lack of long-term efficacy and safety assessments. Molecular mechanism research mostly stays at the pathway level without verification of key targets.

Some herbal preparations are widely used in the treatment of cancer due to their energizing and pro-apoptotic and cytotoxic effect, mainly by enhancing immunity (Chen Z. et al., 2024b). Tumor cells often rely on aerobic glycolysis and oxidative phosphorylation for energy acquisition. Given their rapid growth and high energy requirements, they experience increased glucose uptake as well as increased lactate production. Monocarboxylate transporter protein 1 and MCT4 are able to transport large amounts of lactate produced by tumor cells to the outside of the cell, which is critical for maintaining the acidic environment necessary for glycolysis in tumor cells (Hong et al., 2016). Zhang et al. showed that AS-IV was able to restore the expression of key molecules such as MCT1 and HIF-1α, and at the same time effectively inhibit the expression of the p53-mediated miRNA-34a/LDHA signaling pathway and TIGAR signaling pathway, which ultimately inhibited the development of gastric precancerous lesions (Zhang et al., 2018). Li et al. found astragaloside IV induces M1 macrophage polarization via STAT1 phosphorylation, activating anti-tumor immunity (Li M. et al., 2024b). Xu and colleagues found that AS-IV inhibited IL-13/IL-4 expression, which in turn inhibited induced M2 macrophage polarization and ultimately blocked M2 macrophage-driven A549 cell invasion and angiogenesis (Xu et al., 2018). Overall, Astragalus plays a major role in enhancing anti-tumor immunotherapy through different mechanisms of action (Figure 2).

Critical Evaluation: The immunometabolic regulatory effects of Astragalus are preliminarily established; however, most studies are limited to single cell lines or in vitro immune cell experiments, lacking comprehensive in vivo immune monitoring and clinical validation. The complexity of multiple intersecting metabolic pathways adds difficulty to mechanistic research, and future studies should integrate multi-omics approaches for systematic investigation.

Astragalus is a key metabolites in classical Chinese medicinal formulas, with 2,297 documented formulas containing Astragalus for treating 233 diseases (Liu et al., 2019). Classical Astragalus-based formulas, such as Huangqi Guizhi Wuwu Decoction (Astragalus and Cinnamon Twig Five-Substance Decoction), Buzhong Yiqi Decoction (Middle-Tonifying and Qi-Boosting Decoction), and Huangqi Jianzhong Decoction (Astragalus Center-Fortifying Decoction), are commonly used to alleviate tumor-related symptoms, enhance immune function, and reduce the incidence and severity of adverse reactions. According to TCM theory, tumorigenesis is associated with deficient “righteous qi” (vital energy). In Huangqi Guizhi Wuwu Decoction, Astragalus greatly supplements qi, strengthens immune function, and improves disease resistance. Chen studied 104 postoperative colorectal cancer patients, where the control group received FOLFOX4 chemotherapy, while the study group received additional Huangqi Guizhi Wuwu Decoction (Chen et al., 2014). Post-treatment serum levels of VEGF, TGF-β1, and MMP-9 in the study group were significantly lower than those in the control group, indicating that the decoction inhibits colorectal cancer cell secretion and metastasis, improves immune function, reduces cancer cell regeneration, enhances therapeutic efficacy, and promotes recovery. Yu compared the effects of mecobalamin (control group) with Huangqi Guizhi Wuwu Decoction combined with reverse acupuncture (observation group) on chemotherapy-induced peripheral neurotoxicity and immune function in malignant tumor patients (Yu et al., 2024). The observation group showed superior peripheral neurotoxicity grading and immune markers (CD4⁺, and CD8⁺ ratios). Chen et al. demonstrated that modified Huangqi Guizhi Wuwu Decoction significantly alleviates TP chemotherapy-induced peripheral neurotoxicity, reduces its incidence and severity, improves quality of life, and enhances chemotherapy tolerance (Chen et al., 2022b). Zeng et al. investigated the effects of Buzhong Yiqi Decoction combined with bevacizumab on tumor markers (CEA, CA125, CYFRA21-1) in advanced lung adenocarcinoma patients undergoing chemotherapy. The combination significantly reduced tumor marker levels and alleviated clinical symptoms (Zeng et al., 2024). Qiao et al. explored the role of Buzhong Yiqi Decoction combined with chemotherapy in improving serum tumor markers and nutritional status in advanced CRC patients (Qiao et al., 2025). A study by Xiao and colleagues et al. found that Huangqi Jianzhong Decoction in combination with chemotherapy was effective in relieving the side effects of treatment in patients with stage IIIb-IV gastric cancer and significantly promoted the efficacy of chemotherapy. Some efficacy was achieved in about 50% of the related gastric cancer patients. The combination reduced tumor markers (CEA, CA199, CA724), VEGF, and IL-6 levels, improved immune function and quality of life, and mitigated adverse drug reactions (Xiao et al., 2024). Hu et al. observed that Huangqi Jianzhong Decoction combined with apatinib elevated CD3⁺, CD4⁺, and CD4+/CD8+ ratios in advanced gastric cancer patients, enhancing cellular immune function (Hu et al., 2022) (Table 2).

