Mechanistic insights into the regulation of glucose‒lipid metabolism by the bioactive constituents of ginseng

Abstract

Panax ginseng Meyer (P. ginseng, PG), a historically used phytotherapeutic agent with a long history and wide-ranging applications, has garnered increasing attention in recent years because of its considerable pharmacological value. Amid the global rise in metabolic disorders, P. ginseng, as a natural product, has been demonstrated to contain various bioactive components—including ginsenosides, P. ginseng polysaccharides, and P. ginseng peptides—that have significant pharmacological effects on glucose and lipid metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). These bioactive compounds modulate glucose and lipid metabolism through multitarget mechanisms, including enhancing glucose uptake and glycogen synthesis, inhibiting gluconeogenesis, and regulating adipocyte differentiation and fatty acid oxidation, as well as through gut microbiota-mediated regulation of glucose‒lipid metabolism. These effects help alleviate pathological conditions such as insulin resistance (IR), inflammation, oxidative stress, and endoplasmic reticulum (ER) stress, involving key signaling pathways such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor gamma (PPARγ). As a result, P. ginseng shows significant promise and holds great potential for preventing and treating glucose‒lipid metabolic disorders. Ongoing advances in research and technology may further elucidate its underlying mechanisms and facilitate clinical translation, paving the way for the development of more effective therapeutics for metabolic regulation.

Graphical abstract

1. Introduction

With the continuous improvement in living standards and increasing work-related stress, unhealthy lifestyle habits such as high-fat diets (HFDs) and irregular sleep patterns have become increasingly prevalent, resulting in metabolic imbalances that can lead to serious glucose and lipid metabolic disorders [1]. These disorders have become among the most critical detrimental effects on human health and contribute to the onset and progression of chronic diseases, such as obesity, insulin resistance (IR), type 2 diabetes mellitus (T2DM), hyperlipidemia, hypertension, nonalcoholic fatty liver disease (NAFLD), atherosclerosis, and cardiovascular disease (CVD) [2]. Data from the Global Burden of Disease (GBD) 2023 study indicate that elevated fasting plasma glucose (FPG) and high low-density lipoprotein (LDL) cholesterol—both ranked among the world's top ten health risk factors—together contribute to approximately 9 % of the total global health loss. These metabolic abnormalities are key drivers of the growing burden of chronic diseases related to impaired glucose and lipid metabolism [3]. The IDF forecasts that diabetes will affect 643 million people by 2030 and 783 million by 2045 [4]. NAFLD, which is present in approximately 25 % of the global population, ranks among the top chronic liver diseases [5]. Together, these increasing metabolic disorders impose substantial health and economic burdens worldwide. Thus, discovering new therapies to reduce the effects of these disorders on patients' quality of life is essential.

P. ginseng, a globally recognized and historically treasured medicinal herb often referred to as the “King of Herbs”, has been used for more than 4,000 years [6]. Common species of the Panax genus used in traditional medicine include Panax quinquefolius L. (American ginseng), Panax ginseng C.A. Meyer (Asian ginseng), and Panax notoginseng (Sanqi) [7], all of which are valued for their pharmacological properties. P. ginseng can be classified into white ginseng (WG), red ginseng (RG), and black ginseng (BG) on the basis of its preparation processing techniques. WG is produced by air-drying freshly harvested P. ginseng roots, RG is obtained by steaming fresh or raw roots under controlled conditions, and BG is processed after being steamed nine times in succession and drying. The species and processing differences significantly influence the content and structural characteristics of P. ginseng bioactive compounds, resulting in variability in pharmacological efficacy and therapeutic applications.

Specifically, WG, which undergoes minimal processing, largely preserves the native polar ginsenosides found in fresh roots [8]. Metabolomic studies have demonstrated that WG is rich in primary ginsenosides such as Rb1, Re, Rg1, and Rd, which are prone to degradation during processing [9]. These compounds have been extensively validated in both in vitro and in vivo studies for their significant bioactivities, including regulation of glucose metabolism, enhancement of insulin sensitivity, and anti-inflammatory effects. RG, produced by a single steaming process, induces partial deglycosylation and dehydration reactions in ginsenosides, leading to thermal degradation and the transformation of primary ginsenosides such as Rg1, Re, and Rb1 into minor secondary ginsenosides such as Rg3, Rh1, and Rh2. This endows RG with distinct chemical profiles and pharmacological properties [10]. Compared with WG, RG exhibits more pronounced antioxidant and antitumor activities, making it particularly suitable for interventions targeting chronic diseases [11]. BG is subjected to multiple cycles of steaming and drying, which further promote complex transformations of ginsenosides [12], resulting in a marked increase in less polar secondary ginsenosides, including Rg3, Rg5, and Rk1. These structurally modified compounds display enhanced anti-inflammatory, antioxidant, and anticancer effects, which often render BG pharmacologically superior to both WG and RG in certain contexts [13,14].

Over the past five decades, extensive research has substantiated the potential of P. ginseng for the prevention and management of glucose and lipid metabolic disorders; however, most reports have provided simple summaries of clinical or basic studies and lack a systematic and comprehensive analysis of its efficacy and mechanism of action. The active components of P. ginseng are the core substances that enable the efficacy of ginseng. Their presence helps increase bioavailability, but previous reviews have not comprehensively summarized the role of such components in improving glycolipid metabolism. Therefore, this review comprehensively presents the research achievements in this field, including animal experiments and clinical research evidence, to summarize the safety issues and limitations in the application of P. ginseng as well as describe the research progress of P. ginseng active component extraction technology. The aims were to provide comprehensive evidence support for improving the clinical application of P. ginseng in metabolic diseases and deeply explore its action targets.

