Tonghui Jin
Yu Du2
Tiejun Liu- 1College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
- 2Department of Proctology, Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin, China
- 3Department of Liver, Spleen and Gastroenterology, Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin, China
Common kidney diseases include acute kidney injury, diabetic kidney disease, kidney cancer, and other related conditions. Ginsenosides, the principal bioactive constituents of ginseng, have been widely reported as therapeutic agents against these disorders. However, recent advances regarding their efficacy in kidney diseases have not been comprehensively synthesized. This review addresses this gap by summarizing current findings on the mechanisms and therapeutic targets of ginsenosides. Literature from PubMed, Web of Science, and other databases was systematically retrieved using keywords such as ginsenosides, acute kidney injury, diabetic nephropathy, renal cell carcinoma, lupus nephritis, and aging-related kidney injury. Evidence from cell-based and animal studies demonstrates that ginsenoside compound K, Rg1, Rg3, Rh2, Rb1, Rb3, Rg2, and Rg5 are the most frequently reported for kidney protection. Mechanistically, ginsenosides modulate multiple signalling networks, including NF-κB, PI3K/AKT, MAPK, TGF-β/Smads, PPAR, SIRT1, NLRP3, and Nrf2, to mitigate inflammation, oxidative stress, apoptosis, epithelial-mesenchymal transition, pyroptosis, autophagy, and endoplasmic reticulum stress. Taken together, these findings provide valuable insights into the therapeutic potential of ginsenosides and underscore their promise as candidates for the prevention and treatment of kidney diseases.
1 Introduction
Kidneys play a central role in maintaining homeostasis by filtering blood to remove metabolic waste and by regulating fluid and electrolyte balance (Robson, 2014). Major kidney diseases include acute kidney injury, diabetic kidney disease, and kidney cancer. Acute kidney injury can be triggered by infection, drug toxicity, heart failure, or shock, is characterized by reduced urine output, electrolyte disturbances, and azotemia (Kellum et al., 2021), which leads to death in 25% of the patients, according to a cohort study (Sohaney et al., 2022). The burden of diabetic kidney disease is primarily driven by type 2 diabetes mellitus and hypertension, with prevalence continuing to rise in aging populations (Li Z. et al., 2025). In 2023, chronic kidney disease occurs in 788 million people aged 20 and older with a global age-standardized prevalence of 14.2%, which is the ninth leading cause of death globally and the 12th leading cause of disability-adjusted life years (Collaborators, 2025). Separately, kidney cancer accounts for an estimated 400,000 new cases and 175,000 deaths annually worldwide (Cirillo et al., 2024). Current therapeutic strategies for these diseases include the elimination of causative factors (e.g., drug withdrawal, antihypertensive or antidiabetic therapy), anti-infective treatment, the correction of electrolyte imbalances, and renoprotective agents such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and chemotherapy or immunotherapy, including immune checkpoint inhibitors (Chen et al., 2019; Chowdhury and Drake, 2020; Tamargo et al., 2024). Given the high prevalence and poor prognosis with these conditions, the development of effective interventions for kidney diseases are both urgent and essential (Padala et al., 2020; Kung and Chou, 2023; Jadoul et al., 2024). Consequently, drug discovery and therapeutic development remain a key research frontier worldwide.
Panax ginseng C.A. Mey. (ginseng) is a widely recognized medicinal herb used in the prevention and treatment of multiple conditions, including cardiovascular (Wan et al., 2023; Chang et al., 2025; Yuan et al., 2025), neurodegenerative (Wang et al., 2025; Zhou et al., 2025), and metabolic diseases (Ding et al., 2023; Liu Q. et al., 2024), as well as kidney diseases (Zhang H. et al., 2025; Zhang Y. X. et al., 2025). Ginsenosides, the principal bioactive components of ginseng, which are triterpene saponins structurally, classified as three types of saponins: dammarane-, oleanane-, or octillol-types based on the structure of their aglycone (Li et al., 2022; Ding et al., 2024). The dammarane-type group, the most abundant group, is characterized by a 4-ring, steroid-like structure, which is further divided into protopanaxadiol (PPD; e.g., Rb1, Rb2, Rb3, Rc, Rd, Rg3, Rh2), protopanaxatriol (PPT; e.g., Re, Rf, Rg1, Rg2, Rh1) (Li et al., 2022; Ding et al., 2024). The oleanane-type has a different pentacyclic structure and ginsenoside Ro is the representative example (Li et al., 2022; Ding et al., 2024). The octillol-type is characterized by a tetrahydrofuran ring and less abundant in medicinal herbs (Cao et al., 2020). Different ginsenosides regulate similar pathological steps, such as autophagy, gut microbiota, mitochondrial function to display