Mechanistic insights into the roles of astragalosides and Astragalus polysaccharides in gynecological and breast cancers (Review)

Introduction

Gynecological malignancies, particularly cervical and ovarian cancers, remain a major threat to women's health and contribute substantially to the global disease burden. Cervical cancer is the fourth most common cancer in women worldwide and accounts for ~6.5% of all female cancer cases (1). It is often highly invasive and frequently diagnosed at an advanced stage, resulting in considerable mortality and morbidity (2). Ovarian cancer carries an estimated lifetime risk of ~2% in women, and both incidence and mortality increase with age (3). Each year, ~239,000 new ovarian cancer cases are reported globally, with an estimated 152,000 associated deaths (4). Because ovarian cancer is typically insidious in onset and effective screening strategies remain limited, the 5-year survival rate remains <20%, underscoring the urgency for improved prevention and treatment approaches (5).

Although breast cancer is not traditionally categorized as a gynecological malignancy, it is closely linked to women's health and remains a leading cause of cancer-related mortalities among women. Its complex pathogenesis and heterogeneous clinical presentation continue to pose major challenges for effective prevention and management (6). Breast cancer is the most commonly diagnosed malignancy in women, with ~1.7 million new cases annually, and both incidence and mortality are projected to rise further over the next decade (7). Beyond disease-specific symptoms such as abnormal bleeding, pain and reproductive dysfunction (8), breast cancer, ovarian cancer and cervical cancer can necessitate mastectomy or resection of reproductive organs, and may lead to premature menopause and infertility, with profound consequences for physical and psychological well-being. They also impose substantial psychosocial burdens, affecting family relationships and overall quality of life, and have therefore attracted increasing clinical and public attention (9).

Astragalus membranaceus, known as Huangqi, is a perennial herb in the Fabaceae family. It typically reaches a height of 50 to 100 cm and bears a thick cylindrical root that is light brown on the exterior and yellow white internally, with a firm and fibrous texture. The main and lateral roots are used medicinally, and the most commonly utilized sources are Astragalus membranaceus (Fisch.) Bge. var. mongholicus and Astragalus membranaceus (Fisch.) Bge. (10). Astragalus contains diverse chemical constituents, including saponins, polysaccharides, flavonoids, amino acids, as well as trace elements, such as zinc and iron.. Among these, saponins and polysaccharides are regarded as the principal bioactive components (11). The saponin fraction consists predominantly of triterpenoid saponins, with astragalosides (AST) I, II and IV and isoastragalosides I and II accounting for >80% of total saponins (12). Astragalus polysaccharides (APS) are water-soluble macromolecules extracted mainly from the stems or roots and represent one of the most important naturally derived active ingredients of Astragalus (13). Wild Astragalus species are primarily distributed across northern China, Kazakhstan, Mongolia and the Russian Far East, with the largest cultivation area located in northern China (14). Increasing evidence has identified Astragalus as a rich source of bioactive compounds with potent antitumor potential (15–17).

Previous reviews have largely focused on the anticancer mechanisms of individual Astragalus constituents in single tumor types. By contrast, evidence regarding the effect of AST and APS in gynecological and breast cancers remains scattered and has not been systematically integrated. To address this gap, the present review provided a comprehensive summary of the molecular mechanisms and signaling pathways through which AST and APS exert therapeutic effects in breast, ovarian, and cervical cancers. This study aims to establish an integrated pharmacological framework and to support the development of integrative and precision treatment strategies for women's cancers worldwide, as illustrated in Fig. 1.

Figure 1. Astragalosides and Astragalus polysaccharides in the treatment of gynecological tumors and breast cancer.

Clinical applications and pharmacological basis of Astragalus membranaceus

Major bioactive components of Astragalus membranaceus

Astragalus membranaceus produces a broad spectrum of biologically active secondary metabolites, with triterpenoid saponins and polysaccharides representing the major classes. Triterpenoid saponins are formed through conjugation of triterpene aglycones with sugars or other substituent groups, and their biosynthesis proceeds via multiple enzyme-mediated steps that include precursor generation and carbon ring assembly. Polysaccharides derived from Astragalus comprise heteropolysaccharides, neutral polysaccharides, glucans and acidic polysaccharides, with β- (1→4)-glucosidic linkages as the predominant glycosidic bonds (18). Due to the amphiphilic properties of saponins, a variety of extraction approaches using aqueous or alcoholic solvents have been developed. Among these, n-butanol and methanol are considered particularly efficient for isolating triterpenoid saponins (19). Conventional preparation of APS typically relies on solvent or aqueous extraction followed by ethanol precipitation, which remains a widely used and technically straightforward method (20). Pharmacological evidence indicates that AST can downregulate p21 and Bcl-xL, and upregulate Caspase-3 and cleaved PARP. It mainly exerts its antitumor effects by inhibiting tumor cell proliferation and inducing cell apoptosis (21). APS also displays a broad range of biological activities, including antitumor, anti-aging and antiviral effects (22–24). These actions are mediated through multiple mechanisms, such as modulation of immune responses, promotion of apoptotic signaling, and inhibition of tumor invasion and metastasis (25).