2. Overview of bioactive components of P. ginseng

P. ginseng has a wide range of pharmacokinetic properties [15]. With advancements in scientific techniques and analytical technologies, more than 300 distinct bioactive compounds have been identified in P. ginseng to date. These include ginsenosides, polysaccharides, peptides, flavonoids, and phytosterols, whose chemical structures are illustrated in Fig. 1 and Table 1. Among these compounds, ginsenosides are considered the principal contributors to the pharmacological activity of P. ginseng. Most ginsenosides are triterpenoid saponins [16] and have been shown to have various beneficial effects, including improvements in energy metabolism and the inhibition of autophagy and antioxidant, anti-inflammatory, antiaging, and anticancer properties [17].

Fig. 1.

Active components of P. ginseng regulate glucose–lipid metabolism.

Table 1.

Active components of ginseng in the regulation of glucose–lipid metabolism.

Active component of ginseng	Classification	Sources	Reference
Ginsenoside Rb1	PPD-type ginsenoside	WG > RG	[21]
Ginsenoside Rb2	PPD-type ginsenoside	WG > RG	[24]
Ginsenoside Rg1	PPT-type ginsenoside	WG > RG	[25]
Ginsenoside Rg3	PPD-type ginsenoside	RG, BG > WG	[29]
Ginsenoside Rf	PPT-type ginsenoside	WG > RG	[45]
Ginsenoside Re	PPT-type ginsenoside	Leaves, berries > roots	[47]
Ginsenoside Rd	PPD-type ginsenoside	roots > leaves, berries	[72]
Ginsenoside compound K (CK)	Newly discovered ginsenosides	Leaves, berries > roots	[21]
Ginsenoside T19 (ambiguous)	Newly discovered ginsenosides	/	[54]
Ginseng rare sapogenins 25-OH-PPT	Newly discovered ginsenosides	Leaves, berries > roots	[35]
Ginsenoside Mc1 (ambiguous)	Ginseng polysaccharides	/	[58]
GPS	Ginseng peptide	/	[27]
GP	PPD-type ginsenoside	RG, BG > WG	[81]

On the basis of their chemical structure, ginsenosides are typically categorized into two distinct groups: protopanaxadiol-type ginsenosides (e.g., Rb1, Rb2, Rg3, Rh2, and Rh3) and protopanaxatriol-type ginsenosides (e.g., Re, Rg1, Rg2, and Rh1).

P. ginseng polysaccharides are among the most abundant constituents in P. ginseng and are particularly prevalent in the root and demonstrate a broad spectrum of bioactivities, including anticancer, antiaging, immunomodulatory, and antioxidant effects [18]. As macromolecules, polysaccharides are generally not readily absorbed through intestinal epithelial membranes. Recent studies have revealed their prebiotic role in modulating the gut microbiota, thereby influencing the metabolism and bioavailability of ginsenosides and creating a synergistic pharmacological effect.

3. Mechanisms through which P. ginseng bioactive compounds regulate glucose metabolism

3.1. Regulation of intestinal glucose absorption by P. ginseng bioactives

Glucose serves as the primary source of energy and nutrients for eukaryotic cells. In the context of glucose metabolism, glucose absorption refers to the process by which digested glucose is transported from the intestinal lumen into the bloodstream, primarily occurring in the small intestine. This process is mediated by specific glucose transporters located on the epithelial cells lining the intestinal tract. In healthy individuals, blood glucose levels are maintained within a relatively stable range through a dynamic balance of glucose metabolism. Impaired intestinal glucose absorption can result in clinical symptoms such as malnutrition, weight loss, diarrhea, dehydration, and acidosis [19]. Chronic disruptions in glucose metabolism may, over time, contribute to the development of various metabolic disorders.

RG, Panax ginseng Meyer, which has been traditionally used for thousands of years in several countries, is known for its pharmacological activities, including antidiabetic effects. Its major bioactive components, particularly ginsenosides, have been shown to reduce blood glucose levels and alleviate IR. A study demonstrated that the nonsaponin fraction of red ginseng (KGC 05P0) inhibited the activity of α-glucosidase and α-amylase in Caco-2 cells in vitro at concentrations ranging from 100 to 2000 mg/mL, thereby reducing glucose digestion and absorption and further supporting its potential antidiabetic properties [20].

The regulatory effect of ginsenoside compound K (CK), a deglycosylated metabolite of ginsenoside Rb1 (GRb1) produced by the gut microbiota, on glucose absorption has been investigated. In vitro experiments revealed that CK at concentrations of 0.01 and 0.1 μM significantly induced the expression of sodium‒glucose cotransporter 1 (SGLT1) and enhanced glucose uptake in human intestinal Caco-2 cells. Similarly, in vivo studies also demonstrated a marked promotion of intestinal glucose absorption. Mechanistic investigations revealed that CK upregulates SGLT1 expression by activating the EGFR-CREB signaling pathway [21]. These findings suggest a novel mechanism through which P. ginseng bioactive compounds can modulate intestinal glucose transport.

3.2. Mechanisms through which P. ginseng bioactives regulate glucose uptake and transport

Glucose uptake and transport represent the initial and rate-limiting steps in glucose metabolism, directly influencing systemic energy homeostasis. These processes are mediated by the coordinated actions of glucose transporter proteins (GLUT2 and GLUT4) and are tightly regulated by insulin signaling and energy-sensing pathways such as the AMPK pathway. Improving glucose uptake and disposal in peripheral tissues—including the liver, adipose tissue, and skeletal muscle—is therefore critical for managing metabolic dysregulation [22].

Ginsenoside F2 (GF2), a minor yet pharmacologically potent saponin in P. ginseng, has been reported to enhance glucose metabolism. In an in vitro insulin resistance model using HepG2 cells, treatment with 12.5–50 μM GF2 significantly ameliorated metabolic dysfunction by activating the PI3K/AKT pathway, thereby upregulating the expression of the glucose transporters GLUT2 and GLUT4 [23].

Another study demonstrated that ginsenoside Rb2 improved glucose metabolism in HFD-induced obese mice. Mechanistically, Rb2 (40 mg/kg/day via intraperitoneal injection for 10 consecutive days) increased glucose uptake in 3T3-L1 adipocytes through activation of the IRS-1/PI3K/AKT pathway, confirming that phosphorylated AKT in adipose tissue plays a vital role in glucose regulation [24].