Common modern Astragalus formulations include oral liquids, granules, Astragalus polysaccharide sterile powder for injection, and Astragalus injections. Recent advancements include Astragalus nanoparticles, which offer advantages such as small particle size, high surface area, enhanced reactivity, and strong adsorption capacity (Zhang et al., 2019). Compound Astragalus preparations include Shenqi Fuzheng Injection (Astragalus and Codonopsis), Zhenqi Fuzheng Capsules (Astragalus and Ligustrum), and Kang’ai Injection (Astragalus, Ginseng, and Matrine). Clinical trials confirm that these preparations alleviate cancer-related fatigue, improve gastrointestinal function, modulate inflammatory balance, reduce recurrence and metastasis rates, and enhance quality of life (Yu et al., 2018; Huang et al., 2020; Su et al., 2023).

Astragalus, used for millennia in TCM, is recorded as “non-toxic” in classical texts such as Mingyi Bielu (Supplementary Records of Famous Physicians), Bencaojing Jizhu (Commentary on the Classic of Materia Medica), and Bencaojing Jie (Interpretation of the Classic of Materia Medica) (Spallholz, 1994). Astragalus preparations and active metabolites exhibit low toxicity, with safety validated in clinical and preclinical studies. Recent pharmacological and toxicological research continues to evaluate its safety for broader clinical use. Szabo et al. conducted a 90-day toxicity study in Wistar rats administered Astragalus decoction (45–180 g/kg). No adverse effects were observed in general condition, hematology, urinalysis, organ weights, or histopathology, confirming long-term safety (Szabo, , 2014). Zhang et al. determined the LD50 of Astragalus injection in Kunming mice: intravenous LD50 was 90.39 g/kg (95% CI: 87.57–93.31 g/kg), and intraperitoneal LD50 was 108.11 g/kg (95% CI: 102.90–113.58 g/kg), with no significant acute or chronic toxicity (Zhang et al., 2020).

Astragalus has low acute and chronic toxicity and exhibits high safety even when used at high doses for short periods. However, some studies suggest that long-term high-dose use may be associated with organ toxicity, mutagenicity, and developmental toxicity. Caution is advised when using Astragalus in patients with impaired liver or kidney function and in pregnant women. This review summarizes the clinical application of Astragalus in pro-apoptotic and cytotoxic effects therapy (Table 3).

Current evidence indicates that Astragalus and its active metabolites exert notable cytotoxic and pro-apoptotic effects, primarily demonstrated through in vitro experiments and supported by some animal studies. Recent randomized controlled trials and meta-analyses further suggest that Astragalus may provide adjunctive benefits by alleviating chemotherapy-related adverse effects and improving quality of life in cancer patients. However, several critical limitations remain:

1. Most mechanistic studies are heavily reliant on in vitro models, with insufficient in vivo validation, which limits their translational relevance.

Therefore, well-designed in vivo studies, larger multicenter and multinational clinical trials, and standardized experimental and clinical protocols are urgently required to consolidate and extend the current understanding of Astragalus’ cytotoxic and pro-apoptotic activities.

As a traditional Chinese herbal medicine, the anti-tumor efficacy of Astragalus is undoubtedly significant. However, current research on its metabolites remains insufficient, largely due to the difficulty in separating and properly preserving its metabolites, as well as its low bioavailability. Additionally, given the complexity of traditional Chinese medicine’s syndrome differentiation and treatment, most studies are currently limited to basic research stages such as in vitro cell experiments and animal trials, while the quality of clinical research remains unsatisfactory (Li Z. et al., 2024c). Therefore, future studies urgently need to focus more effort on purification techniques and pharmacological property determination of Astragalus to deeply explore its medicinal value and enhance its clinical effectiveness and safety (Li et al., 2023). Attention should also be paid to the limitations of using quality markers to control the quality of Chinese medicine. These limitations mainly include their inability to reflect the holistic characteristics of interactions and synergistic effects among metabolites, as seen in formulas like Huangqi Guizhi Wuwu Decoction, Buzhong Yiqi Decoction, and Huangqi Jianzhong Decoction, which are important anti-tumor formulations. The effects of Chinese medicine, especially compound formulations, are complex. After compatibility, their functions become diverse, with varying dosages and decoction methods (Tang and Tian, 2024). The corresponding quality markers for different efficacy outcomes may also change, potentially creating a vicious cycle, as the dynamic balance between healthy and pathogenic factors often shifts (Xu et al., 2023).