Clinical indications of Astragalus membranaceus

Astragalus membranaceus has traditionally been used to enhance immune function and support overall physiological homeostasis. In contemporary oncology, it is increasingly applied as an adjuvant therapy, with particular relevance to the management of common malignancies in women, such as breast, cervical and ovarian cancers (26). A pharmacological study indicates that bioactive constituents of Astragalus, such as astragaloside III, exert bidirectional immunomodulatory actions by activating immune effector cells, including lymphocytes and natural killer (NK) cells, thereby strengthening antitumor immunity. These constituents may also mitigate immunosuppressant-associated myelosuppression, which can improve therapeutic efficacy and reduce treatment-related adverse effects (27). In addition, APS has been reported to upregulate IL-12, TNF-α, Bax and Caspase-3, and downregulate Bcl-2, thereby exerting antitumor activities through immune regulation, induction of tumor cell apoptosis, and inhibition of invasion and migration (28,29).

Clinical evidence further suggests that APS can enhance treatment responses and improve immune status in patients with cancer. Compared with radiotherapy alone, combined radiotherapy and APS has been associated with an increased CD4+ to CD8+ ratio in breast cancer and other malignancies, which may contribute to improved clinical outcomes (30). However, clinical studies specifically evaluating AST and APS remain limited. Most available evidence derives from investigations of Astragalus as a whole herb or from traditional Chinese medicine formulas in which Astragalus is a principal component. This pattern reflects current clinical practice, where compound prescriptions are commonly used, and findings from formula-based studies are more readily translatable to real-world application. For example, clinical data indicate that Astragalus-based formulas combined with chemotherapy can reduce post-chemotherapy adverse reactions and chemotherapy-associated hepatorenal toxicity in cervical cancer while improving overall efficacy (31). Additional clinical studies have reported that Astragalus may alleviate common cancer-related complications and improve patient quality of life (32).

Beyond oncology, Astragalus has shown beneficial effects in anti-inflammatory, antioxidant and anti-infective settings (33–35). Accordingly, its use in patients with cancer is primarily supported by its roles in immunoregulation and functional support. In this population, Astragalus may help relieve frequent symptoms such as fatigue (36), anorexia (37) and vomiting (38), while enhancing immune competence and improving quality of life (39). Therefore, in the clinical management of female malignancies, Astragalus and its preparations are widely used as adjunctive interventions to improve treatment tolerance, support therapeutic response and potentially enhance prognosis.

Mechanisms of Astragalus active constituents in female malignancies

Mechanisms of Astragalus constituents in breast cancer

Disruption of cellular homeostasis is a fundamental driver of tumor initiation and progression. Uncontrolled tumor cell proliferation frequently results from impaired apoptosis, a form of programmed cell death that is essential for maintaining tissue integrity. Programmed cell death not only shapes the immunosuppressive tumor microenvironment but also markedly influences therapeutic responses to anticancer treatments (40). Li et al (41) reported that APS activates RAW264.7 macrophages and increases the production of nitric oxide (NO) and tumor necrosis factor alpha (TNF-α), thereby inducing apoptosis and inhibiting the proliferation of breast cancer cells. In a related study, Li et al (42) showed that APS increased ANXA1 mRNA and protein expression while reducing epidermal growth factor receptor (EGFR) mRNA levels in GFP-4T1 cells, suggesting that APS may promote programmed cell death through coordinated upregulation of ANXA1 and suppression of EGFR signaling.

Advances in drug delivery have further expanded the therapeutic potential of APS. A dual-targeted nanodelivery system based on quercetin 3 prime,3 prime dithiodipropionic acid, APS, and folate, termed Nano Pomegranate, effectively induced programmed cell death in breast cancer cells and demonstrated improved antitumor efficacy with fewer adverse effects compared with free curcumin, highlighting its translational promise (43). In triple negative breast cancer (TNBC) 4T1 cells, Sun et al (44) found that 24 h co-treatment with APS and cisplatin significantly enhanced apoptosis by downregulating Bcl-2 and Bcl-xL and upregulating PUMA, cleaved caspase 3, and cleaved PARP. The combination also increased E-cadherin expression. Because E-cadherin is central to cell-cell adhesion, its loss is closely associated with epithelial mesenchymal transition (EMT), enhanced invasiveness, and poor prognosis across multiple cancers (45). Consistently, Yang et al (46) reported that APS treatment for 24 h reduced Snail and vimentin expression, decreased Wnt1 and β-catenin levels, and increased E-cadherin expression in MCF 7 and MDA MB 231 cells, supporting inhibition of Wnt/β-catenin signaling and suppression of breast cancer cell proliferation, invasion, and migration.

