Emerging and underexplored ginsenosides in cancer therapy (2020–2025): Beyond cytotoxic mechanisms

Abstract

Ginsenosides from Panax plants have long been studied as potential anticancer agents. In earlier years, most research focused on a few well-known ginsenosides that showed strong direct cytotoxicity, such as Rg3 and Rh2. As a result, many other ginsenosides were considered less active and received limited attention. However, studies published between 2020 and 2025 indicate that several previously underexplored ginsenosides also exhibit meaningful anticancer activity. These compounds often do not function as strongly cytotoxic agents. Instead, they act through broader and more indirect mechanisms. Many regulate tumor metabolism, oxidative stress, immune responses, and drug resistance. Others enhance drug delivery or protect normal tissues from chemotherapy- or radiotherapy-related toxicity.

This review focuses on these emerging and underexplored ginsenosides, including protopanaxatriol (PPT)-type compounds (Rg1, Rg2, Rh1, Rh4, Re, Rf, and F1) and protopanaxadiol (PPD)-type compounds (Rg5, Rk1, F2, Rc, Rg6, Rb3, Rb2, and Rp1). We summarize recent studies according to cancer type, treatment setting, and therapeutic role. Across these compounds, a consistent pattern emerges: their benefits arise mainly from supportive and regulatory functions rather than from direct cytotoxic effects.

Overall, many ginsenosides appear more effective as combination partners or therapeutic adjuvants than as standalone anticancer drugs. Understanding these broader roles may help guide future research and clinical development of ginsenoside-based cancer therapies.

Graphical abstract

1. Introduction

Ginseng is a traditionally valuable herbal plant with a variety of pharmacological activities such as anti-inflammatory, anticancer, anti-fatigue, anti-aging, antifungal, antibacterial, antiviral, immune-booster, antidiabetic, anti-menopause, and antioxidant activities [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]]. Ginsenosides are major compounds found in Asian ginseng (Panax ginseng) and American ginseng (Panax quinquefolius) [[16], [17], [18], [19]]. They are triterpenoid saponins and are considered the main bioactive principles of ginseng [7,20,21]. For many years, ginseng has been used in traditional medicine to improve vitality, reduce inflammation, and support recovery from illness [22,23]. Modern research has shown that ginsenosides also have antioxidant, immunomodulatory, metabolic, neuroprotective, cardioprotective, and anticancer activities [16,[24], [25], [26], [27], [28], [29], [30], [31], [32], [33]]. Because of these diverse effects, ginsenosides have attracted sustained interest as potential anticancer agents. Chemically, ginsenosides are usually divided into two main groups based on their aglycone backbone structures: protopanaxatriol (PPT) type and protopanaxadiol (PPD) type [[34], [35], [36], [37], [38]]. PPT-type ginsenosides include Rg1, Rg2, Rh1, Rh4, Re, Rf, and F1. PPD-type ginsenosides include Rg3, Rh2, Rb1, Rd, Rg5, Rk1, Rg6, Rb3, Rb2, Rc, Rp1, and F2. Although these structural differences appear small, they strongly influence biological behavior. They affect solubility, membrane permeability, metabolic stability, transport across tissues, and target binding. As a result, each ginsenoside can show very different pharmacological effects, even though they share a similar core structure [23,28,[39], [40], [41], [42], [43], [44], [45], [46], [47]].

For many years, cancer research on ginsenosides followed a simple and direct strategy. Researchers mainly tested whether a compound could directly inhibit cancer cell growth in vitro [20,25,48]. If a ginsenoside induced strong apoptosis or reduced cell proliferation, it was considered promising. If the effect was limited, it often received little further attention. Because of this approach, only a small number of ginsenosides became widely studied. In particular, Rg3 and Rh2 showed clear cytotoxic and antiproliferative effects in many tumor cell lines [29,49,50]. These compounds induced apoptosis, blocked cell-cycle progression, and suppressed tumor growth in xenograft models [16,20,51,52]. As a result, they became the most intensively investigated ginsenosides and the focus of many reviews and mechanistic studies. This research pattern created a strong bias in the field. Most studies equated anticancer activity with direct cytotoxicity. Compounds that did not show strong cytotoxic effects were often considered less effective or of lower priority [7,34,36,37]. Consequently, many other ginsenosides were classified as “minor” or “secondary,” even though their broader biological activities had not been fully examined.

However, our understanding of cancer has evolved significantly over the past decade. Tumors are now recognized as complex tissues rather than simple masses of rapidly dividing cells. A tumor contains not only malignant cells, but also immune cells, fibroblasts, blood vessels, extracellular matrix, and even microbiota. These surrounding components strongly influence tumor growth, metastasis, and response to therapy [16,24,34,35,[51], [52], [53], [54]]. At the same time, clinical outcomes are often limited by factors such as drug resistance, metabolic adaptation, inflammation, and treatment-related toxicity, sometimes more than by how sensitive the cancer cells are to treatment [51,52,55,56]. Because of this broader understanding, the definition of an effective anticancer agent has also expanded. Today, a useful compound does not need to act only through direct cytotoxicity. It may also function by enhancing immune responses, modulating tumor metabolism, overcoming drug resistance, improving drug delivery, or protecting normal tissues from treatment-related damage [2,17,57].

In modern oncology, supportive and regulatory effects can be as important as direct cytotoxicity. Since around 2020, this broader perspective has increasingly influenced ginsenoside research. More studies have begun to examine compounds that were previously overlooked or considered secondary. Interestingly, many of these underexplored ginsenosides show meaningful anticancer activity, even though they are not strongly cytotoxic [38]. Some compounds regulate oxidative stress and cellular redox balance. Others modulate glucose or glutamine metabolism. Some induce ferroptosis or autophagy. Others enhance immune cell function or reduce inflammation [7,36,37]. Several ginsenosides also improve chemotherapy sensitivity or reduce treatment-related toxicities, including cardiotoxicity, nephrotoxicity, and gastrointestinal injury. This imbalance in historical research focus and the recent expansion toward underexplored ginsenosides are visually summarized in Fig. 1, Fig. 2.

Fig. 1.

Distribution of PPT- and PPD-type ginsenosides discussed in this review. This figure illustrates the structural classification and research emphasis of the ginsenosides analyzed in this review. Ginsenosides are divided into protopanaxatriol (PPT)-type and protopanaxadiol (PPD)-type compounds based on their aglycone backbone structures. Historically well-studied ginsenosides with strong cytotoxic activity (e.g., Rg3, Rh2, Rb1, Rd, and compound K) are indicated separately to highlight prior research focus. In contrast, the present review emphasizes emerging and underexplored PPT-type ginsenosides (Rg1, Rg2, Rh1, Rh4, Re, Rf, and F1) and PPD-type ginsenosides (Rg5, Rk1, F2, Rc, Rg6, Rb3, Rb2, and Rp1). The schematic reflects relative research attention rather than precise bibliometric quantification and highlights the shift toward broader functional roles beyond direct cytotoxicity.

Fig. 2.

Relative research attention across ginsenosides discussed in this review. This summarizes the relative research attention devoted to individual ginsenosides discussed in this review, based on the frequency of cancer-related studies reported in the literature. Compounds are grouped according to PPT- or PPD-type classification, and approximate proportions are shown to reflect comparative research intensity rather than exact publication counts. This visualization highlights the disproportionate focus on a limited number of ginsenosides in earlier studies and illustrates the increasing attention given to previously underexplored compounds in the 2020s.

At first glance, these effects may appear indirect. However, they closely address key clinical challenges in cancer therapy. Overcoming drug resistance, reducing side effects, and improving treatment tolerance are critical for patient survival and quality of life. Therefore, ginsenosides that act as combination partners or supportive agents may have substantial translational value, even when their single-agent cytotoxicity is modest. These trends suggest that the field is moving in a new direction. The focus is gradually shifting from “Which compound shows the strongest cytotoxicity?” to “Which compound best supports therapy and improves overall outcomes?”

