Approximately 40 primary flavonoids have been identified in CS (1). Key flavonoids include quercitrin, quercetin, hyperoside, kaempferol, and astragalin (23, 26). Flavonoids are characterized by a C6-C3-C6 structure derived from a parent nucleus, which influences their chemical properties. Most flavonoids form glycoside compounds when combined with sugars, and exhibit diverse medicinal activities. Research on flavonoids in CS began earlier, and these compounds are among the most extensively studied active ingredients (27).

More than 20 different phenolic acids have been identified in CS, with phenolic acids being the main components of C. australis (1). These compounds are characterized by multiple phenolic hydroxyl groups attached to the benzene ring. Phenolic acids are medicinally active ingredients that act as anti-inflammatory, antibacterial, and immune-boosting agents.

More than 20 different lignans have been identified in C. chinensis (1). Lignans are natural compounds produced through the oxidation and polymerization of phenylpropanoids and are characterized by a core structure containing one or more C6-C3 fundamental units. It is one of the primary bioactive components of C. chinensis (23, 24).

CS contains several neutral heteropolysaccharides, such as galactose, glucose, mannose, rhamnose, arabinose, and xylose. Glycosidic bonds are linked to complex molecules. One notable polysaccharide derived from C. chinensis is the Cuscutae polysaccharide, which demonstrates a range of pharmacological benefits including antitumor and anti-aging properties, immune system modulation, blood glucose reduction, and lipid regulation (1, 30).

Fatty acids are organic compounds composed of carbon, hydrogen, and oxygen, featuring extended carbon chains and carboxyl groups that are essential for biological functions. The fatty acid structure plays a crucial role in various biological processes.

Steroids are organic compounds characterized by a fundamental structure consisting of a cyclopentane polyhydrophenanthrene nucleus. Among the four constituent rings, the steroid core exhibited various ring fusion patterns. The hydroxyl groups at the C-3 position often form chemical bonds with sugar molecules, resulting in compounds classified as glycosides.

Terpenoids are compounds derived from mevalonate, which contains diene units (C5 units) as fundamental structural components. The molecular framework of terpenoids is predominantly chain-like or cyclic, incorporating various functional groups, including alcohols, aldehydes, ketones, carboxylic acids, and esters.

Alkaloids are naturally occurring nitrogen-containing compounds with basic properties. These compounds typically have complex ring structures and exert significant physiological effects. Alkaloids are the key active components of Cuscutae.

Research has revealed the presence of essential trace elements in Cuscutae, including Mn, Cu, Mn, Fe, Zn, P, and Se (31), with Mn and Zn being higher in dodder. Zn is also important for sperm motility.

CS contains various amino acids (32), including seven essential amino acids required by the human body: valine, threonine, isoleucine, phenylalanine, methionine, lysine, and leucine. In addition, two semi-essential amino acids, histidine and arginine, have been identified. Arginine is essential for spermatogenesis and improves sperm motility and concentration (33).

Volatile components are among the primary constituents of CS, a seed-based medicinal material rich in oil.

Diverse bioactive compounds in CS have multidimensional medicinal functions. Additionally, CS from C. chinensis and C. australis exhibit significant differences in their phenolic profiles, with hyperoside being predominant in C. chinensis, and kaempferol and astragalin in C. australis (24). However, recent studies have indicated that the seeds of C. australis the main medicinal product of C. australis, exhibit efficacy similar to that of C. chinensis (34), which belongs to the same subgenus and shares similar chemical composition and content, although earlier research primarily focused on C. chinensis as the origin of the dodder.

It is important to note that the major bioactive compounds of Cuscuta species can exhibit variability depending on several factors, including the specific species, the host plant it parasitizes, the geographical location where it grows, and prevailing environmental conditions. This inherent variability underscores the necessity of carefully specifying the Cuscuta species and its origin in both research investigations and therapeutic applications to ensure the consistency and reproducibility of results.

