Ginseng and its active compounds in ovarian aging: mechanistic basis and translational prospects

Current evidence indicates that the material basis of ginseng centers on triterpenoid saponins and polysaccharides (Ye et al., 2023; Zhang et al., 2023c), complemented by polyacetylenes and volatile small molecules that together form a multi-component, structurally diverse chemical profile (Liu et al., 2007; Cho, 2015).

Ginsenosides are the most representative active compounds of ginseng. Based on their steroid-like aglycone backbones, ginsenosides are broadly classified into protopanaxadiol (PPD)–type and protopanaxatriol (PPT)–type, differing systematically in both the number and positions of sugar moieties (Won et al., 2019). Representative PPD-type ginsenosides include Rb1, Rb2, Rc, Rd, Rg3, and CK, whereas PPT-type ginsenosides are exemplified by Rg1, Re, and Rh1 (Sharma and Lee, 2020). These ginsenosides vary in abundance, polarity, and bioavailability within ginseng, and these structural features directly influence their absorption and target engagement in vivo. Recent studies indicate that ginsenosides, including Rg1, Rg3, and CK, can delay ovarian functional decline, enhance follicular quality, and modulate sex hormone levels (He et al., 2021; Zhang et al., 2008; Ye et al., 2022), providing a mechanistic rationale for further evaluation of these active compounds in the context of ovarian aging.

GPS constitute another major class of active compounds, with more complex molecular architectures than ginsenosides (Zhang et al., 2023c). They are known for their immunomodulatory, antioxidant, and tissue-protective effects (Tao et al., 2023; Zhou R. et al., 2021). Their structures consist primarily of monosaccharides such as glucose, galactose and arabinose, and their pharmacological activity is closely linked to molecular weight and higher order conformation (Liu et al., 2021; Xu et al., 2024).

Additionally, ginseng contains polyacetylenes (e.g., panaxynol, panaxydol) (Knispel et al., 2013), as well as volatile small molecules, organic acids, amino acids, flavonoids, and other minor metabolites (Cho, 2015; Lee et al., 2022; Lee H. Y. et al., 2024; Yang et al., 2021). Although these compounds are typically present at low systemic concentrations in circulation and their direct pharmacological actions are still under active investigation, they may contribute to ginseng’s overall efficacy through synergistic modulation of cellular signaling pathways.

Ginseng and its active compounds exhibit marked component specificity and inter-individual variability across absorption, distribution, metabolism, and excretion (ADME) processes in vivo (Chen et al., 2018; Shen et al., 2013).

Ginsenosides, although pharmacologically active, are heavily glycosylated and relatively hydrophilic in their prototype forms, which results in generally low oral bioavailability (Leung and Wong, 2010; Wang et al., 2021). Upon oral administration, intestinal microbiota catalyze the stepwise deglycosylation of parent ginsenosides to produce metabolite type saponins such as CK (Kim, 2018). Compared with their prototypes, these metabolites exhibit enhanced membrane permeability, stronger plasma protein binding, and increased pharmacodynamic activity (Niu et al., 2013). This gut-driven transformation plays a pivotal role in systemic efficacy, resulting in a dual-track exposure pattern in which both prototypes and metabolites coexist in circulation. Notably, the extent and rate of this conversion vary substantially among individuals, influenced by factors such as gut microbiota composition, dietary patterns, and concomitant medications (Kim K. A. et al., 2015; Yang et al., 2011). This variability alters the ginsenoside metabolic spectrum and exposure, potentially contributing to heterogeneous therapeutic responses in interventions targeting ovarian aging. During distribution and elimination, ginsenosides and their metabolites are often handled by membrane transporters (e.g., P-glycoprotein) and may undergo enterohepatic circulation (EHC) (Hu et al., 2023). Pharmacokinetic parameters, such as maximum concentration (Cmax), area under the concentration–time curve (AUC), and elimination half-life (t₁/₂), differ substantially among individual compounds (Xie et al., 2019; Choi et al., 2020). These multi-component, multi-trajectory features should be considered when interpreting exposure–response relationships, dosing regimens, and therapeutic windows. In contrast, GPS, due to their high molecular weight and structural complexity, are less likely to be absorbed across the intestinal epithelium (Zhang J. et al., 2023). Therefore, their effects in vivo may be localized to the gut or mediated indirectly via immune regulation and related pathways (Kim et al., 2024).

Collectively, these features underscore the need, when evaluating ginseng for ovarian aging, to distinguish the bioavailability routes and levels of action of ginsenosides and polysaccharides.

Clinical and preclinical data suggest that ginseng and its active compounds are generally well tolerated within conventional dose ranges and treatment durations (Choi et al., 2020; Lee and Son, 2011; Fan et al., 2020), supporting their safety profile in chronic degenerative settings. The most commonly reported adverse events include mild insomnia, palpitations, and gastrointestinal discomfort, which are typically related to dose, reversible with time, and of low severity (Coon and Ernst, 2002; Li et al., 2023). Nonetheless, differences among preparation types, such as aqueous extracts, ethanolic extracts, total ginsenoside fractions, and multi-botanical formulations (Li et al., 2022; Kwang-Soon et al., 2008; Opuni et al., 2021), can substantially affect constituent profiles, dissolution behavior, and impurity burdens (Lee K.-Y. et al., 2024), which in turn may alter adverse event profiles and affect overall safety (Singh and Zhao, 2017).