Based on this concept, the present review adopts a different strategy from many earlier reviews. Instead of re-summarizing well-established ginsenosides such as Rg3, Rh2, Rb1, and Rd, which have already been extensively discussed, we focus on emerging and underexplored compounds that have gained attention during 2020–2025 [16,18,19,[58], [59], [60]]. These include PPT-type ginsenosides (Rg1, Rg2, Rh1, Rh4, Re, Rf, and F1) and PPD-type ginsenosides (Rg5, Rk1, F2, Rc, Rg6, Rb3, Rb2, and Rp1) (Fig. 1, Fig. 2).

To better understand recent trends, we group these ginsenosides according to how extensively they have been studied. First, we discuss highly investigated compounds such as Rg1 and Rg5. Next, we review moderately studied compounds, including Rh1, Rh4, and Rk1. We then summarize third-tier or formulation-dependent components such as Rg2, F2, Re, and Rc. Finally, we examine minimally studied ginsenosides, including Rf, F1, Rg6, Rb3, Rb2, and Rp1, which may represent future research opportunities. For each group, we focus on several practical questions. Which cancer types have been evaluated? What mechanisms have been reported? Do these compounds act mainly as single agents or in combination with other therapies? Do they regulate metabolism, immunity, drug resistance, or treatment-related toxicity? By organizing the literature in this structured way, we aim to provide a clear and accessible evidence map of recent progress.

Our goal is straightforward. We show that many ginsenosides are more effective as supportive or combination agents than as conventional cytotoxic drugs [25,45]. By emphasizing these broader and more clinically relevant roles, we hope to guide future research toward more practical and translational strategies for developing ginsenoside-based cancer therapies. To provide an overview of the ginsenosides discussed in this review, including their structural classification, research intensity, dominant mechanisms, and functional roles in cancer therapy, we summarize key features of each compound in Table 1. These include PPD-type ginsenosides (Rg5, Rk1, F2, Rc, Rg6, Rb3, Rb2, and Rp1) and PPT-type ginsenosides (Rg1, Rg2, Rh1, Rh4, Re, Rf, and F1), whose structural classification and relative research emphasis are summarized in Fig. 1. Together, Fig. 1, Fig. 2, Fig. 3 provide a structural, bibliographic, and conceptual overview of the emerging roles of underexplored ginsenosides addressed in this review. Fig. 3 summarizes representative ginsenosides based on research intensity and dominant therapeutic roles, highlighting the shift from direct cytotoxicity toward supportive and combination-oriented functions.

Table 1.

Classification, research intensity, and functional positioning of emerging ginsenosides (2020–2025).

Ginsenoside	Type	Research Tier in This Review	Dominant Mechanistic Focus (2020–2025)	Primary Functional Role	Representative Cancer Contexts
Rg1	PPT	Highly studied	Metabolic regulation, chemosensitization, immune support, oxidative balance	Mixed (supportive-dominant)	Breast, lung, colorectal
Rg5	PPD	Highly studied	PI3K/Akt inhibition, resistance reversal, ferroptosis, combination therapy	Cytotoxic + combination enhancer	Breast, gastric, lung, hematologic
Rh1	PPT	Moderately studied	Metastasis suppression, immune modulation, endothelial protection	Host-modulating/anti-metastatic	Breast, lung, liver
Rh4	PPT	Moderately studied	Immunometabolic regulation, ferroptosis, microbiota remodeling	Tumor + immune regulator	Colorectal, liver, lung
Rk1	PPD	Moderately studied	Metabolic stress targeting, glutamine inhibition, AMPK/mTOR modulation	Metabolic vulnerability targeting	Liver, lung, gastric
Rg2	PPT	Third-tier	ROS-mediated apoptosis, AMPK activation, cardioprotection	Supportive + moderate tumor suppression	Breast
F2	PPD	Third-tier	Mitochondrial dysfunction, STAT3 inhibition, ferroptosis synergy	Metabolic cytotoxic + combination	Glioblastoma, liver
Re	PPT	Formulation-dependent	Macrophage modulation, metastasis control, tolerance improvement	Supportive/formulation component	Lung, melanoma
Rc	PPD	Formulation-dependent	Vascular targeting, tissue protection, cooperative apoptosis	Supportive/vascular modulator	Colorectal, liver
Rg6	PPD	Minor	Chemoresistance reversal, autophagy induction	Resistance modifier	Ovarian
Rb3	PPD	Minor	Nephroprotection, Hsp90 inhibition	Organ-protective adjunct	Lung, chemotherapy models
Rp1	PPD	Minor	Microenvironment regulation, AKT/SIRT1 inhibition	Immune–resistance regulator	Radiation, resistant tumors
Rb2	PPD	Minor	Pharmacokinetic support, vascular accumulation, metabolic regulation	Distribution enhancer/supportive	Colorectal, metabolic context
Rf	PPT	Minor	Neuroprotective and stress signaling	Supportive/stress-related	Indirect oncologic relevance
F1	PPT	Minor	Immune modulation	Immunologic adjunct candidate	Emerging

Fig. 3.

Relationship between research intensity and dominant therapeutic roles of representative ginsenosides in cancer studies. This schematic positions selected s according to their relative research intensity during 2020–2025 (horizontal axis) and their dominant therapeutic role in cancer (vertical axis). Classical ginsenosides such as Rg3 and Rh2 cluster near direct cytotoxicity, reflecting early research emphasis on tumor cell killing. In contrast, ginsenosides emphasized in this review—such as Rg1, Rg5, Rh1, Rh4, and Rk1—are positioned toward combination or context-dependent roles, where anticancer benefit arises from modulation of metabolism, immunity, resistance, or treatment tolerance rather than strong single-agent cytotoxicity. Placement reflects dominant roles emphasized in the 2020s literature rather than intrinsic cytotoxic potency. Ginsenosides with predominantly formulation-dependent or cooperative roles (e.g., Re, Rc, and F2) are intentionally not shown to maintain conceptual clarity and are discussed in detail elsewhere in the text and summarized in Table 1, Table 2

2. Rg1 (PPT-type): the most extensively studied compound in the recent research landscape

Recent studies indicate that Rg1 exerts multiple and diverse anticancer effects. Rather than acting mainly through tumor cell death, Rg1 regulates several supportive pathways. It modulates tumor metabolism, reduces oxidative stress, enhances immune responses, improves drug sensitivity, and influences the tumor microenvironment. Because of these broad and coordinated actions, Rg1 functions more as a supportive anticancer modulator than as a conventional cytotoxic agent. [[61], [62], [63], [64]]. As shown in Fig. 2, ginsenoside Rg1 is among the most frequently investigated PPT-type compounds in recent cancer research, justifying its detailed discussion as a leading example of emerging, non-cytotoxic ginsenoside activity.

2.1. Direct antitumor effects on cell cycle, apoptosis, and autophagy

In this context, autophagy is considered a direct antitumor mechanism when it contributes to cell death rather than cytoprotective survival. Several studies indicate that Rg1 directly interferes with cancer cell proliferation by disrupting cell cycle progression and mitotic fidelity. Mechanistically, Rg1 inhibits Haspin kinase–mediated phosphorylation of histone H3 at Thr3, a crucial modification required for chromosomal passenger complex (CPC) recruitment and Aurora B centromere localization during mitosis. Inhibition of this pathway results in chromosome misalignment, spindle instability, prolonged mitotic arrest, and reduced clonogenic survival across multiple cancer cell types, highlighting a novel and noncanonical anticancer mechanism of Rg1 distinct from classical apoptotic pathways [65]. In parallel, Rg1 induces mitochondria-dependent apoptosis through enhanced reactive oxygen species (ROS) generation, mitochondrial membrane potential collapse, and activation of DNA damage responses. These effects are particularly evident in aggressive malignancies such as triple-negative breast cancer (TNBC), where Rg1 suppresses tumor cell proliferation, invasion, angiogenesis, and epithelial–mesenchymal transition (EMT) in vitro, while significantly inhibiting mammary tumorigenesis in DMBA-induced in vivo models [66]. Notably, Rg1 reduces oxidative stress in normal tissues while maintaining apoptosis in tumor cells, indicating good safety and therapeutic benefit. Beyond apoptosis, Rg1 is also capable of inducing autophagic cell death, particularly in colorectal cancer models. Rg1 activates autophagy markers LC3 and Beclin-1 and suppresses AKT/mTOR/p70S6K signaling, with pharmacological inhibition of autophagy partially reversing its antitumor effects. These findings indicate that Rg1 can activate multiple programmed cell death pathways in a tumor-context–dependent manner [67].