The bioactive compounds in CS exhibit therapeutic effects. Flavonoids are the primary material for treating premature ovarian insufficiency (POI) and recurrent spontaneous abortion (RSA) by modulating PI3K/AKT and inflammatory pathways (10, 17, 20, 28). Kaempferol is the primary component of the Wuzi Yanzong Pill for Asthenozoospermia, including CS. Polysaccharides enhance sperm quality and testosterone levels in infertile males, likely through their antioxidant and kidney-nourishing effects (9, 16, 35). Lignans (e.g., sesamin) and phenolic acids synergistically regulate hormone receptors in reproductive disorders (18, 22, 24). Therefore, these bioactive compounds provide the material basis for the medicinal efficacy of CS in reproductive health therapy.

CS, particularly C. chinensis, is often incorporated into compound formulations and has been widely utilized for its potential benefits in the treatment of male and female infertility. The Jiawei Wuzi Yanzong Pill formulation combines Cuscutae with other herbs, such as wolfberry and raspberry, to nourish the liver and kidneys, replenish essence and blood, and address male infertility (25, 36). CS is the most commonly used herb for the treatment of female infertility (14). Jiajian Congrong Cuscutae Pills are effective for treating menstrual disorders (37), endometrial hyperplasia (38), and cystic ovarian syndrome (39). Jiajian Shoutai Pills often combine Cuscutae with other tonics to strengthen the liver and kidneys, invigorate the spleen, and nourish the blood, making them effective for conditions such as fetal loss and miscarriage (40).

Recent evidence has provided insights into the efficacy and mechanism of CS in treating infertility (41–43). Research has shown that CS can enhance sperm motility and membrane function in vitro and modulate the PPAR signaling pathway (44). indicating benefits for male fertility treatment (42, 45). In animal models, it has been shown to enhance the reproductive ability of rats with kidney yang deficiency (18), suggesting a therapeutic effect on male infertility. CS has been associated with improvements in gynecological health, particularly in conditions associated with kidney deficiency. Its use in the treatment of infertility and menstrual disorders has been documented (41, 43); however, more rigorous scientific studies are required to validate these effects.

The action of CS in treating infertility includes nourishing the kidneys, regulating hormones (35, 46–48), antioxidant properties (17, 49), and improving ovarian function (14). CS is primarily recognized in TCM for its ability to nourish the kidneys, which is crucial for reproductive health. Studies have shown that CS can improve sperm quality by enhancing sperm count, motility, and morphology (35, 48). It is believed that CS can address various deficiencies, including kidney yin and yang deficiency, which can lead to male reproductive issues, such as low sperm count and decreased sperm motility (oligoasthenospermia). In women, CS is thought to regulate menstrual cycles and enhance ovarian function, thereby improving the uterine environment for implantation. It has been used to treat menstrual irregularities, endometrial hyperplasia, and premature ovarian failure (POF).

CS has beneficial effects on POI (50). Specifically, its active components, particularly flavonoids such as quercetin, show promise in treating POI by modulating key signaling pathways and improving ovarian function. For instance, these compounds have been found to inhibit POI progression by modulating the PI3K-AKT signaling pathway. Flavonoids found in CS have been shown to enhance the expression of estrogen receptors in the hippocampus, hypothalamus, and pituitary gland (51) as well as luteinizing hormone (LH) receptors in the ovaries of stressed rats, suggesting a potential mechanism by which CS may support ovarian function (10). TCM formulations, such as the Bushen Culuan Decoction, have also shown promise in ameliorating POI by activating antioxidant pathways, which may help protect ovarian function (52). Furthermore, CS has been shown to improve ovulation disorders associated with kidney deficiency by promoting follicular development and increasing the number of secondary follicles (53).