Clinically, reported DDI with ginseng is most commonly observed with anticoagulants and antidiabetic agents. These interactions may occur via pharmacokinetic modulation (e.g., hepatic enzyme induction or inhibition) and pharmacodynamic synergy (e.g., antiplatelet or glucose-lowering effects) (Jiang et al., 2004; Gupta et al., 2017; Kim Y. S. et al., 2015). These risks warrant careful attention in polypharmacy settings. For long-term interventions targeting ovarian aging, particularly in patients with comorbidities or those receiving HRT, it is advisable to prespecify monitoring plans for plausible interaction-sensitive indices, such as coagulation parameters and blood glucose. Study protocols should also define stratified strategies for concomitant medications and clear discontinuation criteria to ensure safety and control.

Given the existing evidence gaps, special populations such as lactating women, women with fertility requirements, patients with major comorbidities, and those with hepatic or renal impairment should use ginseng at the lowest effective dose for the shortest necessary duration. Ongoing safety monitoring and careful assessment of risks and benefits based on available clinical data are recommended (Pitkälä et al., 2016).

Oxidative stress is a key factor in aging and is characterized by an imbalance between reactive oxygen species (ROS) and antioxidants, which leads to cellular damage. The Oxidative Stress Theory of Aging (OSTA) suggests that accumulation of oxidative damage over time is a primary driver of aging processes (Edrey and Salmon, 2014). The ovary is particularly sensitive to oxidative stress because of its dynamic metabolic activity and the cyclic development and maturation of follicles, a combination that places substantial metabolic demands on ovarian tissue and increases susceptibility to oxidative injury. Oocytes are particularly vulnerable to ROS accumulation (Qin et al., 2025), which leads to mitochondrial dysfunction and a compromised cellular environment. Mitochondrial dysfunction, exemplified by decreased mitochondrial membrane potential (ΔΨm) and impaired autophagy regulation, alongside ROS buildup, plays a significant role in accelerating ovarian aging (Agarwal et al., 2005).

ROS are constantly generated as byproducts of cellular metabolism, and when their production exceeds the capacity of endogenous antioxidant defense systems, oxidative stress ensues, leading to cellular dysfunction and structural damage (Sies, 2015). In particular, the oocytes within primordial follicles are especially susceptible to ROS. Accumulation of ROS in primordial follicles can damage oocytes, triggering reproductive aging. Excessive ROS can directly damage oocyte DNA, mitochondria, and membranes, leading to apoptosis or functional inactivation, which accelerates follicular atrophy and depletion of the ovarian reserve (Song et al., 2024; Immediata et al., 2022; Lin and Wang, 2020). In aged mammalian models, ovarian ROS levels are significantly elevated, accompanied by delayed zona pellucida dissolution, disorganized cytoskeletal architecture, and increased granulosa cell apoptosis, hallmarks of oxidative injury (Hamatani et al., 2004; Tarín, 1996; Ben-Meir et al., 2015). Antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx), along with ovarian antioxidant genes like Sod1, Sod2, Gpx1, and Gpx3, are downregulated in aging ovaries, which further weakens the defense mechanisms against oxidative stress (Lim and Luderer, 2011). When mitochondrial function is impaired, ROS production may enter a vicious cycle that perpetuates oxidative damage, disrupts energy metabolism and cellular homeostasis and further accelerates ovarian aging (Sena and Chandel, 2012; Picard and Turnbull, 2013). A classic model of ovarian oxidative stress involves the use of H₂O₂ to induce ovarian damage in mice. The resulting features closely resemble those observed in natural ovarian aging, indicating that oxidative stress not only accompanies aging but may serve as a key driver in the pathogenesis of ovarian dysfunction (Liang et al., 2024). These interrelated mechanisms are schematically summarized in Figure 1. These findings suggest that oxidative stress is not merely a byproduct of aging, but a key driving force in the process of ovarian aging.