2.2. Chemosensitization and protection of normal tissues

One of the most clinically relevant properties of Rg1 is its function as a chemosensitizer. In TNBC models, Rg1 markedly enhances the efficacy of doxorubicin by amplifying ROS accumulation, mitochondrial dysfunction, and DNA damage signaling, while simultaneously reducing cytotoxicity in normal mammary epithelial cells [28,[68], [69], [70], [71]]. This dual effect may reduce the toxicity that limits the safe dose of anthracycline chemotherapy. Nanotechnology-based strategies further extend this concept. Rg1 enables the formation of self-assembled Dox@Rg1 nanoparticles, which improve tumor-targeted drug delivery and significantly attenuate doxorubicin-induced cardiotoxicity by suppressing cardiomyocyte apoptosis. These findings suggest that Rg1 provides both chemosensitizing and cardioprotective effects [72].

Within modernized traditional Chinese medicine–derived injectable formulations—including Aidi, Kangai, and Shengmai injections—Rg1 functions as an active ginseng-derived component that enhances chemotherapy responsiveness while mitigating treatment-related toxicities. Recent systematic reviews and meta-analyses published in the 2020s across lung, liver, and colorectal cancers consistently demonstrate that these Rg1-containing adjunctive regimens improve objective response rates, prolong survival, enhance immune recovery, and reduce chemotherapy- or radiotherapy-associated adverse effects. Nevertheless, most studies remain small or heterogeneous, underscoring the continued need for rigorously designed, large-scale randomized controlled trials to confirm clinical benefit [63,[73], [74], [75]].

2.3. Targeting cancer stemness and drug resistance

Drug resistance represents a critical obstacle in cancer therapy, and emerging data indicate that Rg1 may help overcome resistance at multiple levels. In acute myeloid leukemia, Rg1 suppresses leukemia stem cell (LSC) proliferation, induces G0/G1 arrest, and promotes cellular senescence in CD34+CD38⁻cells through modulation of the SIRT1/TSC2 signaling axis, identifying Rg1 as a potential stemness-targeting agent [76].

Pharmacokinetic analyses further reveal that Rg1 is a substrate of the efflux transporter breast cancer resistance protein (BCRP), and that its intracellular transport can be modulated by coexisting herbal components. These transporter-level interactions provide a mechanistic explanation for improved intracellular retention and synergistic efficacy of Rg1 when administered as part of multi-component formulations, particularly in drug-resistant tumors [77].

2.4. Immunomodulation and tumor microenvironment remodeling

Unlike conventional cytotoxic agents, Rg1 exerts profound effects on the immune system and tumor microenvironment. Rg1 suppresses differentiation of myeloid-derived suppressor cells (MDSCs) by inhibiting the mTOR/S6K1/Myc pathway, thereby alleviating tumor-induced immunosuppression and reducing tumor growth and metastasis in lung cancer models [78].

Rg1 also counteracts chronic stress–induced immunosuppression by restoring granulocyte migration, cytotoxicity, and transcriptional programs disrupted by noradrenaline signaling. These findings are particularly relevant for cancer patients experiencing long-term psychological or physiological stress, suggesting a supportive role for Rg1 in maintaining antitumor immune competence [79]. At the adaptive immune level, Rg1 enhances T-cell activation, mitochondrial biogenesis, and metabolic fitness during ex vivo expansion, resulting in improved antitumor efficacy of both conventional T cells and CAR-T cells. These data support the use of Rg1 as a functional additive in adoptive cell therapy protocols to improve cytotoxicity and persistence [80].

2.5. Synergy with immunotherapy and microbiota regulation

Recent studies highlight the ability of Rg1 to sensitize tumors to immune checkpoint blockade. In microsatellite-stable colorectal cancer, Rg1 overcomes programmed cell death protein 1 (PD-1) resistance by enhancing dendritic cell antigen processing and maturation, thereby increasing cytotoxic T-cell infiltration and tumor recognition. Delivery via apoptotic body–coated nanoparticles further amplifies these effects, enabling robust sensitization of otherwise PD-1–refractory tumors [81].

Rg1 also modulates antitumor immunity indirectly through gut microbiota remodeling. By enriching beneficial gut bacteria such as Lachnospiraceae, restoring intestinal barrier integrity, and normalizing cytokine balance, Rg1 improves systemic immune homeostasis and reinforces host antitumor responses [82].

2.6. Anti-metastatic activity and nano-delivery strategies

Metastasis suppression represents another emerging dimension of Rg1 activity. Rg1 inhibits neutrophil extracellular trap (NET) formation and reverses NET-mediated protumor effects, thereby suppressing metastatic dissemination. Synergistic combinations with cryptotanshinone further enhance this anti-metastatic efficacy, supporting rational design of multi-compound regimens targeting metastatic niches [83].

Beyond its direct tumor effects, Rg1 can also be incorporated into nanomaterial-based delivery systems. These include pH-responsive nanohydrogels, carbon nanodots, and combination nanotherapies. Such formulations improve tumor suppression while maintaining low toxicity [84,85].

2.7. Clinical and translational perspective on Rg1

Together, these studies show that Rg1 acts as a broad and supportive anticancer modulator. In addition to directly suppressing tumor growth, Rg1 enhances immune responses, improves chemotherapy sensitivity, and reduces treatment-related toxicity. Rather than replacing strongly cytotoxic ginsenosides, Rg1 works best as a complementary partner that helps overcome resistance and improves treatment tolerability. These features make Rg1 a practical candidate for combination therapies, especially in drug-resistant or toxicity-limited cancers.

3. Rg5 (PPD-type)

Fig. 2 further illustrates that Rg5 has become one of the most extensively discussed PPD-type ginsenosides in recent literature, particularly within the scope of this review, supporting its focused analysis in this section.

3.1. Direct tumor suppression mechanisms

Across many solid and hematologic cancers, ginsenoside Rg5 shows consistent and strong antitumor activity. Its main actions include inhibition of the PI3K/AKT/mTOR pathway, induction of apoptosis and autophagy, and disruption of the cell cycle [[86], [87], [88], [89]]. Compared with earlier ginsenosides that often show weak or mainly growth-suppressive effects, Rg5 demonstrates broader and more robust activity in breast, gastric, liver, lung, cervical, prostate, osteosarcoma, glioblastoma, and blood cancer models. For this reason, Rg5 is one of the most actively studied minor ginsenosides in recent years [90].

In breast cancer, Rg5 promotes mitochondria-dependent apoptosis together with autophagic cell death. It increases Bax/Bak activation, caspase-3 cleavage, and LC3 lipidation, and enhances autophagosome–lysosome fusion. These changes occur alongside suppression of PI3K/AKT/mTOR signaling, suggesting that this pathway is a key upstream target [86]. Importantly, the autophagy induced by Rg5 supports cell death rather than survival, indicating a coordinated death program instead of a protective response.

In gastric cancer, Rg5 shows stronger inhibition of cell growth and migration than Rg3 in direct comparisons, while causing less toxicity to normal gastric epithelial cells. Rg5 induces S-phase arrest by decreasing Cyclin A1, CDK2, and PCNA and increasing p21. It also reduces invasion by suppressing MMP-2 and MMP-9. In addition, Rg5 inhibits Notch1 signaling, which is linked to gastric cancer stemness and progression. This suggests that Rg5 affects multiple cancer-related pathways beyond PI3K/AKT alone [87].

In osteosarcoma, both laboratory studies and network analyses point to PI3K/AKT/mTORC1 inhibition as a central mechanism. Rg5 reduces cell proliferation, activates LC3-dependent autophagy, and induces caspase-3–mediated apoptosis in a dose-dependent manner [89]. Computational analyses further suggest that Rg5 interacts with several targets, including PIK3CA, MAPK1, EGFR, SRC, TP53, and VEGFA [88]. These findings indicate that Rg5 acts on multiple pathways rather than a single molecular target.