Current clinical and animal evidence indicates that oral administration of Astragalus preparations at conventional doses is generally well tolerated, with no definitive reports of severe hepatotoxicity; notably, the LiverTox database records no significant elevations in serum transaminases or clinical drug-induced liver injury associated with Astragalus. Multiple in vivo studies have shown that total astragalus saponins or astragaloside IV can mitigate chemotherapy- or high-fat-diet–induced hepatic damage, suggesting a hepatoprotective potential. With respect to renal safety, randomized and prospective studies report modest improvements in estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (CKD) and no serious adverse events; however, Cochrane and other systematic reviews note that small sample sizes and short follow-up periods preclude definitive conclusions about long-term renoprotective effects (Li M.-Y. et al., 2025b). It should also be emphasized that commercial herbal supplements vary widely in quality and may contain heavy metals or other contaminants, which could impose additional hepatic and renal burdens with prolonged use. Consequently, Astragalus is regarded as a relatively safe medicine–food homology herb, but individuals with chronic hepatic or renal impairment, autoimmune disorders, or those requiring long-term high-dose therapy are advised to use it under medical supervision, with regular monitoring of ALT/AST and eGFR, and to select GMP-certified, standardized preparations to ensure feasibility and safety.

Despite the promising findings regarding the anti-tumor effects of Astragalus and its metabolites, several methodological limitations in the existing literature hinder definitive conclusions and clinical translation.

1. Inadequate Control Groups:

In the past 5 years, multiple randomized controlled trials have shown that Astragalus membranaceus and its polysaccharides/injections are moving from the traditional “tonifying qi and nourishing the body” to the framework of evidence-based medicine. Research has found that the latest meta-analysis involving over 4,000 patients confirmed that the combination of Astragalus membranaceus alone or its compound preparations with standard anti-tumor regimens can significantly reduce cancer-related fatigue, bone marrow suppression and gastrointestinal toxicity, and simultaneously improve the objective response rate and quality of life score. This clinical benefit is not only reflected in common solid tumors such as breast cancer, non-small cell lung cancer (NSCLC), and colorectal cancer, but also extends to chronic complications such as chemoradiotherapy peripheral neuropathy and Long-COVID fatigue management. Astragalus Polysaccharide Injection PG2 is a single-active metabolites preparation. A multicenter, double-blind Phase II RCT (NCT03314805) demonstrated that intravenous infusion of PG2 500 mg on days 1, 3, and 8 of chemotherapy could reduce chemotherapy-related fatigue in patients with early breast cancer from a median of 7.4 points to 4.6 points, and significantly improve global health and sleep quality (Shen et al., 2024). There was no difference in safety events compared with placebo. In the context of immunotherapy, prospective cohort studies have reported that the combination of PG2 and PD-1 inhibitors can restore NSCLC patients with baseline NLR >5 to NLR<3 within 4 weeks, extend the progression-free survival from 5.5 months to 7.9 months, and there are no new grade III or IV adverse reactions. Compound injections such as Astragalus Injection and Aidi Injection can achieve the advantage of “multi-target synergy”. A study found that after adding Astragalus membranaceus to the treatment plan of NSCLC patients, the objective response rate of patients increased by 14%–18%, the bone marrow suppression of grade three and above decreased by approximately 30%, and the overall 1-year survival rate improved significantly (Chen J. et al., 2024c). A systematic review of 63 RCTS showed that the injection of traditional Chinese medicine containing Astragalus membranaceus combined with FOLFOX/XELOX in the treatment of advanced colorectal cancer could significantly increase the objective response rate (RR 1.34) and reduce grade IIIII - IV bone marrow suppression (RR 0.64) (Wang S. et al., 2021a). In the future, establishing Astragalus quality evaluation methods that link efficacy and safety, along with holographic pharmacodynamic substance-based quality evaluation systems, will better advance the development and utilization of Astragalus, effectively promote its clinical application in anti-tumor therapy, and actively improve the quality of life for cancer patients.

Critical Evaluation: Although recent clinical trials and meta-analyses provide encouraging evidence for the safety and efficacy of Astragalus preparations as adjuncts in cancer therapy, limitations remain. Many clinical studies suffer from heterogeneity in preparation standardization, dosing regimens, and patient populations, which complicates direct comparison and generalization. The majority of RCTs are conducted within China, and few are independently replicated in diverse global cohorts, raising concerns about potential publication bias and regional variability. Furthermore, mechanistic understanding of Astragalus’ multi-target effects remains incomplete, and the lack of robust pharmacokinetic and pharmacodynamic profiling impedes optimization of dosing and safety monitoring, especially in vulnerable populations. Quality control remains a major challenge due to the complex and dynamic nature of herbal metabolites and formula interactions. Future research must focus on rigorous standardization of herbal products, larger multicenter and multinational trials with longer follow-up, and integrated mechanistic studies to substantiate and optimize clinical applications. This will ensure that Astragalus can be more reliably incorporated into evidence-based oncology practice with maximized therapeutic benefit and minimized risks.

Based on the identified gaps and challenges in current studies, future research should prioritize the following aspects:

1. Establishment of standardized research protocols

Addressing these key issues will lay a solid foundation for the standardized and evidence-based clinical application of Astragalus in anti-tumor therapy.