Inflammation is an immune response to pathogens, tissue injury or harmful stimuli that normally serves to eliminate threats and promote repair (Medzhitov, 2008). However, in ovarian aging, this inflammation often becomes chronic, low-grade, and persistent, which disrupts tissue function and cellular integrity (Zhang et al., 2020; Lliberos et al., 2021). As aging progresses, the ovarian microenvironment becomes increasingly proinflammatory, with higher concentrations of cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interferon-γ (IFN-γ) (Bafor et al., 2024; Lliberos et al., 2020). This shift is accompanied by activation of a senescence-associated secretory phenotype, with sustained release of cytokines, chemokines and proteases, a pattern often referred to as inflammaging that contributes to follicular depletion and structural degeneration of the ovary (Zhang et al., 2020; Jiao et al., 2021) (Figure 2). Granulosa cells play a crucial role in maintaining the ovarian microenvironment. Chronic exposure to inflammatory mediators induces granulosa cell apoptosis, reduces proliferative capacity, and impairs follicle development (Crespo et al., 2010; Yamamoto et al., 2015; Alpizar and Spicer, 1994). Prolonged exposure to IFN-γ activates the NF-κB pathway in granulosa cells, upregulating pro-apoptotic genes and promoting cell injury (Zhao et al., 2022; Xiao et al., 2001). Inflammatory signals also recruit immune cells into ovarian tissue, disrupting immune homeostasis and amplifying local inflammatory responses, which leads to further damage (Al-Alem et al., 2015; Wu J. et al., 2015). As ovarian aging progresses, macrophage numbers increase and polarization shifts from anti-inflammatory (M2) to pro-inflammatory (M1) phenotypes, exacerbating the inflammatory microenvironment (Xiao et al., 2022). These changes activate multiple cytokine signaling pathways that alter oocyte and granulosa cell metabolism and survival, further accelerating ovarian aging (Dang et al., 2017; Peluso et al., 2001). Chronic inflammation not only impairs follicle quality but also promotes fibrotic remodeling, alters ovarian structure and disrupts normal follicle recruitment and ovulation (Lliberos et al., 2021; Ma et al., 2024).

From an immunological perspective, both innate and adaptive immune systems collaborate to maintain ovarian homeostasis. With aging, Treg cells decrease, while Th1 and Th17 cells become more prevalent. This imbalance promotes the production of proinflammatory cytokines and chemokines, further reducing immune tolerance and sustaining inflammation (Jiao et al., 2021; Deng et al., 2024). Endogenous damage-associated molecular patterns (DAMPs), including mitochondrial DNA, ATP, and HMGB1, can activate Toll-like receptors and NOD-like receptors in the absence of infection, triggering sustained NF-κB and MAPK signaling pathways and perpetuating low-grade inflammation (Liu Y. et al., 2020; Navarro-Pando et al., 2021; Liu et al., 2025). In ovarian aging, the NLRP3 inflammasome is activated, leading to the processing of pro-caspase-1 and the maturation of interleukin-1β (IL-1β) and interleukin-18 (IL-18), creating a positive feedback loop that accelerates granulosa cell apoptosis and follicular atresia (Lliberos et al., 2020; Navarro-Pando et al., 2021). Additionally, immunometabolic reprogramming stabilizes inflammaging, as M1 macrophages favor glycolysis and ROS production, while M2 macrophages rely on oxidative phosphorylation and fatty acid oxidation. These aging-related metabolic shifts help sustain pro-inflammatory states in immune cells, which further impair the follicular niche and promote ovarian aging (Zhang et al., 2020; Park et al., 2025). At the tissue level, inflammatory signaling via TGF-β and the imbalance between matrix metalloproteinases (MMPs) and their inhibitors contribute to extracellular matrix deposition and ovarian stromal stiffening, further impairing follicular recruitment and ovarian function (Isola et al., 2024). Additionally, upregulation of endothelial adhesion molecules and chemokines such as C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 10 (CXCL10) increases immune cell infiltration and prolongs inflammation, which further disrupts follicle recruitment and ovulation (Wang and Sun, 2022). In ovarian aging studies, key markers of inflammation, such as NLRP3-caspase-1-IL-1β axis activity, NF-κB phosphorylation, and the M1/M2 macrophage ratio, can serve as valuable indicators for evaluating the links between immune imbalance, inflammaging, and tissue remodeling. These evaluation methods provide critical insights into the mechanisms driving ovarian aging.

Apoptosis and autophagy are two key processes that contribute to follicular atresia, granulosa cell turnover, and oocyte quality control in the ovary (Zhou et al., 2019). During aging, the balance between these processes becomes disrupted, with increased apoptosis and dysregulated autophagy playing a significant role in ovarian aging (Jin et al., 2025; Peters et al., 2021; Tang et al., 2025). As ovaries age, granulosa cells and oocytes become more sensitive to both endogenous and exogenous stress signals. These cells exhibit reduced mitochondrial membrane potential (ΔΨm), increased ROS, and DNA damage, all of which trigger apoptotic pathways (Li C. et al., 2025; Martin et al., 2022; Smits et al., 2023). In aged ovaries, dysregulation of Bcl-2 family proteins, along with activation of p53 and caspase cascades, are hallmark features of heightened apoptosis (Kugu et al., 1998). In aged mouse ovaries, the pro-apoptotic protein Bax is upregulated, and the anti-apoptotic protein Bcl-2 is downregulated in granulosa cells, which accelerates follicular apoptosis and atresia (Yao et al., 2024). Autophagy, a protective mechanism that removes damaged organelles and misfolded proteins, plays a double-edged role in ovarian aging (Tang et al., 2025). While moderate autophagy helps maintain oocyte homeostasis (Nakashima et al., 2023), excessive autophagy, especially under oxidative stress or chemotherapy-induced injury, can promote cell death (Liang et al., 2024; Zhang et al., 2023d; Zhu et al., 2024). Key signaling nodes, such as PI3K–Akt–mTOR, regulate the balance between apoptosis and autophagy. In aged ovaries, reduced PI3K–Akt activity increases FoxO3a-mediated expression of autophagy genes, while mTOR inhibition sustains autophagy activity and disrupts the follicular niche (John et al., 2008; Li et al., 2024; Yu et al., 2011). In aged ovaries, changes in autophagy-related proteins like Beclin-1 and LC3-II highlight the imbalance between apoptosis and autophagy, making this dysregulation a crucial feature of ovarian aging (Navarro-Pando et al., 2021; Li et al., 2020). Thus, dysregulated apoptosis and autophagy are critical mechanisms driving ovarian aging and the depletion of the ovarian reserve (Figure 3).