Rg5 also shows activity in hematologic cancers. In chronic myeloid leukemia, it enhances the effect of imatinib, suppresses K562 cell growth, increases apoptosis, and induces G0/G1 arrest. These effects are again associated with PI3K/AKT/mTOR inhibition and a shift in the Bcl-2/Bax balance toward apoptosis [91]. This supports the use of Rg5 as a combination partner in targeted therapies.

Finally, transcriptomic studies in cervical cancer show that Rg5 downregulates genes involved in DNA replication and cell-cycle progression, including MCM6, CCNA2, CDK6, and CDC6. This leads to strong suppression of cell proliferation. MCM6 in particular may represent a useful therapeutic target [92].

3.2. Combination therapy and resistance-focused roles

A major focus of Rg5 research in the 2020s is its ability to improve chemotherapy response and overcome drug resistance. Several studies show that Rg5 works best in combination with existing anticancer drugs rather than as a single agent. One clear example is reversal of ABCB1-mediated multidrug resistance (MDR). Rg5 increases the intracellular accumulation of chemotherapeutic drugs without reducing ABCB1 expression. Instead, it directly interacts with the ABCB1 drug-binding pocket and alters ATPase activity. Rg5 also suppresses downstream AKT/Nrf2 signaling. In docetaxel-resistant tumor models, these effects significantly enhance drug efficacy in vivo while maintaining low systemic toxicity [93]. These results support the use of Rg5 as an MDR-targeting combination partner. Rg5 shows similar benefits in paclitaxel-resistant cervical cancer. It promotes mitochondrial apoptosis and inhibits AKT and NF-κB signaling. By blocking these survival and inflammatory pathways, Rg5 restores paclitaxel sensitivity without adding substantial toxicity [94].

In estrogen receptor–positive breast cancer, Rg5 also helps overcome resistance to CDK4/6 inhibitors. When combined with abemaciclib, Rg5 suppresses PI3K/AKT signaling and disrupts the HSP90–CDC37 chaperone complex. This leads to proteasomal degradation of CDK2, CDK4, and CDK6. As a result, cell-cycle arrest and apoptosis are enhanced. This mechanism suggests that targeting protein stability may be another practical strategy for overcoming resistance to targeted therapies [95].

3.3. Radiotherapy sensitization and tissue-protective effects

Rg5 has also been studied as a radiosensitizer, especially in lung adenocarcinoma. It enhances the effects of radiation by increasing DNA damage, apoptosis, and G1 cell-cycle arrest in both cell and animal models. Mechanistically, Rg5 directly binds HSP90α and disrupts the HSP90–CDC37 complex. This destabilizes pro-survival proteins and suppresses autophagy signaling, which normally helps cancer cells resist radiation. As a result, tumor cells become more sensitive to radiotherapy [96].

At the same time, Rg5 shows protective effects in normal tissues exposed to radiation. In models of radiation-induced lung endothelial injury, Rg5 reduces oxidative stress, apoptosis, and mitochondrial dysfunction. These effects are linked to Sirt1-dependent deacetylation of Mfn2, which helps maintain normal mitochondrial function and preserves endothelial barrier integrity [97]. Importantly, Rg5 sensitizes tumors to radiation while protecting normal tissues. This dual effect may improve the therapeutic window and makes Rg5 a promising adjunct for radiotherapy.

3.4. Ferroptosis induction and emerging therapeutic strategies

In addition to apoptosis and autophagy, Rg5 can also induce ferroptosis, a form of iron-dependent cell death that is important in therapy-resistant tumors. This expands the range of mechanisms through which Rg5 suppresses cancer growth. In glioblastoma, Rg5 reduces the malignant behavior of glioma stem cells by activating ferroptosis. It directly targets NR3C1 and regulates ferroptosis-related genes, including HSPB1 and NCOA4. These changes promote lipid peroxidation and cell death, leading to reduced tumor initiation, invasion, stemness, and intracranial tumor growth [98]. These findings suggest that Rg5 targets both cancer metabolism and stem-cell–like populations, which are often responsible for recurrence and treatment resistance. This makes Rg5 a promising candidate for treating aggressive and refractory tumors.

3.5. Drug delivery systems and formulation strategies

Rg5 is increasingly used in drug-delivery systems in addition to its direct anticancer activity. Because it has both hydrophilic and hydrophobic properties, Rg5 can be easily incorporated into nanocarriers and micelles, where it helps improve drug stability and delivery. One example is a paclitaxel–Rg5 polymeric micelle formulation. This system increases paclitaxel solubility and improves tumor targeting in prostate cancer models. It also enhances antitumor efficacy while reducing side effects. Importantly, Rg5 acts not only as a carrier component but also as an active sensitizer. The formulation reduces inflammation, neurotoxicity, and drug resistance, leading to better overall treatment response [99].

3.6. Safety and translational considerations

Clinical data for Rg5 are still limited, but preclinical safety results are reassuring. Black ginseng extract, in which Rg5 is a major active component, shows no obvious toxicity in animal studies. In a 28-day repeated oral dosing study in rats, no adverse effects were observed at doses up to 2000 mg/kg. This dose was defined as the no-observed-adverse-effect level [100]. These findings suggest that Rg5-containing formulations are generally well tolerated and suitable for further development.

However, careful interpretation is still needed. At least one published study on the anticancer effects of Rg5 has been formally retracted. This highlights the importance of independent validation and reproducible experiments before drawing strong conclusions [101]. Recent reviews describe Rg5 as a promising anticancer candidate, but they also note several gaps. More work is needed to clarify its clinical efficacy, pharmacokinetics, and structure–activity relationships [90]. These factors are essential for translating preclinical findings into clinical use.

Encouragingly, chemical modification may improve the properties of Rg5. For example, hydrogenated Rg5 shows better thermal stability and enhanced biological activity in other disease models, such as NASH, through STING–TBK1–IRF3 pathway inhibition [102]. Although this work is outside oncology, it suggests that stability and formulation engineering could also improve Rg5-based anticancer therapies.

4. Rh1 and Rh4 (PPT-type) and Rk1 (PPD-type): moderately studied compounds in recent research

Beyond Rg1 and Rg5, Fig. 2 reveals a second tier of ginsenosides with growing but more moderate research attention, including Rh1, Rh4, and Rk1, which are discussed in the following section.

4.1. Ginsenoside Rh1 (PPT-type): metastasis control and immune regulation

Compared with Rh4, ginsenoside Rh1 shows a different anticancer pattern. Its main effects are not strong tumor cell killing. Instead, Rh1 mainly regulates metastasis, vascular integrity, immunity, and stress-related tumor progression. This makes Rh1 a host-modulating ginsenoside that may be especially useful in metastatic disease and stress-associated cancer progression [103] [104,105].

At the tumor-cell level, Rh1 shows moderate cytotoxicity but clear anti-invasive activity. In breast cancer, Rh1 increases ROS and induces apoptosis and autophagy by inhibiting PI3K/AKT signaling. These changes suppress tumor growth in vivo [103]. In TNBC, Rh1 mainly reduces migration and invasion rather than proliferation. Increased mitochondrial ROS inhibits signal transducer and activator of transcription 3 (STAT3) phosphorylation and NF-κB activation, leading to reduced MMP2, MMP9, and VEGF-A expression [104,105]. These effects limit invasion, angiogenesis, and metastatic spread. Thus, Rh1 appears to target metastatic behavior more than primary tumor size.

A key feature of Rh1 is its effect on the vascular barrier. Rh1 blocks tumor cell extravasation and helps maintain endothelial integrity. It inhibits CK2α, restores nuclear HHEX, and disrupts the CCL20–CCR6 signaling axis between tumor and endothelial cells. As a result, tumor cells have more difficulty crossing blood vessels [106]. This mechanism operates independently of direct tumor killing and limits the physical process of metastasis. In lung adenocarcinoma, Rh1 also suppresses RhoA/ROCK1 signaling and activates ROS–p53–mediated apoptosis, further reducing metastatic potential [107].

Rh1 also activates stress-response pathways. In TNBC, it induces mitochondrial dysfunction and triggers PERK/eIF2α/ATF4/CHOP–mediated endoplasmic reticulum stress, leading to apoptosis in vitro and in vivo [104]. In gastric cancer, Rh1 inhibits TGF-β/Smad signaling, which reduces proliferation, migration, and EMT [108].