a wide range of therapeutic effects (Huang et al., 2021a; Chen Z. et al., 2022; Ren et al., 2023), which might be not related with ginsenoside structures. Certainly, ginsenosides have various therapeutic efficacies in diverse conditions, such as myocardial ischemia-reperfusion injury, aging, and diabetes and its related complications through different potential targets, such as SIRT1, splicing factor 2 subunit 2 acetylation, nicotinamide adenine dinucleotide metabolism, G protein-coupled receptor 30, and mitosis A-related kinase 7 (Huang et al., 2021b; Wang et al., 2021; Huang et al., 2024; Guo et al., 2025; Tang et al., 2025; Zhu et al., 2025). The unique function and potential target of ginsenosides might be related the glucopyranosyl group at C-3 or C-6 position, which need to be further investigated (Huang et al., 2021b). For kidney protection, it was first reported in 1990 that ginsenosides stimulate p-aminohippurate secretion to reverse its imbalance in renal cortex against acute renal failure (Liu and Gemba, 1990). Gradually, the protective effects of ginsenosides on kidney ischemic damages, cisplatin-induced acute renal failure and hydrogen peroxide or epidermal growth factor-induced cellular injury were studied (Yokozawa et al., 1998; Yokozawa and Liu, 2000; Han et al., 2002). In recent years, increasing evidence specifically highlights the renoprotective effects of ginsenosides in acute kidney injury (Guo et al., 2022), diabetic kidney disease (Chen Q. et al., 2022), kidney cancer (Zhao et al., 2024), and other renal injuries, such as IgA nephropathy (Wu et al., 2020), lupus nephritis (Li Y. et al., 2025), and hypoxia- or aging-related damage (Ji P. et al., 2024; Nguepi Tsopmejio et al., 2025). While several systematic reviews have summarized their benefits of ginsenosides for diabetic nephropathy (Chen et al., 2023) and nephrotoxicity (Luo et al., 2023), the current understanding of their protective mechanisms against kidney diseases remain fragmented and inconclusive. This review aims to consolidate recent advances by comprehensively summarizing the protective effects, pharmacological mechanisms, and therapeutic targets of ginsenosides in kidney diseases, as illustrated in the accompanying figures and tables. By integrating this evidence, the review provides new insights into the therapeutic potential of ginsenosides against renal disorders.
2 Pharmacological effects and molecular mechanisms of ginsenosides against common kidney diseases
Following oral or intravenous administration, ginsenoside monomers such as Rb1, Rc, Rd, Rh3, Rg1, Rg2, and compound K (CK) are detectable in the plasma humans, rats or mice (Wang et al., 2011; Ma et al., 2015; Jeon et al., 2020). Tissue distribution studies show that ginsenoside Rg1 accumulates most abundantly in the kidney, particularly in the renal pelvis, compared to the liver, lung, or heart (Wei W. et al., 2021). Functionally, ginsenosides have demonstrated efficacy in preventing acute kidney injury induced by cisplatin- or lipopolysaccharide (LPS) (Wu et al., 2021; Guo et al., 2024; Ma et al., 2024; Wang L. et al., 2024), ameliorating diabetic nephropathy and fibrosis (He et al., 2022; Han et al., 2023; Ji et al., 2023; Li K. et al., 2025; Zhang H. et al., 2025), and inhibiting renal carcinoma progression (Hwang et al., 2022; Ma et al., 2023; Zhao et al., 2024) in cellular and animal models. These protective and anti-tumor effects are mediated through key biological pathways, including modulation of inflammatory responses, oxidative stress, apoptosis, and autophagy.
2.1 Cisplatin-induced nephrotoxicity
Acute kidney injury is a syndrome of rapid-onset renal dysfunction within hours, characterized by elevated proteinuria, serum creatinine, and blood urea nitrogen levels (Hoste et al., 2018). Its global incidence is rising, contributing to substantial healthcare costs (Gonsalez et al., 2019) and is commonly associated with reduced renal perfusion, major surgery, or drug exposure. Cisplatin, a platinum-based chemotherapeutic widely used for solid tumors, induces nephrotoxicity in nearly one-third of patients and poses an additional risk of long-term renal impairment (Motwani et al., 2022). Once taken up by renal cells, cisplatin forms intra- and interstrand crosslinks with DNA, RNA, and proteins, thereby disrupting replication and transcription (McSweeney et al., 2021). Furthermore, this damage-induced acute tubular necrosis can decrease tubular drainage, elevate intratubular pressure and lower the glomerular filtration rate, thereby exacerbating renal injury (McSweeney et al., 2021). The pathological mechanisms of cisplatin-induced nephrotoxicity are multifactorial, including oxidative stress, inflammation, endoplasmic reticulum (ER) stress, necrosis, and apoptosis with key therapeutic targets, such as CXCL1-CXCR2 axis, NOD-like receptor protein 3 (NLRP3), and TLR4 (Li S. et al., 2019; Wang H. et al., 2020; Badr et al., 2023; Park et al., 2024).