CS and its active components, particularly flavonoids such as quercetin, show promise in the treatment of POI by modulating key signaling pathways and improving ovarian function (10, 17, 54). Compounds in CS, particularly quercetin and other flavonoids, have been found to inhibit POI progression by modulating the PI3K-AKT signaling pathway (10). This pathway is crucial for cell survival and growth, and its modulation may improve ovarian function and hormone levels. Other compounds, such as epicatechin, have shown potential for treating POI via the PI3K/AKT/Nrf2 pathway (52), further supporting the idea that various herbal treatments can target multiple mechanisms involved in ovarian health. TCM formulations containing CS have demonstrated efficacy in improving ovarian function and hormone levels in POI models. These formulations may affect multiple signaling pathways involved in POI, including the PI3K/Akt/mTOR Pathways (19), thereby reducing follicular atresia and enhancing ovarian reserve. CS exhibits a range of medicinal activities, including antioxidant (17, 49), hepatoprotective (55), and modulation of arachidonic acid, glycerophospholipid, and linoleic acid metabolism, as well as steroid hormone biosynthesis (56), which may contribute to its therapeutic potential in the treatment of POI. Other herbal medicines, such as Bushen Huoxue, also act on POI by regulating the TGF-β1 and Smad2/3 signaling pathways (52). CS combined with acupuncture may be beneficial in treating POI, including normalizing menstrual cycles and improving hormone levels, as meta-analyses suggest that this combination may be more effective than hormone replacement therapy in managing symptoms associated with POI (50). However, further high-quality clinical trials are necessary to confirm these findings and to establish the efficacy and safety of herbal treatments for POI.

CS has shown promising effects in the treatment of RSA and in enhancing overall reproductive health (13). Research indicates that flavonoids in CS play a key role in this effect by regulating inflammatory pathways and promoting trophoblast cell invasion, which are crucial for maintaining a healthy pregnancy (20). Studies have demonstrated that flavonoids in CS effectively modulate inflammatory responses (57, 58). This regulation is essential for creating a favorable environment for implantation and fetal development, thereby reducing the risk of spontaneous abortion. In animal models of abortion, CS influences the expression of important proteins, such as Fas, PCNA, and HB-EGF (59). These proteins are involved in cell survival, proliferation, and trophoblast function, suggesting that CS may help maintain pregnancy by enhancing trophoblast activity. CS also exhibits anti-osteoporosis effects in ovariectomized mice (3), indicating its potential to improve bone health under postmenopausal conditions. Flavonoids from CS can ameliorate ovarian endocrine dysfunction, particularly in stressed female rats. CS may help restore hormonal balance and improve ovarian function by modulating hormone receptor expression (60, 61), thus further supporting reproductive health.

A recent study demonstrated the effects of CS in an established PCOS rat model (62). Another study demonstrated that CS, when combined with Salvia, regulates ten core genes involved in PCOS treatment, including IL6, AKT1, VEGFA, TP53, TNF, MAPK1, JUN, EGF, CASP3, and EGFR (63). The experimental animals exhibited abnormalities in the HPG axis, and the administration of varying doses of total flavonoids from CS to PCOS model rats resulted in significant improvements in pathological manifestations. Notably, serum E2 levels were significantly increased, whereas the ovarian index was reduced, indicating a positive effect on ovarian function. CS may play a role in regulating hormonal fluctuations associated with the menstrual cycle because the total flavonoids from CS were found to enhance the concentration of β-endorphin (β-EP) during the luteal phase, which subsequently decreased rapidly (15). CS have been shown to upregulate serum E2 levels and enhance the function of human chorionic gonadotropin (hCG) (64). This evidence suggests that CS may be involved in PCOS pathogenesis. However, it is important to note that CS did not have a significant effect on FSH receptor (FSHR) expression in ovaries (60). Collectively, CS may be beneficial for the treatment of polycystic ovary syndrome by improving hormonal balance and ovarian function. Further research is needed to fully understand the mechanisms and clinical implications of CS in PCOS management.