Importantly, many of Rh1's benefits come from immune regulation rather than direct cytotoxicity. In hepatocellular carcinoma models, Rh1 shows limited killing of isolated tumor cells but strongly enhances antitumor immunity in immunocompetent animals [109]. It suppresses glucocorticoid receptor signaling, increases MHC-I expression, promotes dendritic cell maturation, and enhances CD8⁺ T-cell infiltration. Rh1 also improves the response to lenvatinib, supporting its use as a combination partner [109].

Rh1 further links stress, the gut microbiota, and tumor immunity. Under chronic psychological stress, Rh1 reduces depressive-like behavior, restores gut microbial balance, lowers myeloid-derived suppressor cells, and enhances T-cell–mediated antitumor responses in colorectal cancer models [110]. These findings suggest that Rh1 helps maintain immune function under stress conditions that normally promote tumor growth.

Overall, Rh1 acts mainly as a metastasis- and host-supportive agent rather than a strong cytotoxic drug. Its strengths lie in controlling invasion, protecting vascular barriers, and improving immune responses. Therefore, Rh1 may be most useful in combination therapies aimed at limiting metastasis and supporting antitumor immunity.

4.2. Ginsenoside Rh4 (PPT-type): immune–metabolic regulation and ferroptosis induction

Among PPT-type ginsenosides, Rh4 has attracted increasing attention since 2020. Before this period, it was rarely studied in cancer. However, recent work shows consistent antitumor activity across many cancers, including esophageal, lung, gastric, colorectal, breast, renal, liver, and hematologic malignancies. Both cell and animal models support these effects [[111], [112], [113], [114], [115], [116], [117], [118], [119], [120]]. Unlike classical ginsenosides that mainly induce apoptosis, Rh4 acts through multiple mechanisms, including growth inhibition, metabolic regulation, immune modulation, ferroptosis, and changes in the gut microbiota.

At the tumor-cell level, Rh4 commonly suppresses proliferation and induces G1 cell-cycle arrest. In esophageal cancer, Rh4 directly inhibits AKT/mTOR signaling and reduces aerobic glycolysis, limiting both growth and energy supply [113]. It also lowers programmed death-ligand 1 (PD-L1) expression, linking metabolic control with reduced immune evasion. In lung adenocarcinoma, Rh4 blocks TGF-β1–activated JAK2/STAT3 signaling, which reduces proliferation, migration, invasion, and EMT [119]. In gastric cancer, Rh4 targets the transcription factor SIX1 and inhibits TGF-β/Smad2/3 signaling, leading to reduced metastasis in vivo [115]. Together, these studies show that Rh4 suppresses several key pathways that drive tumor progression.

Beyond apoptosis and cell-cycle arrest, Rh4 strongly engages ferroptosis. In colorectal cancer, Rh4 activates ROS/p53 signaling and induces both autophagy and ferroptosis, resulting in marked tumor suppression with low systemic toxicity [117]. In this setting, autophagy supports cell death rather than survival. In renal cell carcinoma, Rh4 suppresses NRF2 and decreases antioxidant enzymes such as GPX4, SOD1, and catalase. This makes tumor cells more sensitive to ferroptosis inducers like RSL3 [120]. In multiple myeloma, Rh4 induces ferroptosis through inhibition of SIRT2, linking epigenetic regulation to iron-dependent cell death [118]. These findings suggest that Rh4 not only triggers ferroptosis but also increases tumor sensitivity to ferroptotic stress.

Rh4 also shows clear immune-regulatory effects. In breast cancer, Rh4 inhibits HDAC2 and JAK/STAT signaling, induces apoptosis, and reduces PD-1/PD-L1 checkpoint signaling while increasing T-cell infiltration [114]. This indicates that Rh4 can influence both tumor cells and immune responses. In inflammation-driven liver cancer, Rh4 suppresses the HDAC4/IL-6/STAT3 axis, reduces glycolysis, and limits inflammation-associated tumor growth [116]. These results support a role for Rh4 in controlling tumor-promoting inflammation.

Importantly, Rh4 also acts through the gut microbiota. In colorectal cancer models, Rh4 increases beneficial bacteria, enhances bile acid metabolism toward UDCA, activates FXR signaling, and reduces TLR4–NF-κB–mediated intestinal inflammation [111,112]. When the microbiota is depleted, these antitumor effects are largely lost. This shows that part of Rh4's activity depends on host–microbiome interactions rather than direct tumor killing.

Overall, Rh4 acts through combined metabolic, immune, and microbiota-related mechanisms. Its benefits extend beyond direct cytotoxicity, making it a promising candidate for combination and host-supportive cancer therapies.

4.3. Ginsenoside Rk1 (PPD-type): metabolic stress targeting and combination therapy

Among PPD-type ginsenosides, Rk1 has recently gained attention as a metabolism-focused anticancer compound. Rather than acting mainly through strong cytotoxicity, Rk1 targets metabolic stress and survival pathways. It shows activity across lung, liver, gastric, and cervical cancers [[121], [122], [123], [124], [125], [126], [127], [128]]. Key pathways affected by Rk1 include NF-κB, PI3K/AKT, and AMPK/mTOR, which link tumor metabolism with cell survival.

In lung adenocarcinoma, Rk1 reduces cell proliferation and clonogenic growth, induces G1 arrest and apoptosis, and lowers PD-L1 expression [122]. These effects combine tumor growth inhibition with immune-relevant changes. Rk1 also directly targets the insulin receptor (INSR), leading to suppression of INSR/PI3K/AKT signaling. This reduces proliferation, migration, invasion, and survival, while promoting apoptosis and autophagy in both cell and animal models [121]. Because lung tumors often depend on metabolic flexibility, interference with insulin signaling may be particularly important.

A major feature of Rk1 is its effect on metabolic vulnerabilities, especially glutamine dependence. In hepatocellular carcinoma, Rk1 suppresses glutamine metabolism by downregulating GLS1 through the ERK/c-Myc pathway. This lowers intracellular glutathione (GSH), increases ROS, and triggers mitochondrial apoptosis, while maintaining low systemic toxicity [125]. These findings show that Rk1 disrupts the glutamine–redox balance that many resistant tumors rely on. Rk1 also enhances autophagy-dependent apoptosis through AMPK/mTOR modulation, further increasing metabolic stress [127].

In cervical cancer, Rk1 induces G0/G1 arrest, apoptosis, and autophagy by suppressing endoplasmic reticulum protein-processing pathways. Downregulation of YOD1 suggests that ER stress is a key mechanism [124]. In gastric cancer, Rk1 inhibits EMT, activates AMPK, suppresses mTOR signaling, and enhances chemosensitivity. Combination treatment leads to stronger tumor suppression in vivo [123].

Rk1 has also been incorporated into advanced delivery systems. For example, a manganese-doped hollow titania sonosensitizer loaded with Rk1 enables ultrasound-triggered ROS production. At the same time, Rk1 reduces glutaminase and glutathione synthesis, further increasing oxidative stress. This combined strategy allows MRI-guided, minimally invasive treatment of liver tumors [128]. Finally, computational studies suggest that Rk1 may bind the STAT3-SH2 domain and inhibit STAT3 signaling. Although this requires further experimental validation, it indicates additional potential molecular targets [126].

Overall, Rk1 acts mainly by increasing metabolic and oxidative stress in cancer cells. Its strengths lie in targeting tumor metabolism and improving combination or technology-assisted therapies, rather than functioning as a standalone cytotoxic drug.

5. Rg2 and F2: less-studied but promising ginsenosides

As indicated in Fig. 2, ginsenosides Rg2 and F2 have been studied less extensively than Rg1 or Rg5, yet show consistent and reproducible anticancer signals that warrant focused discussion.

5.1. Ginsenoside Rg2 (PPT-type): anticancer activity and cardioprotective effects

Among PPT-type minor ginsenosides, Rg2 shows moderate anticancer activity together with clear organ-protective effects. Its tumor-suppressive effects are not as strong as classical cytotoxic agents, but its protective functions make it attractive as a supportive compound in combination therapy.