Extensive cell and animal studies demonstrate that various ginsenosides, including Rb3, Rh2, Rg3, and others, confer significant nephroprotection against cisplatin-induced injury. Cisplatin administered at 4–25 mg/kg in animal models typically induces nephrotoxicity and acute renal failure (Katagiri et al., 2016; Ozkok et al., 2016; Chatterjee et al., 2017). Multiple ginsenosides target diverse pathways against cisplatin-induced nephrotoxicity. In ICR mouse and HEK293 models, ginsenoside Rb3 significantly reduces serum creatinine, blood urea nitrogen, histopathological damage, and autophagy-related proteins (p62, Atg3, Atg5, Atg7) by modulating AMPK/mTOR signaling (Xing et al., 2019). After 28 days of administration, ginsenoside Rb3 markedly reduces necrotic lesions and TGF-β expression in the kidneys of oral carcinoma xenograft nude mice. In cisplatin-treated GP-293 cells, Rb3 further inhibits mitochondrial apoptosis by suppressing Smad2/3 phosphorylation and blocking the cleavage of PARP and caspase-3/8/9 (Wu et al., 2021). Ginsenoside Re also exhibits nephroprotective effects by improving renal function, lowering malondialdehyde levels (Wang et al., 2018), and attenuating inflammation and apoptosis. Consistently, two independent studies demonstrates that ginsenoside Rg3 mitigates cisplatin-induced nephrotoxicity (Zhai et al., 2021; Zhang et al., 2021). Mechanistically, Rg3 reduced autophagy and NLRP3 inflammasome-associated proteins, including p62, ASC, caspase-1, and IL-1β, thereby protecting against cisplatin-induced cellular injury in HK-2 cells and a murine kidney injury model (Zhai et al., 2021). Another study reveals that Rg3 modulates the PI3K/Akt and NF-κB signalling pathways to alleviate renal apoptosis and inflammation in the kidney tissues of cisplatin-induced mouse model (Zhang et al., 2021). Similarly, ginsenoside Rg5 exerts nephroprotective effects by suppressing inflammation, oxidative stress, and apoptosis (Li et al., 2016). In a cisplatin-induced HK-2 cell model, ginsenoside Rh2 protects renal tubular epithelial cells by inhibiting ER stress and mitochondria-mediated apoptosis (Qi et al., 2019; Wang L. et al., 2024). Ginsenoside Rh3 also demonstrates protective activity, reducing cisplatin-induced apoptosis in renal proximal LLC-PK1 cells through inhibition of the JNK/ERK signaling cascade (Lee and Kang, 2017). Rk1 activates the Nrf2/HO-1 pathway, enhancing glutathione and reducing reactive oxygen species (ROS) production and apoptosis in HEK293 cells (Hu et al., 2020). Combined Rk3 and Rh4 attenuate oxidative damage in cisplatin-induced rat and LLC-PK1 models (Baek et al., 2017). Beyond cisplatin, ginsenosides also protect against other nephrotoxic insults. Rg1 and Rb1 alleviate cadmium- and lithium-induced renal injury by reducing oxidative stress and inflammation (El-Sheikh and Kamel, 2016; Ren et al., 2021). Rb1 prevents bavachin-induced nephrotoxicity by blocking ER stress, epithelial–mesenchymal transition, and fibrosis via Bip/eIF2α/CHOP signaling in HK-2 and zebrafish models (Ni et al., 2022). Similarly, Rb1 mitigates 3-monochloropropane-1,2-diol-induced pyroptosis in mice and rat renal tubules, with chloroquine confirming the role of autophagy (Zhang et al., 2024). In tacrolimus-induced nephrotoxicity, Rb1 inhibits MAPK and caspase activation to reduce apoptosis in LLC-PK1 cells (Lee et al., 2018). Collectively, diverse ginsenosides, including Rb3, Rg3, and others, attenuate drug-induced nephrotoxicity by targeting central mechanisms such as oxidative stress, dysregulated autophagy, ER stress, and mitochondrial apoptosis, thereby offering promising nephroprotective strategies in preclinical models (Table 1; Figure 1A).
Table 1. Protective mechanisms of ginsenosides on the cisplatin-induced nephrotoxicity.
Figure 1. Protective effects and molecular mechanisms of ginsenosides for inhibiting nephrotoxicity and acute kidney injury. (A) Recent findings of ginsenosides for cisplatin-induced nephrotoxicity; (B) Recent findings of ginsenosides for the treatment of acute kidney injury by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP).
2.2 Sepsis-induced acute kidney injury
The bacterial endotoxin, LPS and cecal ligation and puncture (CLP) procedure are widely used experimental models for inducing systemic inflammatory responses and sepsis, conditions that can progress to multiple organ failure or acute injury of the kidney, lung, and liver (Plotnikov et al., 2018; Gonzalez-Nicolas and Lazaro, 2025). Sepsis-associated acute kidney injury is primarily driven by inflammation, microvascular dysfunction, and glomerular/tubular damage. A key mechanism that LPS activates toll-like receptor 4 (TLR4), initiating downstream immune signaling via the NF-κB pathway, which promotes the release of chemokines and cytokines, such as IL-1β, IL-6, IL-8, CXCL2, CXCL10, and CCL20 (Lu et al., 2008). During sepsis, these interleukins, particularly IL-6 and IL-8 further amplify NF-κB signaling, leading to inducible nitric oxide synthase upregulation and nitric oxide (NO) production. Excess NO inhibits cytochrome oxidase and disrupts mitochondrial electron transport, thereby increasing ROS generation (Plotnikov et al., 2018). Similarly, CLP procedure triggers widespread cytokine and chemokine release in the peritoneal cavity, circulation, and peripheral organs (Gonzalez-Nicolas and Lazaro, 2025). Ultimately, multiple signaling axes, including TLR4, IL-18, NADPH oxidase isoform 4 (NOX4), and the Janus kinase/signal transducer and activator of transcription-1/3 (JAK/STAT1/3) pathway, contribute to sepsis-induced acute kidney injury (Nozaki et al., 2017; Yoo et al., 2020; Lee et al., 2024).