Ginsenoside Rg1 and Re [25]have also been shown to increase GLUT4 expression and glucose uptake through the activation of AMPK in C2C12 (Rg1 at 50 μM for 24 h) myotubes and PPARγ (Re at 10–100 μM for 5–8 days) in 3T3-L1 adipocytes, respectively.

In a bioactivity-guided screening study using zebrafish larvae and the fluorescent glucose analog 2-NBDG, GRb1 was identified as a potent stimulator of glucose uptake. Further investigations revealed that GRb1 (administered at 20–200 μg/mL) targets riboflavin transporter and riboflavin kinase, providing a novel mechanism and therapeutic target for the hypoglycemic effects of P. ginseng bioactivities [26]. These findings suggest that P. ginseng bioactive compounds contribute to improved systemic glucose homeostasis by modulating glucose uptake and transport in peripheral tissues.

3.3. Mechanisms through which P. ginseng bioactives regulate glycolysis

Glycolysis, the metabolic pathway that converts glucose into pyruvate, plays a central role in rapid ATP production and provides precursors for various biosynthetic pathways. This process is precisely regulated by cellular energy status, hormone signaling, and metabolic feedback, which require the coordinated action of key enzymes. P. ginseng bioactive compounds have been shown to modulate glycolysis by influencing glycolytic and gluconeogenic signaling pathways, thereby contributing to glucose homeostasis.

P. ginseng polysaccharide (GPS), a primary active component of P. ginseng polysaccharide (PG), has demonstrated protective effects against oxidative stress and plays a significant role in energy metabolism. Studies have demonstrated that GPS (25–100 μg/mL) restores the activities of key glycolytic enzymes, including pyruvate kinase (PK), hexokinase (HK), and phosphofructokinase (PFK), as well as the N-terminal cytoplasmic domain of the band 3 protein. These effects facilitate glycolysis in rat erythrocytes, helping to correct energy imbalances induced by oxidative stress. These findings support the potential of GPS and its derivatives as antioxidant agents for treating oxidative stress–related metabolic disorders and lay the groundwork for elucidating its mechanisms in optimizing glucose energy metabolism [27].

20(S)-Rh2, a ginsenoside isolated from P. ginseng, has been chemically modified by conjugation with protopanaxadiol and 2-deoxyglucose to create a novel 20(S)-Rh2 derivative. At concentrations ranging from 3.125 to 100 μmol/L, this compound exerts a regulatory effect on energy metabolism by inhibiting glycolysis, reducing glucose uptake, and limiting ATP production [28].

Integrated analyses combining metabolomics, proteomics, and targeted metabolomics have revealed that ginsenoside Rg3 (GRg3), a key component of total ginsenosides, modulates glycolytic activity. In a study involving transverse aortic constriction (TAC)-induced cardiac dysfunction in mice, Rg3 significantly improved cardiac function. Mechanistically, Rg3 (administered at 10 or 20 mg/kg/day in vivo and 10 mmol/L in vitro) promoted glucose uptake in insulin-resistant H9c2 cells via activation of AMPK, with effects dependent on insulin signaling. These findings demonstrate that Rg3 alleviates myocardial IR and enhances glycolysis, highlighting the molecular mechanisms through which P. ginseng bioactives regulate glucose metabolism [29]. Overall, P. ginseng bioactive compounds help maintain glucose homeostasis by modulating energy metabolism and glycolytic activity.

3.4. Mechanisms through which P. ginseng bioactives regulate glycogen synthesis

Glycogen synthesis is crucial for energy storage and metabolic homeostasis, with the liver acting as a key organ in this regulatory process. The serine/threonine kinase AKT is a crucial mediator of insulin signaling and hepatic glucose metabolism. It facilitates glycogen synthesis by inhibiting the activity of GSK3β, a key negative regulator of glycogen synthase [30]. However, under insulin-resistant conditions, the insulin-mediated activation of AKT is impaired, leading to decreased glycogen synthesis and elevated blood glucose levels.

Although the role of GRb1, a major bioactive saponin in P. ginseng, in hepatic glycogen synthesis remains underexplored, a recent study revealed that treatment with GRb1 (40 mg/kg/day in vivo and 10 μmol/L in vitro) enhances the phosphorylation of both AKT and GSK3β in the liver of T2DM mice, thereby promoting glycogen synthesis. Additionally, in vitro studies suggest that GRb1 may act through the 15-hydroxyprostaglandin dehydrogenase (15-PGDH)/prostaglandin E2 (PGE2)/EP4 receptor signaling pathway to facilitate glycogen accumulation [31].

Metabolic diseases such as diabetes are often characterized by the dysregulation of AMPK, insulin receptors, and glucose transporters. A study reported that P. ginseng bioactivities significantly reduced blood glucose levels in diabetic rats, potentially by upregulating AMPK, insulin receptor A, and GLUT2. In this study, P. ginseng was orally administered at a dosage of 200 mg/kg/day for 30 days. These compounds also modulate the activity of hepatic glucokinase and glycogen synthase, thereby improving glucose utilization and glycogen synthesis [32]. In summary, these findings indicate that P. ginseng bioactive compounds promote glycogen synthesis by modulating key signaling pathways and enzymatic activities in the liver, thereby contributing to the maintenance of glucose homeostasis.

3.5. Mechanisms through which P. ginseng bioactives regulate insulin levels and insulin signaling pathways

The regulation of glucose metabolism in target tissues primarily depends on two core signaling pathways: the IRS-1/PI3K/Akt pathway and the AMPK pathway. Among them, the IRS-1/PI3K/Akt cascade is widely recognized as a critical mediator of the role of insulin in maintaining glucose homeostasis, whereas AMPK serves as a key regulator of glucose–lipid metabolism [33]. Dysfunctional insulin secretion due to pancreatic β-cell impairment or disrupted signal transduction leads to IR, resulting in glucose metabolic imbalance and hyperglycemia. Through IRS-1 and downstream signaling, insulin facilitates cellular glucose uptake and utilization.