Some clinical evidence involving CS is emerging, while most research on CS is preclinical in nature. Meta-analyses support CS-containing formulations for reproductive disorders, although treatments using CS alone have been less investigated. A recent meta-analysis systematically evaluated the effectiveness of CS-containing Wuzi Yanzong pills in the treatment of oligoasthenospermia in male infertility. The analysis included a total of 16 studies involving 1960 patients, demonstrating that the Wuzi Yanzong pill alone is superior to Western medicine in improving sperm density, sperm motility, conjugal pregnancy rate, and total effective rate (65). The effect of CS contributed to the main role of the Wuzi Yanzong pill because the predominant composites in the formulation were derived from CS, as detected by modern technology (25).

Moreover, a Taiwanese cohort study identified CS as the most commonly prescribed herb for addressing female infertility (41), and a meta-analysis reported that CS were the most frequently observed cases with kidney deficiency acts as a “reinforcing yang herb” to strengthen the liver and kidney, and indicated that herbal medicine significantly boosted pregnancy rates when compared to placebo treatments (43). Another meta-analysis suggested that CS combined with acupuncture may be more effective than hormone replacement therapy for managing POI symptoms (50). Moreover, CS, as one of the important Chinese herbs, was discussed in a meta-analysis to have potentially beneficial effects on the perinatal outcomes of pregnant women in clinical applications (51).

In addition to the meta-analysis, a clinical trial involving a CS-containing formula, designed as a multicenter, randomized, double-anonymized, placebo-controlled study, has been conducted as a therapeutic option for reviving residual follicles in POI, and the study presented a promising strategy to delay ovarian decline and produce significant clinical evidence (66).

However, clinical trials on single CS therapy are lacking, except for clinical trials on formulations containing CS. Meanwhile, the methodological quality of the RCTs may have been poor, although the risk of bias in the included RCTs was generally low. Therefore, more high-quality clinical trials are required to confirm these findings.

CS has garnered attention for its medicinal effects on the reproductive system, particularly through its influence on the hypothalamus-pituitary-gonadal (HPG) axis (60). This intricate neuroendocrine system, comprising the hypothalamus, pituitary gland, and gonads (ovaries or testes), serves as the primary regulatory center for reproductive hormone production and secretion, and plays a vital role in controlling reproductive functions ( Figure 3 ).

CS exerts various medicinal effects on the reproductive system by regulating specific molecules and signaling pathways. The different pathways are illustrated in Figure 4 and summarized in Table 1 . This section outlines the key targeted molecules and signaling pathways influenced by CS, highlighting its potential mechanisms of action in reproductive health.

Molecular mechanisms of several defined compounds in CS therapy for reproductive diseases have been documented, mainly including five primary chemical classes: polysaccharides, flavonoids, phenolic acids, fatty acids, and steroids. These different components play an important role in reproductive diseases through diverse signaling pathways (integrated in Figure 5 ). There exists convergence in different signaling pathways in the treatment of reproductive diseases by CS. On one hand, different ingredients of CS converge on the same molecules via diverse signaling pathways or the same efficacy. For example, in male infertility, polysaccharides and flavonoids share the same HPG axis and MAPK pathway, and phenolic acids and flavonoids share the same Nrf2 pathway. Between female infertility and POI, RSA, or PCOS, phenolic acids and fatty acids share the arachidonic acid pathway. Between males and females, flavonoids play an important role via the same HPG axis, MAPK, and Nrf2 signaling pathways. Signaling crosstalk between different pathways may occur in relevant cells.

CS influences the reproductive system through complex interactions between targeted molecules and signaling pathways. Such interactions result in a wide range of physiological responses. The effect of CS on the reproductive system is further highlighted by its ability to regulate key proteins or receptors. The intricate mechanisms through which CS exerts its effects underscore its potential as a valuable therapeutic agent for various reproductive disorders.