In estrogen receptor–positive breast cancer models, Rg2 increases mitochondrial ROS and activates AMPK signaling. It also suppresses ERK1/2–AKT–mTOR signaling. These changes lead to G0/G1 arrest and caspase-dependent apoptosis in both in vitro and in vivo models [129,130]. When antioxidants are added, these effects are reduced, indicating that ROS generation is the main trigger of tumor suppression [129]. This suggests that Rg2 primarily induces metabolic and oxidative stress rather than directly damaging DNA. Rg2 also contributes to anticancer activity in complex red ginseng extracts. In colorectal cancer models, Rg2 is identified as a key component responsible for tumor cell death. It increases mitochondrial ROS, activates Atg5/Beclin-1/LC3-dependent autophagy, disrupts the Bcl-2–Beclin-1 interaction, and subsequently triggers caspase-mediated apoptosis [131]. Together, these pathways induce strong cellular stress and promote tumor cell death.

An important feature of Rg2 is its cardioprotective effect. Some anticancer drugs, such as trastuzumab, can damage the heart and limit treatment. Rg2 helps protect human cardiomyocytes by reducing mitochondrial apoptosis and activating protective autophagy through AKT/mTOR signaling. It also increases Beclin-1, LC3, and ATG5 expression [132]. In animal models, Rg2 preserves cardiac function, lowers caspase-3/9 and BAX activation, and reduces left ventricular dysfunction [133]. Importantly, these protective effects do not reduce the anticancer activity of therapy.

Overall, Rg2 combines modest tumor suppression with strong heart protection. Therefore, it may be most useful as a supportive adjuvant rather than a primary cytotoxic drug. This profile makes Rg2 well suited for combination regimens aimed at improving treatment safety while maintaining efficacy.

5.2. Ginsenoside F2 (PPD-type): metabolic targeting, STAT3 inhibition, and ferroptosis

In contrast to Rg2, ginsenoside F2 shows stronger direct anticancer activity and mainly targets tumor metabolism. Recent studies indicate that F2 disrupts mitochondrial function and redox balance, which are critical for the survival of rapidly growing and therapy-resistant cancers.

In glioblastoma, F2 reduces mitochondrial membrane potential, oxygen consumption, and ATP production. It also depletes intracellular NAD⁺ and increases oxidative stress [134]. These changes activate AMPK signaling, induce DNA damage responses, and lead to apoptosis. Rather than acting only on downstream signaling pathways, F2 directly weakens the energy supply of tumor cells, which makes cell survival difficult. F2 also directly targets oncogenic transcription factors. In hepatocellular carcinoma, F2 binds STAT3 and inhibits Y705 phosphorylation, nuclear translocation, and transcriptional activity. This results in clear tumor growth inhibition in both cell and animal models [135]. Direct STAT3 inhibition is relatively uncommon among natural compounds and may help block inflammation-driven tumor progression.

Additional metabolic effects are observed in cervical cancer. F2 increases miR-193a-5p, reduces β-catenin and c-Myc stability, and lowers expression of glycolytic enzymes such as HK2, PKM2, and LDHA. These changes suppress glycolysis and promote apoptosis [136]. Thus, F2 interferes with both mitochondrial respiration and glycolytic metabolism.

F2 has also been tested in combination and delivery systems. In glioblastoma, F2 works together with FTY720 to induce ferroptosis by reducing glutathione levels and altering AMPK–mTOR–GPX4 signaling. When delivered using blood–brain barrier–penetrant liposomal nanoparticles, tumor targeting and therapeutic efficacy are further improved [137]. In addition, engineered microbial systems now allow large-scale production of F2, which helps overcome previous supply limitations [138]. F2 also contributes to the chemopreventive activity of multi-component formulations such as Pien Tze Huang in colorectal cancer models [139].

Overall, F2 mainly acts by disrupting tumor metabolism and survival signaling. Its ability to target mitochondria, glycolysis, STAT3, and ferroptosis makes it a useful candidate for combination and nanomedicine-based therapies rather than a simple cytotoxic drug.

6. Re (PPT) and Rc (PPD): underexplored, formulation-dependent, and supportive ginsenosides

6.1. Ginsenoside Re (PPT-type): immune modulation, metastasis control, and improved treatment tolerance

Ginsenoside Re is one of the most abundant PPT-type ginsenosides in Panax species. However, unlike strongly cytotoxic compounds, Re rarely acts as a direct tumor-killing agent. Instead, most recent studies show that Re works mainly within multi-component formulations and supports host protection rather than direct cancer cell death. Re is a major active component of injectable preparations such as Aidi, Shengmai, and Shenfu, where it helps improve efficacy and reduce toxicity [63,64,140,141].

Clinically, Aidi injection containing Re has been reported to improve tumor response rates and quality of life in non-small-cell lung cancer when combined with vinorelbine–cisplatin. At the same time, chemotherapy-related side effects are reduced [63,64]. These benefits likely come from supportive and cooperative effects rather than strong single-agent cytotoxicity. In hepatocellular carcinoma models, Re contributes to mitochondrial membrane depolarization, inhibition of PI3K/AKT signaling, and activation of MAPK-dependent apoptosis when used within these formulations [140]. This suggests that Re enhances the activity of other anticancer components rather than acting alone.

Re also shows clear effects on the immune system and tumor microenvironment. In lung cancer models, Re reduces metastasis by reprogramming tumor-associated macrophages. It inhibits the AMPKα1/STING pathway, prevents M2 polarization, and suppresses EMT, which together reduce tumor spread in vivo [142]. In melanoma, Re targets the MITF–tyrosinase axis, decreases melanogenesis, promotes vascular normalization, and suppresses tumor growth through AKT/ERK-related mechanisms [143]. Re also contributes to chemopreventive effects in colorectal cancer as part of Pien Tze Huang formulations, where it helps reduce inflammation and restore gut balance [139].

Pharmacokinetic factors also support a formulation-based role. Re is a substrate of the BCRP transporter, and its cellular uptake can be influenced by other coexisting ginsenosides. This affects distribution and activity within multi-component preparations [77]. In addition, Re shows little direct cytotoxicity in some cancers, such as renal cell carcinoma [144]. Therefore, its main value likely lies in immune regulation, toxicity reduction, and compatibility with combination therapy rather than direct tumor killing.

Additional studies show that Re-enriched extracts from dark-treated ginseng display stronger anti-inflammatory and pro-apoptotic effects, including suppression of NF-κB/MAPK signaling in tumor and immune cells [145]. These findings further support its supportive role.

Overall, Re acts primarily as a formulation-dependent and host-supportive ginsenoside. Its benefits come from immune modulation, metastasis control, and improved treatment tolerance rather than strong intrinsic cytotoxicity.

6.2. Ginsenoside Rc (PPD-type): vascular targeting, cooperative anticancer effects, and tissue protection

Ginsenoside Rc can be considered the PPD-type counterpart to Re. Like Re, Rc shows high systemic exposure and often works best within multi-component formulations rather than as a strong standalone cytotoxic drug. Although its direct tumor-killing activity is moderate, Rc has favorable pharmacokinetic properties. After repeated dosing, Rc accumulates efficiently in plasma, tumor tissue, and tumor endothelial cells, allowing sustained exposure in vivo [146].

In complex herbal or injectable formulations, Rc contributes to cooperative tumor suppression. In Aidi injection, Rc participates in mitochondrial membrane depolarization and MAPK-mediated mitochondrial apoptosis in hepatocellular carcinoma models [140]. In Shenmai injection, Rc accumulates in tumor blood vessels and works together with Rd to regulate angiogenesis and improve chemotherapy response in colorectal cancer [146]. Rc has also been identified as a synergistic component in optimized multi-drug formulations. In combination with cantharidin, Rc enhances mitochondrial apoptosis by modulating the ubiquitin–proteasome system and activating PP2A [147]. These findings suggest that Rc mainly affects the tumor vasculature and supports other anticancer agents rather than directly killing tumor cells. Rc also shows identifiable molecular targets. It directly binds Hsp90α, which leads to inactivation of SRC and PI3K and suppression of AKT/ERK signaling [148]. Although its potency is modest, this confirms that Rc still interacts with known oncogenic pathways. Screening studies further identify Rc as an active component that contributes to lung cancer suppression in multi-component formulas [149].