PPARγ, a key insulin sensitizer, is a therapeutic target in metabolic disorders. Protopanaxatriol (PPT), a major ginsenoside backbone, has been identified as a novel PPARγ antagonist that alleviates obesity and metabolic syndrome by inhibiting PPARγ activity. Studies have shown that PPT significantly improved obesity, IR, hepatic steatosis, and dyslipidemia in diet-induced obese (DIO) and ob/ob mice (1 g/kg/day orally for 4 weeks in DIO mice and 2 weeks in ob/ob mice). It also improved hepatic insulin sensitivity while reducing body weight and lipid levels in DIO models [34].

The AKT-FoxO1 pathway mediates the inhibitory effect of ginsenoside Rg1 on glucagon-induced hepatic glucose production. Another rare component, 25-hydroxy-PPT, derived from P. ginseng stems and leaves, was shown to ameliorate hyperglycemia and promote glucose homeostasis in mice with diabetes induced by STZ injection (administered orally at 50 and 100 mg/kg/day). Mechanistically, this compound increased GLUT4 and AMPK expression in skeletal muscle and activated insulin signaling, thereby improving insulin sensitivity. In db/db mice, 25-OH-PPT exerted hypoglycemic effects primarily through insulin pathway activation [35].

PPT, a deglycosylated ginsenoside metabolite, significantly increased insulin sensitivity in insulin-resistant mice by activating the AKT pathway. These findings suggest that PT may play a key role in improving IR through the modulation of insulin signaling [36]. Furthermore, P. ginseng oligopeptides (GOPs) partially restored glucose tolerance test (OGTT) outcomes and increased circulating insulin levels while downregulating NF-κB signaling in diabetic rats (administered orally at 0.125, 0.5, and 2.0 g/kg body weight for up to 52 weeks) [37].

AMPK also plays a pivotal role in energy metabolism regulation. Malonyl ginsenosides (PG-MGR), a novel ginsenoside subclass identified by HPLC‒ESI‒MS/MS containing 16 distinct compounds, were effective at ameliorating IR and improving glucose tolerance in both in vitro and in vivo models (administered orally at 150 and 300 mg/kg/day for 5 weeks in vivo). These effects are mediated through the activation of the IRS-1/PI3K/AKT and AMPK pathways, highlighting the potential of PG-MGR to correct metabolic dysfunction [38].

Network pharmacology analysis further revealed that ginsenosides can regulate key proteins such as VEGFA, Caspase-3, and TNF-α, thereby modulating insulin signaling, TNF signaling, and AMPK signaling to mitigate diabetes-related metabolic disorders [39]. Additionally, P. ginseng polysaccharide GPS-1 (administered orally at 200 mg/kg/day for 5 weeks) increased AMPK phosphorylation and influenced its downstream targets by reducing the transcription of sterol regulatory element-binding protein-1c (SREBP-1c) and activating acetyl-CoA carboxylase (ACC), resulting in reduced lipid accumulation and total cholesterol (TC) and triglyceride (TG) levels [40]. In summary, P. ginseng bioactive compounds enhance insulin sensitivity and regulate key insulin signaling pathways, thereby contributing to the maintenance of glucose homeostasis.

3.6. Mechanisms through which P. ginseng bioactives regulate inflammation and oxidative stress

Chronic inflammation significantly contributes to the onset of insulin resistance, with significant evidence connecting chronic inflammation to IR and its potential causative effects [41]. The bioactive compounds in P. ginseng have been shown to reduce the expression levels of genes associated with glucose–lipid metabolism while also lowering leptin, insulin, and adiponectin levels, all of which are crucial in managing metabolic diseases [42]. Oxidative stress is defined as the balance between antioxidants and reactive oxygen species (ROS). ROS produced in white adipose tissue affect adipocyte endocrine function and metabolic activity, while elevated oxidative stress is closely associated with abdominal obesity and IR, leading to the development of metabolic diseases [43]. Over time, this damage can contribute to diabetic complications such as diabetic nephropathy and retinopathy. Therefore, glucose-induced oxidative stress is considered a critical starting point in the pathogenesis of all chronic diabetes complications.

Research has shown that GRb1 and CK maintain the activation of PI3K/AKT signaling. Additionally, Rb1 and CK (both applied at 10 μM in high-glucose–induced 3T3-L1 adipocytes and ex vivo in mouse epididymal adipose tissue) inhibit the activation of the NLRP3 inflammasome associated with endoplasmic reticulum (ER) stress, thereby reducing inflammation and optimizing insulin signaling [44]. Moreover, GRb1 has been shown to restore redox balance and regulate riboflavin metabolism, significantly improving glucose metabolism.

In vitro experiments investigating the effects of ginsenoside Rf on 3T3-L1 adipocytes (30 mg/kg orally for 4 weeks) revealed that Rg1 effectively reduced the activation of the NLRP3 inflammasome, thereby decreasing the induction of proinflammatory cytokines, such as IL-1β and IL-18, and alleviating hepatic inflammation. These findings indicate that Rg1 may play a therapeutic role in NAFLD by regulating lipid peroxidation, alleviating ER stress, and inhibiting inflammasome activation [45]. Additionally, Rg1 (10, 20, and 40 mg/kg, administered via intraperitoneal injection) suppressed the expression of IL-1β, IL-6, TNF-α, NF-κB, and G6β while upregulating p-AKT expression, demonstrating its potential to reduce inflammation and improve IR by reducing glucose output [46].

Studies have also confirmed the antidiabetic and antioxidant properties of ginsenoside Re (30 mg/kg orally for 30 days), demonstrating its ability to increase insulin secretion and activate cannabinoid receptor 1 (CB1) and CaMKKβ, which in turn triggers AMPK signaling and significantly reduces oxidative stress-induced metabolic disorders in T2DM rats [47]. P. ginseng stem-leaf GSL (at doses of 1.25 %, 2.5 %, and 5 %) extracts improve antioxidant and immune functions, lowering serum TG and TC levels [48].