The maintenance of normal ovarian function depends on precise regulation within the HPO axis (Belchetz et al., 1978). However, with aging, feedback control in the HPO axis becomes disrupted. For instance, the frequency of gonadotropin-releasing hormone (GnRH) pulses declines, and the pituitary response to GnRH weakens. Additionally, the sensitivity of ovarian tissues to these hormones diminishes. These changes contribute to disordered follicle development and a decline in ovarian endocrine function (Hall et al., 2000; Jiang et al., 2015). In individuals with ovarian aging, serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) increase, while estradiol (E₂) decreases, indicating a loss of the normal negative feedback regulation (Nelson, 2009; Tepper et al., 2012). At the ovarian level, the expression of hormone receptors is also altered. Dysregulation of the FSH receptor (FSHR) and estrogen receptors (ERα and ERβ) impairs follicle recruitment and granulosa cell differentiation (Bramble et al., 2016; Xu X. L. et al., 2022; Couse et al., 2005). As circulating anti-Müllerian hormone (AMH) levels decline with age, or AMHR2 regulation becomes imbalanced, the recruitment threshold for early follicles is altered. This reduces their sensitivity to FSH, impairing ovarian function. Consequently, the maximal response of follicles to FSH diminishes, and the effective response window shortens, leading to reduced steroidogenesis and proliferative responses to FSH stimulation (Chang et al., 2013; van Rooij et al., 2005). In aged mouse ovaries, FSHR expression declines, which reduces granulosa cell sensitivity to FSH and affects aromatase (CYP19A1) expression and estradiol synthesis (Cuomo et al., 2018; Egbert et al., 2019; Devillers et al., 2019). Additionally, the receptor for LH and human chorionic gonadotropin (LHCGR) shows altered timing or premature upregulation in granulosa cells, leading to premature luteinization and impairing follicle selection and growth (Wu Y. G. et al., 2015). The reduced expression of ERβ in oocytes also diminishes estrogen’s anti-apoptotic effects and its support for follicle growth (Xu X. L. et al., 2022; Antonson et al., 2020; Haddad et al., 2020). These alterations in the HPO axis and receptor expression cause a loss of the finely tuned feedback mechanisms that are essential for normal follicle recruitment, selection, and ovulation, ultimately accelerating ovarian aging and depletion of the ovarian reserve (Figure 4).

Oxidative stress and mitochondrial dysfunction are central contributors to ovarian aging. Evidence suggests that ginseng and its active compounds may provide effective interventions to counter these processes, potentially ameliorating age-related damage in the ovary.

In a D-galactose (D-gal)-induced mouse model of ovarian dysfunction, Rg1 significantly reduced malondialdehyde (MDA) levels in ovarian tissue, reflecting a reduction in oxidative damage. It also enhanced the activity of key antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase (GPx), which are essential for maintaining redox balance. This restoration of oxidative defenses suggests that Rg1 can help the ovary recover from cellular damage. Histological analysis showed that Rg1 alleviated estrous cycle disruption and decreased the levels of senescence markers, including p53, p21, and p16. These results demonstrate that Rg1 not only mitigates oxidative damage but also combats cellular aging, improving ovarian function and fertility (He et al., 2017). In vitro studies further confirmed that Rg1 prevented stress-induced apoptosis in granulosa cells by preserving mitochondrial function and regulating mitophagy (Li X. et al., 2025). Similarly, Rb1 reduced ROS and MDA levels, restored mitochondrial membrane potential (ΔΨm), and activated the Akt-FoxO1 signaling pathway to improve mitochondrial dysfunction and counter oxidative damage (Zhou et al., 2022). This suggests that both Rg1 and Rb1 can work synergistically to improve mitochondrial health and reduce oxidative injury, critical factors in ovarian aging. Furthermore, in a nicotine-induced ovarian injury model, oral ginseng powder increased the number of healthy follicles, reduced atretic follicles, and increased the number of corpora lutea. The Ki-67 proliferation index was elevated in granulosa and theca cells, while the Bax/Bcl-2 ratio and cytochrome c (Cyt c) levels were reduced. These findings indicate that ginseng improves the ovarian microenvironment by alleviating oxidative stress and mitigating mitochondrial-dependent apoptosis (Faghani et al., 2022).