Beyond direct anticancer effects, Rc shows important chemopreventive and microenvironmental benefits. In skin carcinogenesis models, Rc activates Nrf2 signaling, improves redox balance, and enhances immune surveillance during both tumor initiation and progression [150]. Extracts enriched with Rc, such as dark-treated ginseng, also show stronger anti-inflammatory and pro-apoptotic effects, including suppression of NF-κB/MAPK pathways [140].

Importantly, Rc provides clear tissue-protective effects that are highly relevant in clinical oncology. Rc reduces 5-fluorouracil–induced intestinal mucositis by decreasing epithelial apoptosis, restoring tight junction proteins, lowering inflammatory cytokines, and modulating PI3K–AKT and NF-κB signaling [151]. These actions protect gastrointestinal tissues without reducing anticancer efficacy. Such protection can help improve treatment tolerability during chemotherapy.

Overall, Rc acts mainly as a supportive and formulation-friendly ginsenoside. Its strengths lie in vascular regulation, cooperative signaling, and protection of normal tissues rather than strong intrinsic cytotoxicity. Therefore, Rc may be most useful as an adjunct that improves the safety and effectiveness of combination cancer therapies.

7. Underexplored minor ginsenosides: resistance control and host-protective roles

Fig. 2 highlights that several structurally defined ginsenosides—including Rf, F1, Rg6, Rb3, Rp1, and Rb2—remain minimally investigated in cancer research, despite emerging evidence for resistance modulation, immune regulation, and tissue protection. In recent years, most ginsenoside studies have focused on a few well-known compounds such as Rg1, Rg5, Rh4, and Rk1. However, many other ginsenosides are still rarely studied. These include PPT-type Rf and F1, and PPD-type Rg6, Rb3, Rp1, and Rb2. These compounds usually do not show strong direct killing of cancer cells. Because of this, they were often overlooked in early screening studies. But newer research suggests a different story. Many of these “minor” ginsenosides act in supportive ways. They help reduce drug resistance, regulate immunity, protect normal tissues, or improve drug delivery. These functions match current clinical needs. In modern cancer therapy, improving treatment response and reducing side effects are just as important as directly shrinking tumors. Therefore, the low number of publications on these compounds likely reflects past research bias, not low therapeutic value.

7.1. Rf (PPT-type): neuroprotective and stress-related support

Direct anticancer studies of Rf are limited. Most work has focused on neuroprotection and stress regulation. Rf increases brain-derived neurotrophic factor (BDNF) expression through ERK and p38 MAPK signaling and protects neuronal cells from corticosterone-induced damage [152]. Although these findings come from neural models, they may still be relevant to cancer care. Stress, fatigue, and neuroendocrine imbalance often worsen patient outcomes and reduce treatment tolerance. By supporting neural and stress responses, Rf may help maintain overall health during therapy. Thus, Rf is better viewed as a supportive compound rather than a direct anticancer drug.

7.2. F1 (PPT-type): immune-supportive modulation

F1 has also been rarely tested in cancer cell models. Instead, available data suggest immune and inflammatory regulation. F1 appears to influence immune cell activity and cytokine balance rather than directly causing tumor cell death. This pattern is similar to several modern immunotherapies that act indirectly through the immune system. Therefore, weak cytotoxicity in vitro does not necessarily mean low value. F1 may work best in immunocompetent or microenvironment-based models. Overall, F1 is likely more useful as an adjunct or immune-supportive agent than as a standalone anticancer compound.

7.3. Rg6 (PPD-type): resistance reversal and autophagy activation

Among these minor ginsenosides, Rg6 shows the clearest anticancer evidence. In epithelial ovarian cancer, Rg6 restores sensitivity to cisplatin. It suppresses protein fucosylation, inhibits the GRB2–ERK1/2–mTOR pathway, activates autophagy, and increases expression of the copper transporter CTR1. This increases intracellular cisplatin levels and improves drug response [153]. Importantly, Rg6 does not mainly kill tumor cells by itself. Instead, it helps chemotherapy work better. This resistance-reversal role fits well with modern combination therapy strategies.

7.4. Rb3 (PPD-type): organ protection with cooperative anticancer effects

Rb3 shows a different but equally useful profile. Its main strength is tissue protection.

In cisplatin-treated models, Rb3 reduces kidney injury. It suppresses TGF-β/Smad signaling, protects mitochondria, decreases Bax and caspase activation, and preserves renal function [154]. At the same time, Rb3 shows moderate anticancer activity. It binds Hsp90α and inhibits SRC/PI3K–AKT/ERK signaling in lung cancer cells [148]. Thus, Rb3 both protects normal tissues and supports tumor control. This makes it suitable as a chemotherapy-supportive adjuvant.

7.5. Rp1 (PPD-type): microenvironment and inflammation control

Rp1 mainly targets the tumor microenvironment rather than cancer cells directly.

It reduces radiation-induced inflammation in macrophages, lowers nitric oxide and IL-1β production, and decreases macrophage-driven tumor aggressiveness [155]. Rp1 also restores drug sensitivity by inhibiting AKT–SIRT1 signaling and reactivating p53-dependent apoptosis [156]. These actions suggest that Rp1 helps control inflammation and resistance, improving overall treatment response.

7.6. Rb2 (PPD-type): pharmacokinetic and vascular support

Rb2 appears to work through distribution and vascular effects. It accumulates well in blood and tumor tissues and preferentially localizes to tumor blood vessels. This improves drug delivery and supports anti-angiogenic effects in formulations such as Shenmai injection [146]. Rb2 also moderately inhibits CYP1B1, which may influence drug metabolism and resistance [157]. Additional studies show anti-inflammatory and metabolic regulatory effects [145,158]. Overall, Rb2 acts more as a delivery and supportive component than as a direct anticancer agent.

7.7. Future perspectives

Together, these underexplored ginsenosides show that anticancer benefit is not limited to direct tumor killing. Helping chemotherapy work better, reducing resistance, supporting immunity, and protecting normal organs can be equally important. As purification methods, synthesis, and delivery technologies improve, these minor ginsenosides can be studied more carefully. Many may become useful partners in combination therapy. In short, these compounds should not be considered weak or secondary. Instead, they represent practical and supportive tools that may improve safety, tolerability, and long-term treatment success. To integrate these findings across compounds, we summarized the major mechanistic themes and therapeutic contexts shared by different ginsenosides in Table 2. This table highlights how many ginsenosides converge on common biological processes, such as metabolic stress, immune regulation, resistance modulation, and toxicity reduction, despite differences in structure and research intensity. To integrate these findings across compounds, the shared mechanistic themes and therapeutic contexts of underexplored ginsenosides are summarized in Fig. 3.

Table 2.

Mechanistic themes across emerging ginsenosides (2020–2025).