Ginsenosides have emerged as promising interventions against LPS- or CLP-induced acute kidney injury, primarily by suppressing renal inflammation, podocyte apoptosis, and ferroptosis (Gao et al., 2020; Guo et al., 2022; Hu Y. et al., 2024). Ginsenoside Rb1 reduces septic mortality in mice challenged with LPS or cantharidin by inhibiting proinflammatory cytokine release, COX-2 and inducible nitric oxide synthase levels in LPS-stimulated RAW264.7 cells and bone marrow-derived macrophages, through modulation of TLR4/MyD88 and NF-κB/MAPK pathways (Gao et al., 2020). Likewise, ginsenoside Rg1 protects against sepsis-induced acute kidney injury in both cellular and animal models (Guo et al., 2022; Guo et al., 2024; Hu Y. et al., 2024). In CLP rats and LPS-stimulated HK-2 cells, Rg1 decreases serum creatinine, blood urea nitrogen, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) levels, while reducing iron accumulation, lipid peroxidation, and ferroptosis (Guo et al., 2022). Mechanistically, Rg1 suppresses renal tubular epithelial ferroptosis via the ferroptosis suppressor protein 1–CoQ10–NAD(P)H pathway (Guo et al., 2024). Additionally, the protective role of Rg1 involves in enhancing SIRT1 activity to inhibit NF-κB signaling, thereby reducing apoptosis, oxidative stress, and inflammation in septic kidneys (Hu Y. et al., 2024). Beyond acute injury, Rg1 also protects against low-dose LPS-induced chronic renal injury and fibrosis by inhibiting NOX4 and the NLRP3 inflammasome (Zhang et al., 2022) or through Nrf2-mediated suppression of AIM2 inflammasome activation (Ji P. M. et al., 2024). Ginsenoside Rk1 provides further renoprotection by blocking NF-κB and JAK2/STAT3 signaling in LPS-induced murine and podocyte injury models (Ma et al., 2024). Moreover, a combination of minor ginsenosides Rg2 and Rh1 exerts synergistic anti-inflammatory effects by targeting macrophages and suppressing TLR4/STAT1-dependent cytokine and NO production (Huynh et al., 2020). Collectively, ginsenosides Rg1, Rb1, and Rk1 confer multi-faceted renoprotection against sepsis-induced acute kidney injury through multiple mechanisms, including TLR4, NF-κB, NLRP3, STAT1/3, and ferroptosis-associated pathways (Table 2; Figure 1B).
Table 2. Protective effects and molecular mechanisms of ginsenosides for reducing acute kidney injury induced by LPS or CLP.
2.3 Diabetic nephropathy
Diabetic nephropathy, a leading cause of end-stage renal disease, is characterized by persistent albuminuria and a progressive decline in renal function (Selby and Taal, 2020). Its hallmark pathological changes include glomerular basement membrane (GBM) thickening, mesangial expansion, glomerulosclerosis, podocyte injury, extracellular matrix accumulation, epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells, and progressive fibrosis (Zhao et al., 2025). Chronic hyperglycemia induces metabolic dysregulation, abnormal hemodynamics, activation of the renin–angiotensin–aldosterone system, fatty acid accumulation, oxidative stress, and inflammation to drive renal damage. These alterations collectively promote the upregulation of growth factors (transforming growth factor-β1, TGF-β1 and vascular endothelial growth factor, VEGF), cytokines (TNF-α, IL-6), and chemokines (CCL2, CXCL10), reinforcing a vicious cycle of renal injury (Chang and Chen, 2020; Tuttle et al., 2022).
The progression of diabetic nephropathy is driven by multiple molecular mechanisms (Tuttle et al., 2022; Hou et al., 2025), including TGF-β1/Smads, NF-κB, MAPK, PI3K/AKT, NLRP3 inflammasome, peroxisome proliferator-activated receptors (PPARs), JAK/STAT, and sodium-glucose cotransporter-2 (SGLT2) pathways. During the process, high glucose enhances TGF-β signaling and Smad-mediated transcription, leading to inflammatory injury, GBM thickening, and extracellular matrix overproduction, thereby driving diabetic renal fibrosis (Wang Y. et al., 2020; Xu et al., 2020). Similarly, PI3K/AKT signaling contributes to the pathology of diabetic nephropathy by promoting inflammation, apoptosis, and EMT (Wang H. et al., 2024). Concurrently, hyperglycemia-induced MAPK and TLR4 activation also enhance NF-κB-dependent TNF-α expression, aggravating renal damage (Abhirami et al., 2025). Recent studies highlight NLRP3 inflammasome, PPAR subtypes, and JAK/STAT signaling as key therapeutic targets, given their critical roles in regulating inflammation, autophagy, EMT, and fibrosis in diabetic nephropathy (Yang et al., 2021; Gao and Gu, 2022; Liu et al., 2023). Importantly, SGLT2 inhibition offers broad renoprotective benefits, mitigating multiple pathological features of diabetic nephropathy (DeFronzo et al., 2021; Papaetis, 2024).