A study evaluating the protective effects of P. ginseng saponins (GSs) administered at a dosage of 300 mg/kg in α-naphthyl isothiocyanate (ANIT)-induced endotoxemia (IC) mice demonstrated that GSs upregulated Nrf2 and its downstream targets, significantly alleviating oxidative damage induced by ANIT. Through the SIRT1/AMPK signaling pathway, GSs aided in restoring the interplay between lipid synthesis and breakdown and oxidative status in the hepatic environment of ANIT-induced IC mice [49]. Collectively, these findings indicate that P. ginseng bioactives mitigate inflammation and oxidative stress, thereby supporting systemic glucose regulation. The mechanisms of P. ginseng active components in the regulation of glucose metabolism are described in (Fig. 2; Table 2). The anti-inflammatory and antioxidant mechanisms of the active components of P. ginseng are summarized in Table 3.

Fig. 2.

Active components of P. ginseng regulate glucose metabolism.

Table 2.

Summary of the mechanisms underlying the glucose metabolism of the active components of ginseng.

Glucose metabolism mechanism	Active component	Source	Disease(s)	Model(s)	Targets	Reference
Promotes glucose uptake	Ginsenoside Rb1	American ginseng	IGT	Zebrafish larvae	SLC52A1, SLC52A3, RFK	[26]
Promotes glucose uptake	Ginsenoside Rb2	/	Obesity; insulin resistance	3T3-L1 adipocytes; HFD-induced male C57BL/6J mice	AKT, IRβ, IRS -1, PI3K, p-AKT, JNK, MAPK, NF -κB	[24]
Promotes β-cell dysfunction and death	GOPs	Panax ginseng C.A. Meyer	T2DM	HFD-induced male SD rats	NF-κ B, Bcl - 2	[37]
Promotes glycogen synthesis	Ginsenoside Rb1	Panax ginseng C.A. Meyer	T2DM	HFD + STZ-induced male C57BL/6J mice	AKT, GSK3β, 15 - PGDH, PGE2, EP4	[31]
Regulate insulin levels and insulin signaling pathways	Ginsenoside Rg1	/	T2DM	HFD-induced male C57BL/6J mice; HepG2 cells	Akt, FoxO, G6Pase, PEPCK	[35]

Table 3.

Summary of the inflammatory or oxidative stress mechanisms associated with the active components of ginseng.

Inflammation/oxidative stress mechanism	Active component	Source	Disease	Model(s)	Targets	Reference
Suppresses inflammatory response	Ginsenoside Rg1	/	Insulin Resistance	HFD-induced adult SD rats	IL-1β, IL-6, TNF-α, NF-κB, IRS/PI3K/Akt, G6pase	[45]
	Ginseng rare sapogenins 25-OH-PPT	ginseng stems and leaves	T2DM	Male C57BL/6J mice; male DB/DB mice	GLUT4, AMPK, IR, IRS, pAKT.	[35]
	GPs	/	T2DM	Male db/db mice	p-P38, p-JNK, p-ERK 1/2, GLUT2, INSR, p-IRS-1, p-PI3K, p-AKT, SOD, GSH-Px, MDA, IL - 6, TNFα	[103]
Suppresses oxidation effects	Ginsenoside Re	Panax ginseng C.A. Meyer	T2DM	HFD-induced male Wistar rats	CB1, CaMKK β, AMPK	[47]

4. P. ginseng active components and the regulation of lipid metabolism

4.1. Mechanisms through which P. ginseng active components regulate lipid synthesis and accumulation

Lipid synthesis and accumulation involve a multilayered molecular regulatory network involved in lipid metabolism. Liver and adipose tissues play central roles in this process, with the liver being a key organ in both lipid production and clearance. Excessive accumulation of hepatic lipids can result in lipid metabolic disorders and poses a risk for the development of diabetes, syndromes of metabolic imbalance and cardiovascular complications. Therefore, maintaining lipid homeostasis is particularly important.

Ginsenoside Rg1, a steroidal glycoside and triterpenoid saponin derived from P. ginseng, has shown promising effects in a zebrafish model. Research has indicated that in vivo dietary supplementation with an unspecified dose of Rg1 (25–100 μM) significantly reduces lipid accumulation during the early stages of 3T3-L1 adipocyte differentiation compared with that of the intermediate and late stages. HOP10, which suppresses early adipocyte differentiation by inhibiting the expression of adipogenic factors such as C/EBPα and PPARγ while stimulating fatty acid synthase (FASN) expression. This inhibition of early adipocyte differentiation ultimately reduces fat accumulation in vivo [50]. Additionally, Rg1 (at in vitro concentrations of 50, 100, and 200 μg/mL; 50 mg/mL via gavage in vivo) significantly downregulates the transcriptional activity of genes related to fatty acid synthesis and lipid metabolism [51], aiding in the regulation of lipid metabolism and the reduction of fat accumulation. These findings suggest potential targets and pathways involved in this process.

Treatment with Rg3 (at concentrations of 50–100 μM) also reduced lipid accumulation and TG levels in 3T3-L1 cells. Active components from fermented P. ginseng extract (HPG) (100–200 μg/mL) reduce lipid accumulation in 3T3-L1 adipocytes [52]. Experimental results further revealed that active P. ginseng components (at 10 μg/mL in vitro) inhibit intracellular lipid and TG accumulation and suppress the activity of glycerol-3-phosphate dehydrogenase (GPDH), a key enzyme in TG synthesis [53]. GPDH activity and intracellular lipid levels were notably lower in the HPG group than in the WRG group.