Mechanistic Theme	Representative Ginsenosides	Example Molecular Pathways/Targets	Therapeutic Context and Clinical Relevance
Cell-cycle control & apoptosis	Rg5, Rg1, Rh4, Rk1	PI3K/AKT/mTOR inhibition; Cyclin/CDK suppression; caspase-3/9 activation; Bax/Bcl-2 modulation; ERK inhibition	Direct tumor growth suppression; foundational mechanism in solid tumors; baseline anticancer activity
Autophagy regulation	Rg5, Rg2, Rk1	LC3 lipidation; Beclin-1 activation; AMPK/mTOR modulation; autophagosome–lysosome fusion	Enhances stress-induced tumor death; supports combination therapy; may overcome adaptive survival pathways
Ferroptosis induction/sensitization	Rh4, F2, Rg5	GPX4 suppression; NRF2 inhibition; ROS amplification; SIRT2 modulation; AMPK–mTOR–GPX4 axis	Targets therapy-resistant tumors; useful in high-grade cancers (glioblastoma, colorectal); metabolic vulnerability exploitation
Metabolic reprogramming	Rg1, Rk1, F2, Rh4	Glycolysis inhibition (HK2, PKM2, LDHA); glutamine metabolism (GLS1); INSR/PI3K axis; mitochondrial dysfunction	Exploits tumor metabolic dependency; relevant for aggressive and drug-resistant cancers
Drug resistance reversal	Rg5, Rg6, Rp1	ABCB1 interaction; AKT/Nrf2 inhibition; GRB2–ERK1/2–mTOR suppression; AKT–SIRT1–p53 regulation; CTR1 upregulation	Restores chemotherapy sensitivity; supports combination regimens; addresses MDR tumors
Immune modulation & checkpoint regulation	Rh4, Rh1, Rg1, Re	PD-1/PD-L1 downregulation; JAK/STAT inhibition; HDAC suppression; MHC-I upregulation; macrophage polarization (M1/M2 balance)	Enhances immunotherapy response; useful in immunologically “cold” tumors; tumor–host interaction targeting
Metastasis & EMT suppression	Rh1, Rh4, Rk1, Re	TGF-β/Smad inhibition; STAT3 blockade; MMP2/9 suppression; RhoA/ROCK1 inhibition; vascular barrier stabilization	Prevents dissemination and secondary tumor formation; important in advanced-stage disease
Tumor microenvironment regulation	Rh1, Re, Rp1, Rb2	CCL20–CCR6 axis; AMPKα1/STING modulation; inflammatory cytokine suppression (IL-6, NF-κB); endothelial stabilization	Alters stromal and inflammatory support for tumor growth; improves therapy response
Organ protection during therapy	Rg2, Rb3, Rc	TGF-β/Smad suppression; mitochondrial protection; anti-apoptotic balance in normal tissues; PI3K–AKT modulation	Reduces cardiotoxicity, nephrotoxicity, intestinal mucositis; improves treatment tolerance
Formulation-dependent cooperative effects	Re, Rc, Rb2	Vascular accumulation; transporter interactions (BCRP); Hsp90 binding; cooperative MAPK signaling	Improves drug distribution; enhances multi-component formula efficacy; supportive oncology role
Nanotechnology integration	Rg1, Rg5, F2, Rk1	pH-responsive nanohydrogels; liposomal delivery; polymeric micelles; sonosensitizer platforms	Improves tumor targeting; reduces systemic toxicity; enables modality-driven therapy

8. Conclusions

This review shows that research on ginsenosides in cancer therapy has changed clearly over the past two decades. In earlier years, most studies focused on a simple question: can a compound directly kill cancer cells? Researchers mainly measured apoptosis and tumor shrinkage. Compounds that showed strong cytotoxicity were considered promising. Because of this approach, ginsenosides such as Rg3 and Rh2 became the most widely studied and reviewed. However, strong cytotoxicity alone does not guarantee clinical benefit. Cancer is not composed solely of tumor cells. Tumors also contain immune cells, stromal cells, blood vessels, metabolic changes, and inflammatory signals. In addition, drug resistance and treatment-related toxicity often limit therapy more than the intrinsic sensitivity of cancer cells. These factors strongly affect real patient outcomes. For this reason, compounds that support therapy or regulate the tumor environment can be just as important as those that directly kill tumor cells. Importantly, Fig. 2 demonstrates that publication frequency does not necessarily correlate with therapeutic relevance, reinforcing the need to evaluate ginsenosides based on functional roles rather than historical research intensity alone.

Recent studies from the 2020s clearly reflect this shift. Many underexplored ginsenosides do not act as strong cytotoxic drugs. Instead, they work through broader and more supportive mechanisms. Several examples in this review illustrate this new direction. Rg1 and Rg5, the most extensively examined compounds in this review, still show classical effects such as apoptosis induction and growth inhibition. But they also improve drug sensitivity, regulate metabolism, and reduce therapy-related stress. Therefore, they function not only as tumor suppressors but also as combination partners that enhance overall treatment efficacy. Moderately studied compounds such as Rh1, Rh4, and Rk1 show even clearer context-dependent roles. Rh1 and Rh4 regulate immunity, metastasis, and tumor–host interactions. Rk1 and F2 mainly target metabolic stress, redox imbalance, and ferroptosis-related pathways. These mechanisms weaken tumor survival and adaptability rather than simply causing direct cell death. Other ginsenosides, including Rg2, Re, and Rc, often act as supportive or formulation-dependent components. Some protect the heart, kidney, or intestine during chemotherapy. Others improve drug delivery or reduce inflammation. Even minimally studied compounds such as Rg6, Rb3, Rb2, Rp1, Rf, and F1 show useful functions, including resistance reversal, immune support, and tissue protection, despite weak direct cytotoxicity. Taken together, these findings highlight a clear conceptual shift. Many ginsenosides function more effectively as combination partners or therapeutic adjuvants than as standalone anticancer drugs. Their main value often lies in improving treatment response, reducing side effects, and supporting the whole treatment process.

Although pharmacokinetic and bioavailability data remain limited for many underexplored ginsenosides, these factors are critical for clinical translation. Several compounds, including Rg1 (PPT-type) and Rg5 (PPD-type), have begun to show more defined pharmacological and formulation-related properties, suggesting potential for further development. However, many ginsenosides have primarily been evaluated within complex mixtures or herbal formulations, making compound-specific pharmacokinetic characterization challenging. As more systematic studies are conducted, these ginsenosides may approach a level of translational understanding comparable to well-studied compounds such as Rg3 and Rh2. Future research should therefore prioritize pharmacokinetic profiling, bioavailability optimization, and formulation strategies to support clinical application.

This review also highlights an important point. The number of publications does not always reflect true therapeutic value. Some compounds became popular mainly because they showed strong cytotoxicity in early laboratory tests. Meanwhile, others were overlooked even though they may offer practical clinical benefits. Therefore, future research should not focus only on how strongly a compound kills cancer cells in vitro. Instead, broader and more realistic questions should be asked. Does it improve drug sensitivity? Does it regulate immunity or metabolism? Does it reduce toxicity? Does it work well in combination therapy? These questions are often more relevant for patients. Overall, the field is shifting from direct tumor killing toward improving overall therapeutic outcomes. With advances in purification, semi-synthesis, delivery systems, and better animal models, many underexplored ginsenosides can now be studied more accurately. These improvements will help clarify their real clinical potential.

In conclusion, ginsenoside research is entering a new stage. The focus is no longer limited to a few highly cytotoxic compounds. Instead, many emerging ginsenosides—including Rg1 and others discussed here—show broader supportive and regulatory roles. By using these compounds strategically in combination therapies, ginsenosides may help make cancer treatment safer, more effective, and more sustainable.

Declaration of competing interest

The authors have no conflicts of interest to declare.

Abbreviation List

Abbreviation	Full term
PPT	Protopanaxatriol
PPD	Protopanaxadiol
CK	Compound K
TNBC	Triple-negative breast cancer
ER	Estrogen receptor
PR	Progesterone receptor
HER2	Human epidermal growth factor receptor 2
HR	Hormone receptor
MDR	Multidrug resistance
P-gp	P-glycoprotein (ABCB1/MDR1)
ABCB1	ATP-binding cassette subfamily B member 1
ABCG2	ATP-binding cassette subfamily G member 2
MRP1	Multidrug resistance-associated protein 1
EMT	Epithelial–mesenchymal transition
TME	Tumor microenvironment
ROS	Reactive oxygen species
PD-1	Programmed cell death protein 1
PD-L1	Programmed death-ligand 1
STAT3	Signal transducer and activator of transcription 3
IL-6	Interleukin-6
VEGF	Vascular endothelial growth factor
HIF-1α	Hypoxia-inducible factor-1 alpha
MDSC	Myeloid-derived suppressor cell
PARP	Poly(ADP-ribose) polymerase
EGFR	Epidermal growth factor receptor
TKIs	Tyrosine kinase inhibitors
DOX	Doxorubicin
PTX	Paclitaxel
GEM	Gemcitabine
DDP	Cisplatin (cis-diamminedichloroplatinum II)
5-FU	5-Fluorouracil
TMZ	Temozolomide
PK	Pharmacokinetics
OS	Overall survival
PFS	Progression-free survival
ORR	Overall response rate
NSCLC	Non-small-cell lung cancer
HCC	Hepatocellular carcinoma
CRC	Colorectal carcinoma
PEG	Polyethylene glycol
MMP	Matrix metalloproteinase
CAR-T	Chimeric antigen receptor T cell
BCRP	Breast cancer resistant protein