These results highlight the therapeutic potential of ginseng as an intervention to slow ovarian aging by enhancing antioxidant defenses and restoring mitochondrial function. However, much of the current evidence is inferred from oxidative stress indices and mitochondrial membrane potential (ΔΨm), although a subset of studies extends these readouts to ovary level phenotypes and endocrine indices, such as improved estrous cyclicity in D-gal models and increased healthy follicles and corpora lutea in nicotine-exposed mice. At the cellular level, granulosa cell stress assays further support preservation of mitochondrial function, including restoration of mitochondrial membrane potential (ΔΨm) together with measures of ATP production, but these short-term systems cannot on their own address oocyte competence or long-term functional reproductive outcomes. Direct links between mitochondrial energy metabolism, oocyte competence, and sustained reproductive outcomes remain limited. In addition, several commonly used models capture acute oxidative injury or toxicant induced ovarian dysfunction, which may not fully reflect the gradual and multifactorial course of physiological ovarian aging. Taken together, the strongest support for this mechanism comes from in vivo studies that connect oxidative stress and mitochondrial changes with ovary-level phenotypes, whereas evidence based mainly on short-term cell stress assays or isolated marker changes should be interpreted more cautiously. These findings support redox control and mitochondrial preservation as a plausible mechanistic node for ginseng-related interventions in ovarian aging.

Ginseng and its active compounds modulate inflammatory and immune processes within the ovarian microenvironment. Their actions converge on key features of the chronic low-grade inflammatory state and senescence-associated secretory phenotype (SASP) activation that characterize ovarian aging. The inflammatory phenotype in this context is not limited to elevated levels of a few cytokines but involves broader remodeling of resident immune cells, including macrophages, dendritic cells, natural killer cells and T cell subsets, together with a persistently amplified SASP signature (Zhang et al., 2020; Tang et al., 2023; Chen et al., 2022; Zhu et al., 2025).

Inflammasome activation drives ovarian inflammatory responses that contribute to age-related follicle depletion, and suppression of these processes may help delay ovarian aging and extend the reproductive window (Lliberos et al., 2020). In rat models of ovarian aging, rare ginsenosides known as heat transformed saponins (HTS) suppress p38 MAPK/NF-κB p65 signaling, lessening both inflammatory and oxidative stress burden. Combined in vivo and in vitro studies have identified a specific inhibitory effect of these saponins on the NLRP3 inflammasome, with reduced caspase-1 activation and lower maturation and secretion of interleukin 1β (IL-1β). This pattern is consistent with modulation of the NF-κB and NLRP3 axis as an important mechanism of inflammatory control within the ovarian microenvironment (Tao et al., 2024). In parallel, ginsenoside Rg3 specifically inhibits NLRP3 inflammasome activation, which reduces caspase-1 activation and decreases IL-1β maturation and secretion (Shi et al., 2020). Rare ginsenosides thereby dampen the NLRP3–caspase-1–IL-1β axis, which may in turn limit SASP amplification and inflammatory injury in ovarian tissue. Among ginseng metabolites, CK provides more direct insight into immunomodulation. In a lipopolysaccharide (LPS)-induced inflammatory model of RAW264.7 macrophages, CK selectively inhibits phosphorylation of AKT1 and downstream activation of IKKα, IKKβ and NF-κB signaling, leading to reduced expression of pro-inflammatory mediators such as IL-1β and TNF-α (Lee et al., 2019). In this setting CK reshapes innate immune responses by altering macrophage activation states and secretory profiles. Given the central role of ovarian macrophages in follicle recruitment, atresia and corpus luteum remodeling, the AKT1–IKK–NF-κB axis functions as a key signaling hub that links macrophage polarization, cytokine patterns and follicular fate, and it is a useful focus when evaluating ovarian targeted immunomodulatory actions of CK and related metabolites. In a three-dimensional ovarian follicle culture system, ginseng extract promoted follicle growth and functional maintenance, including hormone secretion, indicating a supportive effect on the ovarian microenvironment (Majdi Seghinsara et al., 2019).

Across both in vivo models and three-dimensional culture systems, ginseng combines antioxidative and anti-inflammatory effects with remodeling of the ovarian immune microenvironment. By modulating immune cell activity, cytokine networks and the SASP profile, ginseng and its active compounds may attenuate chronic inflammatory and immune activation in the ovary and help restore a microenvironment that is more favorable for long-term follicle survival. To avoid overinterpreting these findings, we distinguish between observations relevant to the ovary that suggest inflammatory remodeling of the ovarian microenvironment and mechanistic support at the pathway level derived from established immune cell systems. The latter is used to strengthen biological plausibility, but validation in the ovary is still needed. Accordingly, in the studies reviewed here, much of the mechanistic evidence for NF-κB and NLRP3 modulation is currently supported by macrophage-based inflammatory systems, including LPS-stimulated RAW264.7 cells and supporting luciferase reporter measurements, which strengthens pathway-level plausibility but still warrants deeper validation in ovary-relevant immune contexts. Evidence from ovarian aging models is emerging, for example, HTS reduced ovarian NF-κB p65 signaling and inflammatory mediators while improving estrous cyclicity and follicle related indices in cyclophosphamide induced ovarian failure models, yet the links between immune remodeling and functional reproductive outcomes remain insufficiently defined. In addition, three-dimensional follicle culture data support improved follicle growth and hormone secretion under ginseng extract exposure, but these systems lack local immune components and therefore cannot directly address immune cell dynamics. Collectively, evidence in this domain is anchored in ovary-relevant in vivo models and three-dimensional follicle culture systems, where modulation of inflammatory signaling aligns with improved ovarian indices and a more favorable follicle milieu. In contrast, pathway-level evidence derived mainly from macrophage-based inflammatory systems supports mechanistic plausibility, but it is less informative for ovary-specific immune remodeling and its links to long-term reproductive function. Therefore, future studies should prioritize ovary-based immune phenotyping and should directly characterize which immune cell populations are altered in the ovary, where they localize, and whether these changes differ across follicle stages and the corpus luteum. They should also test whether dampening inflammasome and SASP related signaling translates into maintained endocrine function and fertility outcomes during follow-up in appropriately controlled in vivo designs.