Beyond direct cytotoxicity, APS also exerts immunomodulatory and synergistic anticancer effects. Zhou et al (47) showed that APS stimulates RAW264.7 macrophages to secrete immunoregulatory mediators including NO, TNF-α, IL-1β, and IL-6 through activation of the Toll-like receptor 4- and MyD88-dependent pathways, thereby enhancing antitumor immunity. Moreover, Bao et al (48) demonstrated that APS attenuates paclitaxel-induced cytotoxicity in RAW264.7 cells by downregulating phospho-histone H2A (P-HA), PARP, checkpoint kinase 1, p53 and p21 while upregulating Bcl-xL and Mcl-1. This selective protection of immune cells may improve the therapeutic index of paclitaxel in breast cancer treatment.

Mechanisms of AST in breast cancer

Accumulating evidence indicates that ASTs, particularly astragaloside IV (AS-IV), exert robust antitumor effects through multiple mechanisms (49). Because chemoresistance remains a major barrier to effective cancer therapy (50), a study has investigated the potential of AS-IV to restore treatment sensitivity. Lou et al (51) reported that AS-IV upregulates Nrf2 and increases intracellular ATP levels, thereby enhancing the efflux function of breast cancer resistance protein (BCRP). Huang et al (52) showed that AS-IV markedly reduces the stemness of breast cancer stem cells and reverses paclitaxel resistance in MCF7-derived cancer stem cells by modulating the (hypoxia-inducible factor) HIF-1α/HIF-2α axis and inhibiting Notch, PI3K/Akt/mTOR and JAK/STAT3 signaling. Caveolin-1, a membrane protein linked to metastasis and drug resistance (53), has also been reported to be downregulated by AS-IV in a dose-dependent manner. This change activates the endothelial nitric oxide (NO) synthase (eNOS)/NO/peroxynitrite (ONOO−) pathway, promotes oxidative damage, and increases paclitaxel sensitivity in MCF 7 and MDA MB 231 cells (54). In addition, a liposomal co-delivery system incorporating oxymatrine and AS-IV suppresses cancer-associated fibroblast activation and increases tumor-infiltrating lymphocytes, thereby potentiating the efficacy of programmed cell death protein 1 inhibitors and supporting the potential utility of AS-IV-based strategies in breast cancer immunotherapy (55).

Beyond chemosensitization, AS-IV also inhibits invasion and metastasis through modulation of tumor and microenvironmental signaling. Yu et al (56) found that AS-IV downregulated TGF-β and suppressed Akt/forkhead box protein (FOX)O1 signaling in THP-1-derived macrophages. This effect reduced M2 polarization and decreased the expression of IL-10, MMP-9, CD206, CD163 and TGF-β, which in turn limited macrophage-mediated breast cancer cell proliferation, invasion and migration. Vav3, a guanine nucleotide exchange factor that promotes tumor proliferation and invasion when overexpressed (57), has been identified as another target of AS-IV. Jiang et al (58) reported that AS-IV downregulated Vav3 and its downstream effectors, ERK1/2, JNK, MMP-2 and MMP-9, thereby reducing Rac1 activation and inhibiting breast cancer cell viability and motility. Similarly, Hu et al (59) demonstrated that AS-IV induced the long non-coding RNA TRHDE-AS1 in MCF-7 and MDA-MB-231 cells in a dose- and time-dependent manner, leading to reduced proliferation and invasion in vitro and in vivo. Moreover, Yang et al (60) demonstrated that AS-IV activated the transcription factor FOXA1 and upregulates galactose-3-O-sulfotransferase 1, thereby suppressing proliferation and viability in obesity-associated triple negative breast cancer by remodeling sphingolipid metabolism.

Collectively, APS related studies in breast cancer have primarily employed RAW264.7 macrophages and TNBC 4T1 cells, with an emphasis on inhibiting proliferation, inducing apoptosis, modulating immunity and enhancing chemotherapeutic efficacy (41–44,46–48). By contrast, studies of AS-IV have largely relied on MCF-7 and MDA-MB-231 models and have highlighted regulation of Akt/FOXO1, eNOS/NO/ONOO and Rac1/MAPK signaling, together with their associated molecular targets (51,52,54–56,58–60), as summarized in Fig. 2.