Ginsenosides have been evaluated in diverse animal models of diabetic kidney disease, including high-fat diet (HFD) and streptozotocin (STZ)-induced rodent models and Db/Db mice with leptin receptor mutations, to assess their protective effects against diabetic kidney disease (Chen et al., 2023; Fan et al., 2023). Ginsenoside Rb1 suppresses high glucose-induced cell death, mitochondrial injury, and diabetes-associated glomerular hypertrophy and mesangial expansion by binding to and inhibiting aldose reductase (He et al., 2022). In chronic kidney disease, vascular calcification characterized by calcium deposition and vascular smooth muscle cell osteogenic transdifferentiation, is attenuated by Rb1 via regulation of the PPARγ/Wnt/β-catenin axis in both chronic kidney disease-induced vascular calcification rats and β-glycerophosphate-stimulated vascular smooth muscle cells (Zhou et al., 2019). Another major metabolite, CK, prevents HFD/STZ-induced diabetic nephropathy and high glucose-mediated mesangial cell damage by inhibiting NLRP3 inflammasome activation and the NF-κB/p38 pathway (Song et al., 2018). Furthermore, 16-week CK supplementation remodels the gut microbiota, reducing the level of its metabolite imidazole propionate, thereby downregulating TLR4 signaling and improving renal morphology and microalbuminuria (Chen Q. et al., 2022).
Additional ginsenosides, including Rg1, Rg2, Rg3, Rg5, and Rh1, protect against diabetic kidney disease by preserving podocyte and mesangial cell integrity and inhibiting renal fibrosis. Podocyte and diabetic rat studies show that ginsenoside Rg1 downregulates the mTOR/NF-κB pathway, suppressing hyperlipidemia-induced NLRP3 inflammasome activation and mitigating podocyte injury (Wang T. et al., 2020). Rg1 also alleviates epithelial-mesenchymal transition in high-glucose podocytes and improves renal function in STZ-injected rats through autophagy induction mediated by the AKT/GSK3β/β-catenin pathway (Shi et al., 2020). In mesangial cells, Rg1 markedly counters high-glucose-induced inflammation, oxidative stress, and apoptosis by increasing phosphorylated PI3K/AKT levels and promoting nuclear export of FOXO3 (Liu et al., 2021). In renal fibrosis, multiple studies demonstrate that Rg1 inhibits renal injury and fibrosis through diverse mechanisms. For instance, in a T2DM mouse model induced by HFD/STZ, 8-week Rg1 treatment reduces urinary protein, serum creatinine, and blood urea nitrogen levels by inhibiting CD36/TRPC6/NFAT2 signaling (Han et al., 2023). Other reports show that Rg1 suppresses NOX4-MAPK and TRPC6-ChREBP-TXNIP pathways to limit lipid deposition, ROS accumulation, and glycoprotein deposition in T2DM-associated fibrosis (Ji et al., 2023; Zhang H. et al., 2025). Importantly, Rg1 targets TRPC6 channels to buffer lipid, inflammatory, and oxidative stress signals in diabetic kidneys, as confirmed in Trpc6 knockout mice and through combination with the TRPC6 antagonist BI749327 (Zhang H. et al., 2025). Additionally, Rg1 alleviates aldosterone-induced podocyte injury in diabetic nephropathy and chronic kidney disease by inhibiting oxidative stress and enhancing autophagy (Mao et al., 2014). Collectively, these findings establish Rg1 as a multi-target protective agent against diabetic nephropathy.
Among the ginsenosides, Rg3 is particularly well-studied for diabetic nephropathy. Transcriptomic analysis of renal cortex tissue from diabetic rats revealed that Rg3 modulates genes involved in fatty acid metabolism and PPAR signaling (Wang et al., 2016). Consistently, Rg3 reduces proteinuria, creatinine, and triglyceride levels, while suppressing inflammation via downregulation of TGF-β1, NF-κB p65, and TNF-α (Zhou et al., 2020). Similar effects are observed in HFD/STZ-induced mice, where Rg3 regulates the MAPK/NF-κB pathway to improve glucose and lipid homeostasis, enhance antioxidant capacity, and alleviate renal inflammation (Li et al., 2021). At the cellular level, Rg3 enhances proliferation and prevents apoptosis in high glucose-stimulated SV40 mesangial cells, while ameliorating renal pathological changes in diabetic mice, in part, through the miR-216a-5p/MAPK pathway (Chen et al., 2024). In Db/Db mice, Rg3 improves renal function by regulating inflammation, fibrosis, and PPARγ expression, with effects comparable to ginsenoside Re (Sui et al., 2023). In summary, Rg3 confers comprehensive renoprotection by concurrently targeting inflammation, fibrosis, and fatty acid metabolism through TGF-β1, NF-κB, and PPAR signaling pathways.