During ovarian aging, enhanced apoptosis of granulosa cells together with dysregulated autophagy drive follicular atresia and a progressive decline in ovarian reserve. Active compounds from ginseng, represented by Rg1, Rg3, Rb1, CK and GPS, mainly act through coordinated regulation of the mitochondrial apoptotic pathway and autophagy signaling. In this way they reduce the apoptotic burden on granulosa cells and help preserve their synthetic and proliferative functions.

Preclinical studies have identified convergent regulatory effects of ginsenosides such as Rg1, Rb1 and Rg3 on mitochondrial apoptosis and autophagy balance. In a hydrogen peroxide induced oxidative stress model of granulosa cells, Rg1 preserved mitochondrial function and suppressed excessively activated, deleterious mitophagy, which lowered the apoptosis rate of granulosa cells. At the molecular level, Rg1 treatment was associated with downregulation of Bax, upregulation of Bcl-2 and reduced cleaved Caspase-3, together with concordant changes in LC3 and p62 expression, a pattern consistent with appropriately regulated autophagic flux (Li X. et al., 2025). In a D-gal-induced mouse model of ovarian aging, Rg1 further downregulated Akt, mTOR and S6K at both protein and mRNA levels and increased expression of the autophagy related marker LC3-II. This profile is in line with involvement of the PI3K–Akt–mTOR autophagy pathway in the regulation of ovarian function and coincides with improvement in estrous cycle disturbances and attenuation of histological ovarian damage (Liu et al., 2020a). A separate study extended these observations to systemic aging phenotypes. Rg1 reduced the expression of senescence-associated proteins p53, p21 and p16 in ovarian tissue, with concurrent improvement in estrous cyclicity, a more physiological sex hormone profile and less histological damage, indicating that Rg1 can also buffer apoptotic stress on granulosa cells through combined antioxidative and anti-inflammatory actions (He et al., 2017). Data on Rg3 and Rb1 from different experimental models further emphasize shared features of the mitochondrial apoptosis axis. In a human granulosa cell model, Rg3 markedly inhibited mitochondria-dependent apoptosis, reduced the proportion of apoptotic cells and increased the Bcl-2 to Bax ratio, while limiting cytochrome c release. These changes were accompanied by lower ROS levels, linking its anti-apoptotic action to relief of upstream oxidative stress (Zhou P. et al., 2021). In a cyclophosphamide induced model of ovarian aging, Rb1 corrected the imbalance in Bcl-2 and Bax expression, reduced granulosa cell apoptosis and exerted protective effects on ovarian structure and function (Tang et al., 2014). CK and GPS provide complementary evidence for granulosa cell protection from the perspectives of inflammation driven apoptosis and preservation of proliferative capacity. Consistent with the pathway level evidence summarized above, in LPS-stimulated RAW264.7 macrophages, CK suppresses AKT1 phosphorylation and downstream activation of IKKα and IKKβ and NF-κB signaling, supporting the concept that attenuating inflammatory drive may indirectly reduce granulosa cell apoptosis within an aging-like ovarian microenvironment (Lee et al., 2019). GPS primarily confers functional protection by maintaining the proliferative capacity and synthetic activity of granulosa cells. Studies have reported that GPS enhances DNA synthesis in granulosa cells and counteracts stress induced proliferation arrest (Feng et al., 2007), and promotes cell proliferation with upregulation of proliferation related genes such as PCNA, CDC42 and CDK2 (Chen et al., 2025). These findings indicate that GPS helps sustain granulosa cell renewal and functional integrity during follicular development and, beyond limiting apoptosis alone, provides cellular replenishment and functional support that contribute to the maintenance of ovarian reserve.