Figure 2. Mechanism of action of Astragalus polysaccharides and astragalosides in treating breast cancer. ANXA, annexin A1; NO, nitric oxide; P-HA, phospho-histone H2A; Chk1, checkpoint kinase 1; BCRP, breast cancer resistance protein; BCSC, breast cancer stem cells; ONOO, peroxynitrite; eNOS, endothelial nitric oxide synthase; CAV-1, caveolin-1; TIL, tumor-infiltrating lymphocytes; CAF, cancer-associated fibroblasts; TRHDE-AS1, the lncRNA of TRHDE antisense RNA 1; FOXA1, forkhead box A1; GAL3ST1, galactose-3-o-sulfotransferase 1.

Mechanisms of Astragalus active constituents in ovarian cancer

APS are natural compounds with strong immunomodulatory and antitumor properties (61) and have gained attention as potential therapeutic agents for ovarian cancer. Growing evidence indicates that APS suppresses tumor growth by inhibiting cancer cell proliferation and promoting apoptosis. Guo et al (62) reported that APS reduced microRNA (miR)-27a expression in a dose-dependent manner, which increased the expression of the tumor suppressor FBXW7 and consequently inhibited proliferation while inducing apoptosis in the human ovarian cancer cell line OV-90. Consistently, Li et al (63) showed that APS combined with cisplatin markedly decreased SKOV3 cell viability and enhanced apoptosis by downregulating Bcl-2, upregulating Bax and caspase-3, and activating JNK1/2 signaling. This synergistic interaction increased cisplatin sensitivity and strengthened its antitumor activity in ovarian cancer.

Cancer stem cells are closely linked to recurrence and chemoresistance (64). Peng et al (65) demonstrated that APS downregulates PTEN-induced kinase 1 (PINK1) and suppresses mitochondrial autophagy through the PINK1/Parkin pathway, thereby increasing the sensitivity of ovarian cancer stem cells to poly (ADP-ribose) polymerase inhibitors. This combination promoted apoptosis and reduced both viability and self-renewal capacity of ovarian cancer stem cells.

APS also modulates immune responses relevant to ovarian cancer. Shokati et al (66) found that 7 day exposure of peripheral blood mononuclear cells to APS significantly increased cell proliferation, reduced the proportion of regulatory T cells in the T cell population, decreased expression levels of anti-inflammatory mediators including IL-10, TGF-β and VEGF-A, and increased the levels of proinflammatory cytokine IL-6, collectively supporting enhanced antitumor immunity. In addition, Liu et al (67) developed an APS-based micellar delivery system modified with methotrexate and podophyllotoxin. This formulation increased TNF-α and IL-12p40 levels while reducing IL-4 and TGF-β1 expression levels, and it promoted repolarization of tumor associated macrophages from an M2-like state toward an M1-like phenotype, supporting immune mediated targeting of ovarian cancer.

Mechanisms of AST in ovarian cancer

Given the high rates of chemoresistance and recurrence in ovarian cancer, natural products with intrinsic antitumor activity, including AST, are increasingly investigated as potential adjunctive therapies. Zhang et al (68) demonstrated in both in vitro and in vivo models that astragaloside II enhances cisplatin efficacy by downregulating multidrug resistance protein 1 (MDR1), the cell cycle regulator cyclin D1 and proliferating cell nuclear antigen, while upregulating apoptosis-associated proteins PARP and caspase-3. This coordinated regulation promoted apoptosis and inhibited ovarian cancer cell proliferation, thereby increasing cisplatin sensitivity. AS-IV has also been reported to influence ovarian cancer progression through immune microenvironment modulation. Wang et al (69) treated IL-4/IL-13-induced THP-1 derived macrophages with AS-IV and found that it suppressed the overexpression of high mobility group box 1 (HMGB1) and Toll-like receptor 4 (TLR4), reduced the secretion of M2-associated factors including TGF-β, MMP-9 and IL-10, and inhibited ovarian cancer cell proliferation, invasion and migration by promoting macrophage repolarization. In addition, Dekinash et al (70) profiled methanolic Astragalus extracts using HPLC-MS/MS and identified six saponins and five flavonoids with moderate cytotoxic activity against SKOV3 ovarian cancer cells, as reflected by reduced cell viability, which supports a direct antiproliferative potential of the extract.

Collectively, APS-related studies in ovarian cancer, which primarily use human cell lines such as OV-90 and SKOV3, have focused on mechanistic axes including miR-27a/FBXW7, JNK1/2 and PINK1/Parkin. These findings suggest that APS inhibits proliferation, induces programmed cell death, regulates immune responses, modulates macrophage polarization and can synergize with chemotherapeutic agents to enhance efficacy while reducing toxicity. The development of APS-based delivery systems further supports translational potential (62,63,65–67). By contrast, studies on AST have mainly examined their roles in suppressing proliferation, promoting apoptosis, improving chemosensitivity and reshaping macrophage polarization, with particular emphasis on HMGB1-TLR4 signaling (68–70), as summarized in Fig. 3.