Additionally, other ginsenosides such as Rg2, Rg5, and Rh1 have been shown to regulate novel mechanisms relevant to diabetic kidney disease, particularly inflammasome activation and pyroptosis (Zhu et al., 2020; Su et al., 2021; Li K. et al., 2025). Ginsenoside Rg2 reduces NF-κB p65 phosphorylation, suppresses NLRP3 inflammasome activation, and decreases IL-18 and IL-1β release, thereby improving hyperglycemia, dyslipidemia, and renal dysfunction in HFD/STZ-induced diabetic mice (Li K. et al., 2025). Similarly, ginsenoside Rg5 protects against HFD/STZ-induced renal pathology by inhibiting NLRP3 activation, oxidative stress, and inflammatory responses (Zhu et al., 2020). For ginsenoside Rh1, activation of the AMPK/PI3K/AKT pathway mediates the inhibition of advanced glycation end product accumulation and inflammatory factor release, explaining its renoprotective effects in diabetic nephropathy (Su et al., 2021). Combination therapy with ginsenosides and other bioactive compounds is emerging as a promising strategy for the prevention and treatment of diabetic nephropathy. For example, ginsenoside Rb combined with trigonelline ameliorates renal dysfunction and pathological changes in diabetic rats by regulating miR-3350 expression and modulating the Wnt/β-catenin pathway (Shao et al., 2019). Likewise, co-administration of ginsenoside Rg1 and astragaloside IV inhibits diabetic nephropathy-related renal fibrosis through suppression of oxidative stress and the TGF-β1/Smads signaling pathway (Du et al., 2018). Collectively, these evidences from both single-agent and combination studies confirms that multiple ginsenosides, including Rg1 and Rg3, confer protection against inflammation, oxidative stress, apoptosis, and fibrosis in diabetic nephropathy progression through diverse pathways such as PI3K/AKT, TGF-β1, NF-κB, MAPK, and PPAR signaling (Table 3; Figure 2).
Table 3. Protective effects and molecular mechanisms of ginsenosides against diabetic nephropathy.
Figure 2. Protective mechanisms of ginsenosides against HFD/STZ- or STZ-induced diabetic nephropathy.
2.4 Renal cell carcinoma
Renal cell carcinoma is the predominant form of kidney cancer, accounting for approximately 90% of cancers (Rose and Kim, 2024). Key signaling pathways implicated in renal cell carcinoma progression include von Hippel–Lindau–HIF-1α/2α, VEGF, BRCA1-associated protein-1/host cell factor-1, mTOR, and PD-1 signaling (Nabi et al., 2018). Commonly used research platforms for drug evaluation include renal cell carcinoma cell lines (786-O, ACHN, Caki-1, A-498), xenograft models, and genetically engineered mouse models (Shapiro et al., 2022). Several ginsenosides, particularly Rg3 and Rh4, demonstrate anti-tumor effects or enhance drug sensitivity in renal cell carcinoma (Ma et al., 2023; Zhao et al., 2024). In both renal cell carcinoma cell and xenograft models, CK inhibits proliferation, invasion, and migration, while inducing cell cycle arrest and caspase-dependent apoptosis through ROS modulation and regulation of lncRNA THOR (Chen et al., 2021). Ginsenoside Rg3 exerts comparable anti-cancer activity, primarily though the promotion of DNA demethylation and histone acetylation (Ma et al., 2023). Importantly, ginsenosides can potentiate the efficacy of tyrosine kinase inhibitors. For instance, ginsenoside Rh2 enhances sunitinib’s inhibitory effect on renal cell carcinoma by promoting oxidative DNA damage and cell cycle arrest (Hwang et al., 2022). Similarly, ginsenoside Rh4 suppresses Nrf2 signaling, thereby reducing the activities of SOD1, GPX4, and catalase to increase ferroptotic sensitivity, which highlights a promising therapeutic strategy for renal cell carcinoma (Zhao et al., 2024). Collectively, ginsenosides exhibit direct anti-cancer activity and improve drug sensitivity for renal cell carcinoma via regulation of lncRNA THOR, epigenetic remodeling, and Nrf2-mediated ferroptosis (Table 4).
Table 4. Protective effects and molecular mechanisms of ginsenosides against renal cell carcinoma and other kidney diseases.
2.5 Other kidney-related diseases
Multiple studies have demonstrated the renoprotective effects of ginsenosides across a broad spectrum of other kidney diseases, including obstructive nephropathy, IgA nephropathy, glomerulonephritis, and aging-related kidney injury.
In mouse models of ureteral obstruction and aristolochic acid nephropathy, as well as in HK-2 cells, ginsenoside Re treatment suppresses autophagy and reduces TGF-β-stimulated profibrotic markers, thereby mitigating fibrotic injury and preserving kidney function (Liu Y. Y. et al., 2024). Similarly, in rats with unilateral ureteral obstruction, ginsenoside Rg1 inhibits TGF-β1-induced Smad3 phosphorylation while restoring Klotho and Smad7 expression, which collectively attenuate EMT and renal fibrosis (Li et al., 2018). In the monosodium urate-stimulated HK-2 cell model, ginsenoside Rg5 reduces uric acid content, the levels of urate transporter proteins and oxidative stress to reverse the cell damage. In the yeast extract and adenine-induced hyperuricemic mice, it significantly reduces urine uric acid, blood urea nitrogen and serum creatinine levels, reverses pathomorphological changes and uric acid transport. These protective effect of Rg5 above is mediated by the inhibition of oxidative stress, inflammation, and pyroptosis through the modulation of NOX-1-dependent TLR4 and BCL-2 pathways (Zhang Y. X. et al., 2025). In complementary IgA nephropathy models, CK exerts therapeutic effects by suppressing NLRP3 inflammasome activation in renal tissues and macrophages and promoting SIRT1-mediated autophagy (Wu et al., 2020). In an anti-GBM glomerulonephritis mouse model and IL-1β–induced MPC5 podocytes, ginsenoside Rg1 reduces inflammation and apoptosis via Nrf2 activation, an effect confirmed by the Nrf2 inhibitor ML385 (Guo et al., 2019). In lupus nephritis, PPD inhibits PTX3 overexpression, suppresses mesangial cell proliferation, and improves renal pathology in MRL/lpr mice through blockade of the PTX3/MAPK/ERK1/2 pathway (Li et al., 2024). For more aggressive lupus nephritis, M1, a ginsenoside metabolite, markedly reduces albuminuria and renal injury by inhibiting NLRP3 inflammasome, modulating T-helper cell activation, and promoting regulatory T-cell differentiation (Lin et al., 2019). Furthermore, recent multi-omics analyses further reveal that CK alleviates podocyte injury in MRL/lpr mice by regulating bile acid receptor/YAP and SIRT1/AMPK pathways, thereby attenuating mitochondrial fission and suppressing B-cell to plasma cell transition (Song et al., 2024; Li Y. et al., 2025).