Within this mechanistic domain, ginsenosides represented by Rg1, Rg3 and Rb1 mainly act through refined regulation of the mitochondrial apoptotic pathway and autophagy signaling to directly reduce granulosa cell death. CK mitigates inflammatory signaling and thereby offers immunological support for limiting inflammation driven apoptosis. GPS enhances synthetic and proliferative capacity and in doing so stabilizes the granulosa cell pool and supports preservation of ovarian reserve. In summary, support for this domain is derived largely from ovary-relevant in vivo models, where reduced granulosa cell apoptosis and autophagy marker patterns consistent with a balanced autophagy state are accompanied by improved follicle and endocrine indices. In contrast, evidence based mainly on short-term granulosa cell stress paradigms and static marker measurements remains more preliminary for judging whether these pathways can preserve follicle survival and fertility-relevant outcomes over time. However, the current evidence base is dominated by short-term injury models and marker-centered outcome measures, including apoptosis markers and autophagy-associated protein levels assessed in granulosa cell stress paradigms or chemotherapy-related ovarian injury settings. Such designs support mechanistic plausibility but still leave two unresolved translational questions: first, whether these pathways are engaged in a follicle stage dependent manner during physiological aging, and second, whether their modulation is sufficient to preserve follicle survival, endocrine function, and ultimately fertility relevant outcomes. Moreover, reliance on static marker abundance rather than evidence that reflects autophagic flux, together with limited dose response characterization and scarce exposure information, constrains interpretation of how mitochondrial apoptosis and autophagy regulation map onto ovarian concentrations attainable in vivo. To strengthen causal interpretation, future work should test pathway necessity in ovary-relevant settings by directly assessing granulosa cells, oocytes and ovarian stromal cells, determining whether effects differ across follicle stages and the corpus luteum, and linking apoptosis and autophagy modulation to functional outcomes such as follicle viability, hormone levels and fertility related endpoints, while incorporating exposure guided dosing wherever feasible.

Ginseng and its active compounds, particularly Rg1 and GPS, have demonstrated the ability to enhance receptor expression and promote follicle development in ovarian aging models. These effects are accompanied by improvements in hormone profiles and antioxidative status, which help recalibrate the HPO axis.

In a D-gal-induced mouse model of ovarian aging, Rg1 treatment resulted in more follicles and no signs of vacuolation, while the D-gal group exhibited fewer follicles and significant ovarian damage. E₂ levels increased, whereas FSH levels decreased. Furthermore, antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) were upregulated. These results suggest that Rg1 improves sex hormone levels and alleviates oxidative stress, thereby contributing to the restoration of ovarian function and overall health (Liu et al., 2020b). In another ovarian aging model, Rg1 significantly upregulated FSH receptor (FSHR) expression in granulosa cells, accompanied by increased serum E₂ and anti-Müllerian hormone (AMH) levels, while FSH levels decreased. Follicular development improved, with a higher number of follicles in the Rg1 group compared to controls, and fertility outcomes were enhanced. This suggests that Rg1 boosts ovarian responsiveness to gonadotropins, thereby restoring a more youthful hormonal profile and enhancing reproductive function (He et al., 2017). In vitro, ginseng extract applied to mouse preantral follicles increased the expression of FSHR and PCNA mRNA. This was associated with improved follicle survival, antrum formation, and metaphase II (MII) maturation rates. Additionally, culture supernatants from treated follicles showed elevated E₂ and progesterone (P4) levels, while oocyte ROS levels were reduced. These results support the idea that ginseng compounds directly modulate ovarian receptor expression and secretory function, promoting healthier ovarian function (Majdi Seghinsara et al., 2019). GPS further enhances ovarian function by regulating steroidogenesis and second-messenger signaling. In bovine granulosa cells, GPS enhanced E₂ secretion and increased the levels of steroidogenic enzymes, such as CYP11A1, CYP19A1, 3β-HSD, and STAR. This suggests that GPS promotes estrogen biosynthesis, contributing to the restoration of hormone balance in the ovarian microenvironment (Chen et al., 2025). In a rat in vitro human chorionic gonadotropin (hCG) stimulation system, GPS suppressed progesterone production in luteal cells and enhanced progesterone secretion in granulosa cells. It also increased cyclic AMP (cAMP) levels, suggesting bidirectional modulation of ovarian responsiveness downstream of the HPO axis (Sun et al., 2007). In a rat model of estrogen decline induced by ovariectomy, intragastric administration of ginseng decoction prolonged the estrous phase, increased the uterine index, and raised serum E₂ levels while lowering LH. Metabolomic analysis revealed significant changes in several biomarkers, with pathway analysis indicating alterations in steroid hormone metabolism, fatty acid biosynthesis, the tricarboxylic acid cycle, and tryptophan metabolism. These findings suggest that ginseng corrects system-level metabolic changes associated with estrogen loss, offering a promising approach to mitigating the effects of ovarian aging (Lin et al., 2018).

Collectively, these findings indicate that ginseng and its active compounds function as multi-level modulators of the HPO axis, integrating improved receptor expression, steroidogenesis, antioxidant defenses, and systemic metabolism to partially rejuvenate the ovarian microenvironment and mitigate the endocrine and reproductive consequences of ovarian aging. However, the current support relies largely on changes in circulating hormones together with ovarian receptor and steroidogenic markers, while evidence directly characterizing hypothalamic or pituitary signaling responses remains scarce. On balance, the strongest support for HPO-axis modulation comes from in vivo studies that combine circulating hormone shifts with ovary-level receptor and steroidogenic changes, and, where reported, improvements in cycle regularity or ovulation-related measures. In contrast, evidence is less definitive when it is limited to serum hormone changes and ovarian marker expression without direct characterization of hypothalamic or pituitary signaling dynamics. In vitro follicle and granulosa cell data help substantiate direct ovarian actions, but differences in preparation definition and exposure reporting constrain cross-study interpretation. Accordingly, future studies should link endocrine shifts to functional endpoints such as ovulation and fertility outcomes, and integrate ovary-relevant receptor and steroidogenic assessments with exposure-informed study designs to clarify dose–response relationships along the HPO axis.