Figure 3. Therapeutic mechanism of Astragalus Polysaccharides and astragalosides against ovarian cancer. miR, microRNA; FBXW7, F-box and WD-40 domain protein 7; PINK1, PTEN-induced kinase 1; Treg, regulatory T cells; MDR1, multidrug resistance protein 1; PCNA, proliferating cell nuclear antigen; box1, high mobility group box 1; TLR4, toll-like receptor 4.

Mechanisms of Astragalus bioactive constituents in cervical cancer

As principal bioactive constituents of Astragalus membranaceus, APS have potential therapeutic value in cervical cancer. Liu et al (71) reported that 24 h treatment of cisplatin-resistant cervical cancer cells with APS increased peroxisome proliferator-activated receptor δ (PPARD) expression, which in turn suppressed CDC20 transcription and inhibited Wnt/β-catenin signaling. This regulatory effect markedly enhanced cisplatin sensitivity, reduced proliferative capacity, and promoted apoptosis. These findings suggest that APS may exert antitumor activity in cervical cancer by modulating cell cycle regulation and reversing chemoresistance.

Mechanisms of AST in cervical cancer

Clarifying the mechanisms through which AST regulate cervical cancer progression is essential for defining their clinical potential. Available evidence indicates that AST can inhibit cervical cancer cell invasion and migration through multiple signaling pathways. Xia et al (72), using integrated in vitro and in vivo assays together with quantitative proteomics, reported that AS-IV increased Atg12 expression and upregulated mRNA-decapping enzyme 1A and Thymosin β-4, thereby inducing autophagy and suppressing cervical cancer cell proliferation and invasion. EMT is a critical process that promotes tumor cell invasion and migration (73). Zhang et al (74) found that 24 h AS-IV treatment reduced TGF-β1 expression and increased E-cadherin levels, while inhibiting phosphorylation of MAPK and PI3K. These effects were associated with EMT suppression and reduced invasive and migratory capacity of cervical cancer cells. Macrophages, which are abundant stromal components within the tumor microenvironment, also contribute to cancer progression through polarization-dependent functions (75). Shen et al (76) demonstrated that AS-IV downregulated TGF-β and decreased phosphorylated Smad2 and Smad3 in cervical cancer cells. Inhibition of TGF-β/Smad2/3 signaling reduced macrophage M2 polarization and consequently restrained EMT progression, migration and angiogenesis.

Overall, the study of APS in cervical cancer has focused primarily on enhancing chemosensitivity, suppressing proliferation and inducing programmed cell death through pathways involving PPARD, CDC20 and Wnt/β-catenin signaling (71). Research on AST, largely conducted in SiHa cervical cancer cells and macrophage models, has emphasized regulation of MAPK/PI3K signaling and the TGF-β/Smad2/3 axis (72,74,76). Reported mechanisms include inhibition of EMT, suppression of invasion and migration, and induction of autophagy (72,74,76), as summarized in Fig. 4.

Figure 4. Mechanisms by which Astragalus polysaccharides and astragalosides act against cervical cancer. PPARD, peroxisome proliferator-activated receptor δ; DCP1A, mRNA-decapping enzyme 1A; TMSB4X, thymosin β-4; p-, phosphorylated.

In summary, the antitumor mechanisms of APS across breast, ovarian and cervical cancers are most consistently linked to immunomodulation and apoptosis induction, with frequent involvement of JNK1/2, Wnt/β-catenin and PINK1/Parkin signaling, as well as downstream effectors including TNF-α, IL-6, IL-1β, NO, Bcl-2 and Bax. By contrast, the predominant actions of AST involve reversal of drug resistance, enhancement of chemosensitivity, and inhibition of invasion and metastasis. These effects are largely mediated through the PI3K/Akt/mTOR, TGF-β/Smad, eNOS/NO/ONOO and Rac1/MAPK pathways, highlighting the multitarget antitumor potential of Astragalus bioactive constituents in gynecological malignancies, as summarized in Table I.

Table I. Mechanism of Astragalus polysaccharides and astragalosides in gynecological tumors and breast cancer.

Table I.

Mechanism of Astragalus polysaccharides and astragalosides in gynecological tumors and breast cancer.