As mentioned earlier, the novel ginsenoside 25-hydroxyl-protopanaxatriol (T19) (administered in vivo at 30 and 60 mg/kg/day) not only lowers blood glucose by activating the insulin signaling pathway but also significantly improves plasma biochemical parameters—such as LDL-C, HDL-C, TG, and TC—in HFD/STZ-induced diabetic mice, thereby reducing lipid accumulation and ameliorating lipid metabolism disorders [54].

Ginsenoside Rb1 (GRb1, 20 μM in vitro; 2-week treatment in vivo) improves hepatic steatosis by upregulating adiponectin expression and enhancing insulin sensitivity via activation of the AMPK pathway, thereby reducing hepatic fat accumulation. These effects are significantly diminished in adiponectin-deficient mice [55]. In another study using Rg1 treatment in HFD-induced obese mice, Rg1 (20 mg/kg/day via gavage for 4 weeks) showed anti-fat accumulation effects by modulating the expression of genes involved in lipid metabolism [56], significantly reducing body weight and TG and TC levels.

Treatment of 3T3-L1 adipocytes with ginsenoside Rf (administered at concentrations of 1, 10, 50, and 100 μM for 48 h) resulted in the downregulation of PPARγ and apolipoprotein expression and dose-dependent reductions in lipid accumulation [57]. Moreover, the ginsenoside compound Mc1, a newly identified deglycosylated ginsenoside, has been shown to reduce lipid synthesis induced by obesity and prevent hepatic fat accumulation in HFD-fed mice (administered intraperitoneally at 10 mg/kg/day for 4 weeks). These findings indicate that Mc1 could serve as a potential therapeutic agent for preventing IR-related NAFLD [58].

4.2. Mechanisms through which P. ginseng active components regulate lipophagy

Autophagy is a fundamental intracellular degradation process that maintains cellular stability by breaking down aged or damaged organelles, misfolded proteins, and other cellular components, thereby promoting the recycling of intracellular materials and providing energy for cell survival. Lipophagy, a distinct form of autophagy, is essential for preserving intracellular lipid homeostasis [59]. By reducing hepatic lipid accumulation, autophagy can help alleviate lipid metabolism disorders, making it an essential mechanism in the regulation of lipid metabolism.

Palmitic acid, a major saturated fatty acid derived primarily from a HFD, undergoes lipolysis and is subsequently absorbed and utilized by various organs and tissues, such as adipose tissue, liver, heart, and skeletal muscle. In states of overweight or obesity—especially when coupled with IR—the production of nonesterified fatty acids (NEFAs) is significantly elevated [60].

GRb1 has been shown to stimulate autophagic flux in both HFD-fed mice and palmitic acid (PA)-treated HepG2 cells (administered intraperitoneally at 30 mg/kg/day for 30 days in vivo; 25–100 μM in vitro, with 50 μM being most effective). It does so by suppressing miR-128 expression, thereby enhancing the transcription of TFEB and its downstream lysosomal genes, which in turn increases the ability of the lysosome to degrade autophagosomes. This process facilitates the degradation of lipid droplets through lipophagy and diminishes lipid accumulation caused by a HFD and exposure to palmitic acid [61].

Ginsenoside Rb2 has also been shown to effectively induce autophagic responses both in vivo and in vitro, thereby preventing excessive lipid accumulation in the liver. Experimental data revealed that Rb2 treatment (40 mg/kg, intraperitoneal injection, daily) in male db/db mice markedly increased glucose tolerance, reduced hepatic lipid deposition, and restored hepatic autophagic function. Furthermore, in vitro experiments demonstrated that treatment with Rb2 (10–40 μM) significantly modulates liver lipid retention and autophagy, effects that are markedly attenuated when either the SIRT1 or AMPK pathway is pharmacologically inhibited [62].

4.3. Mechanisms through which P. ginseng active components regulate lipolysis

Abnormal lipolysis in hyperlipidemic animal models can be effectively reduced through P. ginseng treatment. Studies have shown that heat processing significantly increases the content of ginsenosides in P. ginseng. Furthermore, in vivo experimental data confirm that heated P. ginseng (5 % w/w in diet, administered daily for 8 weeks to ovariectomized SD rats) can effectively suppress excessive fat accumulation while promoting lipid catabolism. Plasma lipid factor measurements indicated that rats fed heat-processed P. ginseng had a significantly reduced risk of obesity-induced hyperlipidemia [63].

GRb1 (administered at a dosage of 20 mg/kg/day intraperitoneally for 14 days in db/db mice) has been reported to lower free fatty acid levels in obese mice and significantly inhibit lipolysis in 3T3-L1 adipocytes [64]. Another study compared the effects of high-temperature and high-pressure-treated red ginseng (HRG) and commercially available red ginseng (RG) on β-oxidation in C2C12 myotubes. HRG (200 μg/mL, 24 h in vitro) significantly enhanced metabolic function in C2C12 myotubes by activating AMPK and promoting lipid breakdown and β-oxidation [65].

Korean red ginseng (KRG) has been shown to influence lipid metabolism and reduce body weight in obese mice. Bisphenol A (BPA), an endocrine disruptor, is associated with various metabolic disorders. Studies investigating KRG have demonstrated that it can inhibit BPA-induced changes in fatty acid composition and overall fatty acid synthesis. Transcriptomic analysis further revealed that KRG suppressed BPA-induced alterations in the expression of lipid metabolism genes [66]. These findings suggest that KRG can modulate BPA-induced disruptions in lipid metabolism processes.

4.4. Mechanisms through which P. ginseng active components regulate adipose tissue browning

Adipose tissue serves as a central regulator of metabolic function, integrating nutrient sensing, lipid storage, and energy expenditure, and acting as a hub for whole-body energy metabolism. White adipocytes, a specialized cell type, primarily store energy as triglycerides and release it as fatty acids. Their metabolic activity is essential for maintaining systemic homeostasis, and dysfunction constitutes a key pathological basis for insulin resistance and related metabolic disorders. Browning of white adipose tissue, the conversion of white adipocytes into brown or beige fat, represents a critical adaptive process that remodels lipid metabolism and enhances thermogenesis [67]. Brown adipocytes utilize energy reserves and generate heat via brown fat-specific uncoupling protein 1 (UCP1) while simultaneously improving mitochondrial function, thereby increasing overall energy metabolism efficiency [68]. The metabolic plasticity of adipose tissue underscores the potential of P. ginseng active components to ameliorate lipid metabolic disorders and support systemic energy homeostasis.