Chronic estrogen deficiency due to ovarian aging is a major contributor to various long-term comorbidities affecting multiple organ systems. Clinical management of ovarian aging should not be limited to immediate fertility or menstrual concerns, but should also incorporate long-term strategies to prevent downstream comorbidities. Accordingly, structured follow-up should be considered for key clinical measures closely linked to these risks, such as bone health indicators relevant to osteoporosis prevention, glycemic control measures and parameters related to metabolic syndrome and cardiovascular risk markers, to integrate symptom management with comorbidity prevention. Given the central role of estrogen decline in skeletal remodeling, accelerated bone loss and osteoporosis risk often represent an early, clinically relevant, and preventable consequence of ovarian aging. In the skeletal system, imbalances in RANKL/OPG, combined with oxidative stress and mitochondrial dysfunction, contribute to bone loss and increase the risk of fragility fractures (Zhao et al., 2025; Azizieh et al., 2019; Zhang C. et al., 2023). In the cardiovascular system, reduced endothelial nitric oxide (NO) bioavailability, adverse lipid profiles, and persistent low-grade inflammation accelerate atherosclerosis development (Nair et al., 2021; Somani et al., 2019). In the nervous system, diminished estrogenic support for synaptic plasticity and mitochondrial energy metabolism, compounded by oxidative and inflammatory stress, heightens the risk of cognitive decline and related impairments (Hara et al., 2015; Lejri et al., 2018; McCarthy and Raval, 2020). At the metabolic and muscular levels, estrogen deficiency associated with ovarian aging predisposes to insulin resistance and fat redistribution and disrupts mitochondrial homeostasis. These alterations are closely linked to the development of metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and phenotypes such as sarcopenia and frailty (Eng et al., 2023; Camon et al., 2024; Feng et al., 2024; Chen et al., 2023).

In the skeletal system, the ginseng metabolite CK inhibited RANKL-induced osteoclastogenesis and reduced oxidative stress in ovariectomized (OVX) models, leading to improved bone mass and trabecular microarchitecture (Ding et al., 2023). Similarly, Rc increased bone mass and improved bone structure in OVX mice (Yang et al., 2022), while Re suppressed osteoclast differentiation, further indicating that ginseng compounds can effectively limit bone loss (Park et al., 2016). In the cardiovascular system, Rb1 enhanced nitric oxide (NO) signaling, thereby protecting endothelial function via the GPER–PI3K–Akt pathway (Yang et al., 2019). Rg1 further promoted endothelial nitric oxide synthase (eNOS) activity, which increased NO production and improved vascular reactivity, reinforcing its potential as a therapeutic target for postmenopausal atherogenesis (Zhang et al., 2025). In the nervous system, Rg1 improved learning and memory, reduced hippocampal neuronal apoptosis, and lowered the accumulation of pathological proteins in models of vascular cognitive impairment and Alzheimer’s disease. These neuroprotective effects were associated with the activation of estrogen-related signaling pathways, including GPR30 (Shen et al., 2021; Li et al., 2016). Moreover, long-term administration of ginseng water extract reshaped the gut microbiota in naturally aged mice, and fecal microbiota transplantation from ginseng-treated donors alleviated markers of age-related brain damage. This highlights the potential neuroprotective effects of ginseng, which may be mediated through modulation of the microbiota–gut–brain axis (Lin et al., 2024). In terms of metabolism and muscle function, Rb1 activated AMP-activated protein kinase (AMPK), improving insulin sensitivity and correcting lipid metabolism (Shen et al., 2015; Zou et al., 2022). CK reduced inflammation, alleviated hepatic steatosis, and improved insulin resistance in models of high-fat diet-induced obesity, type 2 diabetes (T2DM), and NAFLD (Xu J. et al., 2022; Wei et al., 2015). Additionally, Rc mitigated muscle atrophy induced by oxidative stress and promoted mitochondrial biogenesis, suggesting that ginseng compounds provide protection across a broad spectrum of aging-related disorders, from sarcopenia to frailty (Kim et al., 2023).

Collectively, these studies suggest that ginseng-related compounds may mitigate a range of estrogen deficiency–associated systemic phenotypes, spanning bone remodeling, endothelial function, neurocognitive performance, and metabolic homeostasis. However, much of the evidence is derived from OVX models or organ-specific disease models, and the reported benefits are often based on heterogeneous outcome measures rather than clinically anchored endpoints. In practical terms, the strongest support comes from in vivo models where ginseng-related interventions improve organ-level functional measures, such as bone structural parameters, vascular function, metabolic indices, or cognition-related performance. In contrast, when findings are based on diverse measures across different OVX or organ-specific disease models, interpretation requires more context, and cross-model generalization to systemic benefit in ovarian aging is naturally more constrained. Accordingly, future work should prioritize designs that incorporate clinically meaningful outcomes such as bone density and strength, vascular function and atherosclerotic burden, cognition-related performance, and metabolic indices, while also clarifying dose–exposure relationships and safety considerations under real-world polypharmacy conditions.