A, Breast cancer (treated with APS)
Experimental models (animal/cell)	Possible mechanisms	Targets	Doses	(Refs.)
Cell: MCF-7, RAW264.7	Induce apoptosis in tumor cells and inhibit tumor cells proliferation	NO↑, TNF-α↑	1,000 µg/ml	(41)
Animal: BALB/c mice Cell: GFP-4T1	Induce programmed cell death in tumor cells and inhibit tumor cells proliferation	ANXA1 mRNA↑, ANXA1↑, EGFR mRNA↓, EGFR↓	200 mg/kg	(42)
Cell: MCF-7	Induce programmed cell death in tumor cells	NA	20 mg/ml	(43)
Cell: TNBC 4T1 Animal: BALB/c mice	Synergistic cisplatin, induce apoptosis in tumor cells	Bcl2↓, Bcl-xL↓, Puma↑, Cle-Caspase3↑, Cle-PARP↑	2.5 mM, 100 mg/kg	(44)
Cell: MCF7, Mda-MB-231	Inhibit tumor cells proliferation, invasion, and migration	Snail↓, vimentin↓, Wnt1↓, β-catenin↓	800 µg/ml	(46)
Cell: RAW264.7	Regulate immunity	NO↑, TNF-α↑, IL-1β↑, IL-6↑	400 µg/ml	(47)
Cell: 4T1 mouse breast cancer cell lines, RAW 264.7 Animal: BALB/c mice	Synergistic paclitaxel, regulate immunity	P-HA↓, PARP↓, Checkpoint kinase 1↓, p53↓, p21↓, Bcl-Xl↑, Mcl-1↑	50 µg/ml, 40 mg/kg	(48)
B, Breast cancer (treated with AST)
Experimental models (animal/cell)	Possible mechanisms	Targets	Doses	(Refs.)
Animal: Male C57BL/6 mice, Male Nrf2-/- C57BL/6 mice	Enhance the efflux activity of breast cancer resistance protein	Nrf2↑, ATP↑	150 mg/kg, 25 µM	(51)
Cell: HepG2
Cell: MCF7-CSCs48	Synergistic paclitaxel, reduce the	NA	60 nM,	(52)
Animal: 5-week-old	stemness of breast cancer stem		40 mg/kg
Balb/c-nu/nu female mice	cells
Cell: MCF-7, MDA-MB-231	Enhance sensitivity to the	CAV-1↓, eNOS↑, NO↑,	30 µM	(54)
	chemotherapy drug paclitaxel	ONOO↑
Animal: BALB/c mice	Synergistically enhance the	CAF↓, TIL↑	1.5 mg/kg	(55)
Cell: 4T1-luc, CTLL-2	antitumor efficacy of programmed
	cell death protein-1 inhibitors
Cell: THP-1	Inhibit tumor cells proliferation,	TGF-β↓, IL-10↓, MMP-9↓,	50 µM	(56)
	invasion, and migration	CD206↓, CD163↓
Cell: MDA-MB-231	Inhibit tumor cells invasion and	ERK1/2↓, JNK↓, MMP-2↓,	40 µg/ml	(58)
	migration	MMP-9↓, Vav3↓, Rac1↓
Cell: MCF-7, MDAMB-231	Inhibit tumor cells proliferation,	TRHDE-AS1↑	80 µg/ml,	(59)
Animal: BALB/c mice	invasion, and migration		20 mg/kg
Cell: MDA-MB-231,	Inhibit tumor cells proliferation	FOXA1↑, GAL3ST1↑	60 µM	(60)
MDA-MB-468, MCF-10A	and viability
C, Ovarian cancer (treated with APS)
Experimental models (animal/cell)	Possible mechanisms	Targets	Doses	(Refs.)
Cell: OV-90, SKOV-3, HEK 293T	Induce apoptosis in tumor cells and inhibit tumor cells proliferation	miR-27a↓, FBXW7↑, caspase-3↑, Bax↑	1 mg/ml	(62)
Cell: SKOV3	Inhibit tumor cells viability, promote tumor cells apoptosis, and enhance sensitivity to the chemotherapy drug cisplatin	Bcl-2↓, Bax↑, Caspase-3↑	800 µg/ml	(63)
Cell: 3AO, SKOV3	Induce tumor cells apoptosis and enhance sensitivity to PARPi	PINK1↓	200 mg/l	(65)
Cell: PBMC, A2780	Regulate immunity	Treg↓, IL-10↓, TGF-β↓, VEGF-A↓, IL-6↑	1,000 µg/ml	(66)
Cell: ID8, RAW264.7, SKOV3	Regulate immunity	TNF-α↑, IL-12p40↑, IL-4↓,	30 µM,	(67)
Animal: Female C57BL/6 mice		TGF-β1↓	80 mg/kg
D, Ovarian cancer (treated with AST)
Experimental models (animal/cell)	Possible mechanisms	Targets	Doses	(Refs.)
Cell: A2780, SKOV3	Promote tumor cells apoptosis, inhibit tumor cells proliferation, and enhance sensitivity to the chemotherapy drug cisplatin	MDR1↓, Cyclin D1↓, PCNA↓, PARP↑, Caspase-3↑	160 µM, 320 µM	(68)
Cell: THP-1, SKOV3	Inhibit tumor cells proliferation, invasion and migration	Box1↓, TLR4↓, TGF-β↓, MMP-9↓, IL-10↓	100 µg/ml	(69)
Cell: SKOV-3	Reduce tumor cells viability	NA	100 µg/ml	(70)
E, Cervical cancer (treated with APS)
Experimental models (animal/cell)	Possible mechanisms	Targets	Doses	(Refs.)
Cell: Hela, SiHa, HCerEpics	Promote tumor cells apoptosis, inhibit tumor cells proliferation, and enhance sensitivity to the chemotherapy drug cisplatin.	PPARD↑, CDC20↓, Wnt↓, β-catenin↓	3 mg/ml	(71)
F, Cervical cancer (treated with AST)
Experimental models (animal/cell)	Possible mechanisms	Targets	Doses	(Refs.)
Cell: SiHa, HeLa	Inhibit tumor cells proliferation, invasion and migration	Atg12↑, DCP1A↑, TMSB4X↑	25 µM	(72)
Cell: SiHa	Inhibit tumor cells invasion and migration	TGF-β1↓, E-cadherin ↑, MAPK↓, PI3K↓	800 µg/ml	(74)
Cell: THP-1, HeLa, SiHa, HUVECs	Inhibit macrophage M2 polarization, inhibit tumor cells migration, inhibit angiogenesis	TGF-β↓, p-Smad2↓, p-Smad3↓	20 µmol/l, 40 µmol/l	(76)