PPARγ, a versatile constituent of the family of receptors within the nucleus, plays a fundamental role not only in regulating glucose homeostasis but also in adipocyte differentiation, lipogenesis, and survival. GRg3 has demonstrated significant potential in combating obesity and improving metabolism. At doses ranging from 10 to 100 μM in vitro and 20 to 40 mg/kg in vivo, it regulates PPARγ expression via STAT5, improves lipid metabolism, activates AMPK, and induces the expression of browning-related genes. These effects contribute to the suppression of lipid droplet accumulation, indicating the potential of Rg3 for treating obesity and related metabolic diseases—especially in strategies targeting differentiated adipocytes [69]. Moreover, Rg3 (at concentrations of 20–60 μM in vitro and 2.5 mg/kg in vivo for 8 weeks) alleviates the LPS-induced suppression of browning by restoring UCP1 expression and oxygen consumption [70].

GRb1 (at a concentration of 10 μM in vitro) also promotes adipose browning by modulating the PPARγ pathway in 3T3-L1 adipocytes [71]. Ginsenoside Rd improves obesity and IR by increasing thermogenic gene expression, increasing cold tolerance, and promoting white adipose tissue browning (administered daily at 15 mg/kg via intraperitoneal injection in high-fat diet-induced obese mice) under cold stress [72]. In DIO mice, Rb2 (10 mg/kg/day, administered intraperitoneally for 10 days) has been demonstrated to increase energy expenditure, as indicated by decreased lipid droplet accumulation, increased UCP1 staining, and upregulation of thermogenic and mitochondrial genes. These effects were validated in 3T3-L1, C3H10T1/2, and primary adipocytes, demonstrating the ability of Rb2 to increase energy expenditure and thermogenesis, thereby ameliorating obesity and metabolic disorders [73].

Additional studies have demonstrated that Rg1 (25–100 μM, with 50 μM as the primary experimental concentration in vitro) enhances lipid metabolism by inducing UCP1 expression and mitochondrial function, thereby facilitating the browning of 3T3-L1 cells and subcutaneous white adipocytes [74]. Studies investigating the regulatory role of Rg3 in lipid metabolism have shown that it dose-dependently upregulates the expression of browning-associated genes, such as Ucp1, Prdm16, Pgc1α, Cidea, and Dio2, as well as the brown adipocyte markers CD137 and TMEM26. These effects were observed in 3T3-L1 adipocytes treated with Rg3 (20 and 40 μM, administered for 24 h). Additionally, the expression of genes involved in lipid metabolism, including FASN, SREBP1, and MCAD, was also elevated. These findings indicate that Rg3 may promote lipid metabolic activity and ameliorate metabolic dysfunction [75].

Collectively, these findings indicate that P. ginseng active components regulate adipose tissue browning through multiple targets, including PPARγ, AMPK, activation of thermogenic genes, and mitochondrial remodeling, thereby enhancing energy expenditure and improving systemic metabolic health. These mechanisms highlight adipose browning as a key pathway linking ginseng bioactivity to its therapeutic potential in lipid metabolic disorders. The mechanism through which P. ginseng active components regulate lipid metabolism is illustrated in (Fig. 3; Table 4).

Fig. 3.

Active components of P. ginseng regulate lipid metabolism.

Table 4.

Summary of the mechanisms underlying the lipid metabolism of the active components of ginseng.

Lipid metabolism mechanism	Active component	Source	Disease	Model(s)	Targets	Reference
Regulate lipid synthesis and accumulation	Ginsenoside Rg1	Panax ginseng C.A. Meyer	Obesity	Caenorhabditis elegans	sod-2, sod-3, nhr-49	[56]
	Ginsenoside Rf	/	Obesity	3T3-L1 adipocytes	PPARγ, perilipin	[57]
	Ginsenoside Rg1	/	Obesity	3T3-L1 adipocytes; HFD-induced obese zebrafish	C/EBP, CHOP10, NOX4, GSK3b, ERK	[50]
Inhibits lipogenesis	Ginsenoside Rg1	/	Obesity	3T3-L1 adipocytes; HFD-induced male C57BL/6J mice	PPARγ, C/EBP, SREBP, AMPK, p-AMPKThr172, ACC	[51]
Regulates autophagic lipid degradation	Ginsenoside Rb1	/	T2DM	HFD-induced male C57BL/6J mice	miR-128, TFEB	[61]
Upregulates adiponectin	Ginsenoside Rb1	/	Obesity	Male db/db mice; 3T3-L1 adipocytes	Perilipin, FFA, TNF α, adiponectin	[55]

5. Mechanisms through which P. ginseng active components modulate glucose-lipid metabolism via the gut microbiota

A complex microbial community, known as the gut microbiota, resides in the human digestive tract. Long-term consumption of a HFD disrupts the ecological equilibrium of the intestinal microbiota, triggering disturbances in gut microbial homeostasis, damage to the intestinal mucosal structure, and impaired intestinal barrier function. These adverse effects ultimately contribute to metabolic dysfunction [76]. Increasing scientific evidence has highlighted that the integrity of the gut microbiota and the intestinal barrier is crucial in the onset and progression of obesity and its associated metabolic disorders.

Alterations in the gut microbial composition are closely associated with multiple phenotypes of T2DM, especially hyperglycemia and hyperlipidemia, which have garnered increasing research interest. Numerous studies have indicated that the gut microbiota of T2DM patients significantly shifts and that microbial dysbiosis may be a key factor in the onset or exacerbation of T2DM [77]. Regulating the metabolic activities of the gut microbiota may help alleviate glucose–lipid metabolism disorders in patients with T2DM. In this context, a growing body of research has demonstrated that ginsenosides, as natural active compounds, can effectively restore gut microbial balance and exhibit notable regulatory effects, suggesting new strategies and potential means for the prevention and treatment of T2DM [78].