For aging-associated kidney injury, ginsenoside monomers consistently demonstrate anti-fibrotic and renoprotective effects across multiple models, including naturally aged mice, SAMP8 mice (a spontaneous amyloid precursor protein-overexpressing strain), and D-galactose-induced subacute aging models. In SAMP8 mice, ginsenoside Rg1 reduces renal tubular injury, fibrosis, glycoprotein deposition, and tubular cell apoptosis by inhibiting ER stress pathways involving GRP78, PERK, and CHOP (Ding et al., 2020). Comparable benefits are observed in D-galactose-treated mice, where Rg1 ameliorates glomerular injury and enhances anti-oxidant capacity (Fan et al., 2016). Similarly, 20(R)-Rg3 prevents oxidative stress-induced renal injury by activating PI3K/AKT signaling (Li W. et al., 2020). A comparative study further indicates that Rg2, PPT, and arginyl-fructosyl glucose attenuate renal dysfunction and aging markers via regulation of insulin/IGF-1, mTOR, and PI3K/AKT pathways (Nguepi Tsopmejio et al., 2025). Collectively, these findings indicate that ginsenoside monomers like CK, Rg1, and Rg5 confer broad protection against nephropathies, including obstructive, hyperuricemic, glomerular, lupus, and aging-related forms through key mechanisms involving inflammasome inhibition, ER stress modulation, pyroptosis suppression, and autophagy regulation (Table 4).
3 Discussion
At present, drug-induced nephrotoxicity, sepsis-associated acute kidney injury, diabetic nephropathy, and renal cell carcinoma remain leading contributors to chronic kidney disease and end-stage renal disease, severely impairing patient survival and quality of life (Turin et al., 2012). This urgent need for novel nephroprotective agents has directed attention to ginseng, a traditional medicinal herb from Jilin Province, China, long recognized as both food and medicine (Song et al., 2025). Among its constituents, ginsenosides, the principal active components of ginseng, have been extensively investigated in both preclinical and clinical studies for their renoprotective effects (Xu et al., 2017; Jin et al., 2021; Fan et al., 2023). While, other constituents, including polysaccharides (Liu et al., 2012; Wei X. M. et al., 2021), arginyl-fructosyl-glucose (Li R. Y. et al., 2019; Tsopmejio et al., 2025), and pectin lyase-modified ginseng extract (Kim et al., 2017; Jung et al., 2021), also show protective effects against nephrotoxicity and diabetic nephropathy, their mechanisms are less well characterized than those of ginsenosides. Reported mechanisms overlap with those of ginsenosides, such as regulation of ER stress, ROS production, and apoptosis, but require further validation in animal and cellular models (Jung et al., 2021; Wei X. M. et al., 2021; Tsopmejio et al., 2025). Comparative studies with other medicinal plants highlight both shared and distinct mechanisms. For instance, Panax notoginseng saponins exhibit renoprotection against cisplatin-induced acute kidney injury and lupus nephritis comparable to those of ginsenosides, but act primarily through HIF-1α/mitochondrial pathways (Li Q. et al., 2020) and macrophage-derived exosome–mediated autophagy (Pan et al., 2025). Differently, astragaloside IV protects podocytes from diabetic nephropathy by modulating the NLRP3 inflammasome (Hu Z. et al., 2024), a mechanism that parallels the action of ginsenosides Rg1, Rg2, and Rg5 (Wang T. et al., 2020; Zhu et al., 2020; Li K. et al., 2025). Together, these findings suggest that saponins from the Araliaceae family provide a broad nephroprotective spectrum, shielding the kidney from diverse drug-induced, inflammatory, and metabolic insults.
This review synthesizes recent advances on the pharmacological efficacy and molecular mechanisms of ginsenosides in protecting against common kidney diseases, including cisplatin-induced nephrotoxicity, sepsis-induced acute kidney injury, diabetic nephropathy, renal cell carcinoma, lupus nephritis, and aging-related kidney injury, as illustrated in the accompanying figures and tables. After reviewing, we find that ginsenosides possess several significant advantages as potential therapies for kidney diseases. Firstly, ginsenosides exhibit a broad-spectrum efficacy from acute injury and chronic diseases to autoimmune diseases and cancer, which enable them to be more holistic therapeutic strategy. Furthermore, they are multi-target agents, which can simultaneously inhibit multiple pathological processes, such as inflammation, oxidative stress, cell death to demonstrate more pronounced effectiveness. This protection is that ginsenosides protect podocytes, mesangial cells, and tubular epithelial cells from various damages to preserve renal structure and function. More importantly, as a bioactive compound mixture, ginsenosides might synergistically enhance their overall efficacy against kidney diseases. Based on these advantages, ginsenosides represent promising candidates for the development of novel therapeutic drugs or potential alternative agents for kidney diseases.