[i] ↓, downregulation; ↑, upregulation; NO, nitric oxide; TNF-α, tumor necrosis factor-α; ANXA1 mRNA, annexin A1 mRNA; EGFR mRNA, epidermal growth factor receptor mRNA; Bcl-2, B-cell lymphoma 2; Bcl-xL, B-cell lymphoma-extra large; Puma, p53 upregulated modulator of apoptosis; Cle-Caspase3, cleaved caspase-3; Cle-PARP, cleaved poly(ADP-ribose) polymerase; Snail, snail family transcriptional repressor 1; Wnt1, Wnt family member 1; IL-1β, interleukin-1β; IL-6, interleukin-6; P-HA, phospho-histone H2A; PARP, poly(ADP-ribose) polymerase; p53, tumor protein p53; p21, cyclin-dependent kinase inhibitor 1A; Mcl-1, myeloid cell leukemia 1; Nrf2, nuclear factor erythroid 2-related factor 2; ATP, adenosine triphosphate; CAV-1, caveolin-1; eNOS, endothelial nitric oxide synthase; ONOO, peroxynitrite; CAF, cancer-associated fibroblasts; TIL, tumor-infiltrating lymphocytes; TGF-β, transforming growth factor-β; IL-10, interleukin-10; MMP-9, matrix metalloproteinase 9; CD206, cluster of differentiation 206; CD163, cluster of differentiation 163; ERK1/2, extracellular signal-regulated kinase 1/2; JNK, c-Jun N-terminal kinase; MMP-2, matrix metalloproteinase 2; Vav3, vav guanine nucleotide exchange factor 3; Rac1, Rac family small GTPase 1; TRHDE-AS1, the lncRNA of TRHDE antisense RNA 1; FOXA1, forkhead box A1; GAL3ST1, galactose-3-O-sulfotransferase 1; miR-27a, microRNA-27a; FBXW7, F-box and WD-40 domain protein 7; caspase-3, cysteine-aspartic protease 3; Bax, Bcl-2-associated X protein; PINK1, PTEN-induced kinase 1; Treg, regulatory T cells; VEGF-A, vascular endothelial growth factor A; IL-12p40, interleukin-12 subunit p40; IL-4, interleukin-4; MDR1, multidrug resistance protein 1; PCNA, proliferating cell nuclear antigen; Box1, high mobility group box 1; TLR4, toll-like receptor 4; PPARD, peroxisome proliferator-activated receptor δ; CDC20, cell division cycle 20; Wnt, wingless-type MMTV integration site family; Atg12, autophagy-related gene 12; DCP1A, mRNA-decapping enzyme 1A; TMSB4X, thymosin β-4; E-cadherin, epithelial cadherin; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; p-Smad2, phosphorylated Smad2; p-Smad3, phosphorylated Smad 3.