The toxicity and safety of CS have been investigated (90). Cuscuta chinensis Lam. water extract (CLW) is safe for ICR mice when the dose is lower than 1250 mg/kg (90); the LD₅₀ (median lethal dose), reflecting acute toxicity, was over 5000 mg/kg in ICR mice; and subacute toxicity results showed no mouse death or severe toxic reactions. Some indicators changed when different doses were tested in the study: the body weight at doses of 1250, 2500, and 5000 mg/kg CLW in both male and female mice was reduced, and only the feed intake of female mice was reduced; only at the 2500 mg/kg and 5000 mg/kg doses, CLW had very few organ coefficients involving organs such as the brain, liver, lungs, testes (males), and thymus; decreased platelet count, lymphocyte count, and hematocrit and increased neutrophil count; and affected liver functions, increasing aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP), and decreasing albumin, total cholesterol, and triglycerides; only at the 5000 mg/kg dose, daily oral administration of CLW induced mild toxic effects on the liver in both sexes, which may be a matter of concern (90).

CS has low toxicity and is considered safe because its safe dosage is significantly higher than the 6–12 g of dried crude herb recommended daily for humans by the China Pharmacopoeia, although standardized dosing guidelines are not well established. At a dosage of 1250 mg/kg CLW, the safe dosage in mice (90) may be converted to approximately 6.6 grams CLW per day in humans, according to the standard for inter-species dose conversion using the body surface area normalization method. Furthermore, 1250 mg/kg in CLW is 16.2 times (estimated from 6.17% extraction yield) concentrated from the aqueous extract of dried crude herb (90), so 6.6 grams CLW each day in humans is equivalent to 106.9 grams dried crude herb, which is much higher than the dosage recommended by the China Pharmacopoeia, which also suggests that the Pharmacopoeia dose is safe. According to the safe dosage, it is speculated that the adverse effects of CS in humans are very few, although there is limited information on the adverse effects of CS in humans.

The consistency of the diverse chemical compositions of CS should be considered. CS contains a wide and distinct array of flavonoids, chlorogenic acids, and lignans (23), as demonstrated by multiple analysis methods. Despite this diversity, the consistent presence of key components, such as chlorogenic acid and quercetin, across various samples indicates a higher degree of uniformity in chemical composition and potential therapeutic benefits (88). Notably, chemical profiles vary by species (e.g., C. chinensis vs. C. australis), host plants, and geographical location (27, 34). Therefore, the standardization of marker compounds is essential. For example, hyperoside, as recommended by the China Pharmacopoeia, is used to distinguish C. chinensis from astragalin in C. australis (24). For future applications of CS, it is necessary to clarify its origin, develop cultivation protocols to reduce variability, develop different key compound markers for robust quality control and prediction, and conduct clinical RCTs using standardized extracts.

CS may be involved in herb-drug interactions, including hormonal drugs, antidiabetic drugs, immunosuppressants, and drug metabolism, although most interactions are based on preclinical studies or theoretical mechanisms. 1) The hormonal drug flavonoids from CS can promote testosterone secretion and expression of androgen receptor (9, 18), ER, and progesterone receptor (61) owing to their effects on the HPG Axis. Thus, it may affect the outcomes of hormonal therapies, such as dydrogesterone treatment (64), including other potential oral contraceptives and hormone replacement therapy, although the evidence is limited. 2) Antidiabetic drugs: A study found that the CS extract reduced blood glucose levels in streptozotocin-induced diabetic rats (91), suggesting synergistic effects with hypoglycemic agents. Concurrent use with antidiabetic drugs may potentiate hypoglycemia, increasing the risk of low blood sugar. 3) The immunosuppressant kaempferol from CS attenuates the function of dendritic cells in the immune system (7) and inhibits inflammatory factors such as TNF-α and IL-6 (57). When used in conjunction with immunosuppressants, CS may counteract the immunosuppressive effects of the drugs. 4) The enzymes critical for drug metabolism, flavonoids in CS, may interact with cytochrome P450 (92) and carboxylesterases 2, which affect the metabolism of ester-containing drugs (93). This suggests that CS can alter the function of drug-metabolizing enzymes and plasma levels of drugs metabolized by these enzymes, even altering their efficacy or toxicity. Therefore, CS should be applied at a safe dosage, with caution to avoid potential herb-drug interactions with specific drugs.