Despite promising preclinical data, several critical issues and future directions warrant attention and could be addressed. First, clinical evaluation remains limited, with only one trial involving 177 patients reporting that ginsenoside Rb1 improves renal function and delays chronic kidney disease progression at early stages by reducing oxidative stress and inflammation to (Xu et al., 2017). Given the lack of robust clinical evidence, more high-quality, large-scale clinical trials are urgently needed to substantiate the therapeutic potential of ginsenosides. Secondly, most studies emphasize the effects of individual ginsenoside on kidney injury and diabetic nephropathy, while their roles in glomerulonephritis, renal pelvis nephritis, and renal failure are rarely investigated. Preclinical studies using diverse animal models of nephritis and chronic kidney disease are crucial to expand our understanding of their pharmacological application. Third, although potential target networks for ginsenoside-mediated renal protection have been proposed, definitive evidence for direct molecular targets is elusive. Gene-edited cell and animal models should be employed to validate these targets, and identify the binding sites using protein interaction technologies or site-directed mutagenesis. Fourth, nanomaterial-based delivery systems, including those incorporating Rg1, Rg3, or combinations of ginsenosides with other drugs, hold significant promise for enhancing bioavailability and therapeutic efficacy (Kim et al., 2018), offering an innovative direction for kidney disease treatment. Collectively, this review consolidates the most recent understanding of ginsenosides against various kidney diseases and discusses ginsenosides’ advantages, and current existing challenges, which provides a clear outlining potential directions for future research.
4 Conclusion
In conclusion, we present the pharmacological efficacy and molecular mechanisms of ginsenosides in cisplatin-induced nephrotoxicity, acute kidney injury, diabetic nephropathy, renal cell carcinoma, lupus nephritis, and aging-related kidney injury, based on evidence from cellular and animal models. Among the commonly studied ginsenosides, CK, Rg1, Rg3, Rh2, Rb1, Rb3, Rg2, and Rg5, are the most extensively investigated. These compounds concurrently modulate diverse signalling pathways, including NF-κB, PI3K/AKT, MAPK, TGF-β/Smad, PPAR, SIRT1, NLRP3, and Nrf2, thereby regulating key pathological processes such as inflammation, oxidative stress, apoptosis, EMT, pyroptosis, aberrant autophagy, and ER stress (Figure 3). This review provides new insights into recent advances for nephroprotective properties and potential mechanisms of ginsenosides. Despite abundant preclinical studies, the clinical investigation of ginsenosides, their renoprotective potential, and direct molecular mechanism still remains slow progression. Future research must prioritize clinical validation, emphasize synergistic potential, and pinpoint precise mechanisms of ginsenosides, which could pave promising avenues for ginsenosides as novel therapeutic agents in kidney diseases.
Figure 3. Protective roles and potential mechanisms of ginsenosides against common kidney diseases, including nephrotoxicity, acute kidney injury, diabetic nephropathy, renal cell carcinoma, and other kidney-related injuries.
Author contributions
TJ: Data curation, Methodology, Writing – original draft, Writing – review and editing. YD: Writing – review and editing, Data curation. CL: Writing – review and editing. JZ: Writing – review and editing, Supervision. TL: Conceptualization, Supervision, Writing – review and editing, Visualization.
Funding
The authors declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Abbreviations
CLP, Cecal ligation and puncture; EMT, Epithelial-to-mesenchymal transition; ER, Endoplasmic reticulum; GBM, Glomerular basement membrane; HFD, High-fat diet; LPS, Lipopolysaccharide; NLRP3, NOD-like receptor protein 3; PPAR, Peroxisome proliferator-activated receptors; ROS, Reactive oxygen species; STZ, Streptozotocin; TLR4, Toll-like receptor 4.
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Keywords: ginsenosides, common kidney disease, diabetic nephropathy, acute kidney injury, ginseng
Citation: Jin T, Du Y, Liu C, Zhao J and Liu T (2025) Advances in ginsenoside treatment for common kidney diseases: pharmacological evaluation and potential mechanisms. Front. Pharmacol. 16:1702234. doi: 10.3389/fphar.2025.1702234
Received: 09 September 2025; Accepted: 24 November 2025;
Published: 03 December 2025.
Edited by:
Abeda Jamadar, University of Kansas Medical Center, United StatesReviewed by:
Aabid Hussain, Cleveland Clinic, United StatesSwetha Thiyagarajan, Independent Researcher, Sunnyvale, CA, United States
Ayantika Sen Gupta, Stowers Institute for Medical Research, United States
Copyright © 2025 Jin, Du, Liu, Zhao and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jingming Zhao, emptNjcwMThAaG90bWFpbC5jb20=; Tiejun Liu, bGl1dGllanVuNjk5QDE2My5jb20=