Discussion

APS and AST show therapeutic potential against breast, ovarian and cervical cancers by acting on diverse molecular targets and signaling pathways. The present review systematically synthesizes the antitumor mechanisms of APS and AST, the major bioactive constituents of Astragalus membranaceus, in gynecological malignancies and delineates their key targets and regulatory networks. These insights provide a mechanistic rationale for the clinical use of Astragalus as an adjuvant therapy in breast, ovarian and cervical cancers. Notably, because intratumoral heterogeneity is substantial across malignancies, the biological effects of Astragalus constituents are likely to vary among tumor subtypes. In clinical practice, breast cancer is commonly classified according to molecular features and biological behavior (77) into Luminal A, Luminal B, HER2-enriched and TNBC (78). The studies included in the current review placed particular emphasis on TNBC, where APS and AST most consistently suppress tumor cell proliferation and promote apoptosis, thereby offering mechanistic support and new directions for therapeutic development in this refractory subtype. By contrast, subtype-specific evidence in ovarian and cervical cancers remains limited. A number of studies have treated these malignancies as single disease entities in mechanistic investigations, and the present review reflects the current evidence base. This gap highlights the need for future research integrating refined pathological and molecular subtyping to better define subtype dependent responses and therapeutic potential.

Emerging evidence also indicates that the pharmacological actions of Astragalus extend beyond gynecological oncology to common non-neoplastic disorders of the female reproductive system. For example, AS-IV has been reported to activate peroxisome proliferator-activated receptor-γ (PPARγ), induce autophagy, suppress granulosa cell proliferation and promote apoptosis, suggesting potential relevance to polycystic ovary syndrome (PCOS) (79). Similarly, APS ameliorates PCOS-like phenotypes in mice by improving serum metabolic profiles, increasing gut microbiome diversity, and reducing insulin resistance and oxidative stress (80). In addition, aqueous extracts of Astragalus roots, in which AST are major constituents, upregulated uterine and ovarian PPARα mRNA and increased mitochondrial 2,4-dienoyl-CoA reductase expression, thereby suppressing estrogen-dependent uterine hyperplasia (81). APS has also been shown to alleviate bovine mammary fibrosis through reduction of reactive oxygen species, inhibition of NLRP3 and modulation of EMT (82). Collectively, these findings suggest that Astragalus bioactive compounds exert broad regulatory effects across female reproductive disorders and may help maintain reproductive axis homeostasis through multi-target and multi-level mechanisms.

Despite encouraging preclinical evidence, important challenges remain for the clinical translation of APS and AST in gynecological oncology. Current knowledge of their in vivo metabolism, bioavailability and interactions with the tumor microenvironment remains incomplete, and the mechanisms that determine efficacy across distinct subtypes of female malignancies require further clarification. Although available studies suggest that APS and AST can influence drug disposition and therapeutic response by regulating metabolic enzymes and transporters such as BCRP and MDR1, systematic characterization of absorption, distribution, metabolism and excretion profiles remains insufficient. Clinical development is further constrained by poor water solubility, low oral bioavailability and suboptimal tissue distribution, which limit accumulation at tumor sites. Advanced delivery platforms including lipid based carriers, polymeric micelles and nanoparticle formulations may improve bioavailability, enable controlled release and reduce adverse effects, yet barriers related to formulation complexity, large scale manufacturing and safety evaluation continue to impede translation (83). In addition, chemotherapy remains a cornerstone of treatment for breast, ovarian and cervical cancers, but its effectiveness is frequently limited by resistance and dose-limiting toxicities that reduce adherence and quality of life. Building on the immunomodulatory and cytoprotective properties of APS and AST, future studies should develop natural immunomodulatory adjuvants with improved bioactivity and tumor targeting capacity to mitigate chemotherapy-related toxicities and enhance therapeutic outcomes. Notably, most existing evidence is derived from cellular and animal models, and high quality clinical data remain scarce regarding long-term efficacy, optimal dosing and rational combination strategies. Future work should prioritize multidisciplinary collaboration to clarify molecular mechanisms, optimize delivery technologies, conduct rigorous clinical trials and establish standardized quality control systems, thereby accelerating clinical translation and maximizing the therapeutic potential of Astragalus in gynecological malignancies.

Acknowledgements

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Funding

This work was supported by the Shandong Province Collaborative Innovation Center for Classic Traditional Chinese Medicine Formulas (grant no. 2019KFY12) and the National College Students' Innovation and Entrepreneurship Training Program (grant no. 202510441006).

Availability of data and materials

Not applicable.

Authors' contributions

RL wrote the manuscript and drew the pictures. ZL and YL collected and organized literature and participated in the revision of the manuscript. YC and ZG proofread the manuscript. ZX is responsible for the study designing, research fields, drafting and finalizing the manuscript. All authors read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References