In another investigation [79], P. ginseng was used as a liquid fermentation substrate and processed by Monascus purpureus to yield a P. ginseng fermentation product (PM). This study evaluated the hypolipidemic activity and underlying mechanisms of PM. The results indicated that PM (administered at 10–40 mg/mL in vitro for cell studies and orally at doses equivalent to 0.5–2 g/kg in HFD-fed rats) could significantly modulate the HFD-induced alteration in gut microbiota structure, restoring microbial diversity and abundance, reducing lipid levels in the blood and liver, and effectively ameliorating lipid metabolism disorders.

Polysaccharides, another class of P. ginseng active compounds, possess notable bioactivity and low toxicity. They can regulate the gut microbiota by increasing the abundance of beneficial bacteria and safeguarding the intestinal barrier, thereby improving metabolic abnormalities. For instance, the P. ginseng polysaccharide GPH1 (50 mg/kg/day orally administered) promotes the proliferation of antiobesity strains such as Lactobacillus and Lactobacillus reuteri and increases the expression of tight junction proteins, thereby improving the gut microbiota composition and alleviating obesity symptoms and hepatic lipid accumulation in obese mice [80].

The synergistic regulation of the gut microbiota by ginsenosides and P. ginseng polysaccharides has also attracted attention. A study examined the combined effects of Rb1 (20 mg/kg/day, orally administered) and P. ginseng polysaccharide GP (0.2–1.0 g/kg/day, orally administered) on fasting blood glucose in diabetic rats and the in vitro transformation of Rb1 by the gut microbiota. The results indicated that GP could restore the disturbed intestinal microbiota and increase β-D-glucosidase activity in the feces. Therefore, P. ginseng polysaccharides may correct the gut microbiota dysbiosis caused by diabetes and potentiate the hypoglycemic effect of GRb1 [81]. The gut microbiota–modulatory effects of the active components of P. ginseng are summarized in Table 5.

Table 5.

Summary of the intestinal microbiota associated with the active components of ginseng.

Intestinal microbiota mechanism	Active component	Source	Disease	Model(s)	Targets	Reference
Regulates intestinal microbiota	Fermented Panax ginseng (PM)	Panax ginseng fermented by Monascus ruber	obesity	HFD-fed SPF SD rats	Cholesterol-metabolism genes; bile acid excretion; hepatic lipid accumulation	[79]
	Ginseng polysaccharide GPH1	Panax ginseng	obesity	HFD-fed obesity mice	Increased beneficial bacteria (Akkermansia muciniphila, Lactobacillus intestinalis, Lactobacillus reuteri,Streptococcus hyointestinalis, Lactococcus garvieae)	[80]
	Ginseng polysaccharides (GP) + Ginsenoside Rb1	Panax ginseng	T2DM	Diabetic rat model	Restored gut microbiota; enhanced fecal β-D-glucosidase activity; altered Rb1 biotransformation pathways	[81]

6. Clinical evidence of the active components of P. ginseng in glucose-lipid metabolism and challenges

Although extensive in vitro and in vivo studies have suggested that ginseng and its bioactive constituents have potential benefits in regulating glucose and lipid metabolism, a substantial gap remains in the translation of these preclinical findings into clinical practice. Current clinical investigations on ginseng and its active compounds are predominantly small-scale randomized controlled trials (RCTs) or observational studies, with research populations comprising mainly individuals with T2DM, impaired glucose metabolism, or obesity. Moreover, the effects of ginseng on glucose–lipid metabolic disorders appear to be heterogeneous.

Several clinical trials have reported favorable outcomes. In a double-blind, placebo-controlled study [82], oral administration of 200 mg ginseng improved the levels of glycated hemoglobin (HbA1c) and serum procollagen type III N-terminal propeptide (PIIINP). In another 8-week randomized [83], double-blind, placebo-controlled trial, hydrolyzed ginseng extract (HGE, 960 mg/day) significantly reduced both fasting and postprandial blood glucose, primarily by enhancing glucose absorption and peripheral utilization rather than stimulating insulin secretion, with good short-term safety. Ginsam, a vinegar extract of ginseng enriched in ginsenoside Rg3, administered at 1500, 2000, or 3000 mg/day for 8 weeks, modestly improved HbA1c levels and was well tolerated in patients with poorly controlled T2DM [84]. Korean red ginseng (KRG) also has potential for glycemic regulation: in T2DM patients with well-controlled blood glucose, supplementation with KRG (2 g per meal, 6 g/day for 12 weeks) maintained glycemic stability and improved postprandial glucose (PG) and insulin (PI) regulation [85]; in individuals with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), KRG supplementation (5 g/day) improved both serum and whole-blood glucose levels [86].

Evidence also supports potential lipid-modulating effects. Compared with placebo, American ginseng extract (AG) significantly reduced HbA1c levels, fasting plasma glucose (FPG), low-density lipoprotein cholesterol (LDL-C), and the LDL-C/high-density lipoprotein cholesterol (HDL-C) ratio [87]. In another study [88], Zhenyuan capsule, which is rich in ginsenosides derived from ginseng fruit, improved postprandial glucose levels, reduced insulin resistance, and increased HDL-C levels in prediabetic patients when combined with lifestyle intervention. Additionally, a randomized controlled trial in postmenopausal women with hypercholesterolaemia revealed that compared with the placebo, 4 weeks of KRG supplementation (2 g/day) significantly decreased total cholesterol and 7-hydroxycholesterol (7-OHC) levels [89].

Nonetheless, not all studies have demonstrated significant benefits. For instance, in a trial involving 202 participants receiving hydrolyzed ginseng and 199 receiving a placebo for 6 months, no significant differences in fasting glucose levels were observed between groups, potentially because of the low oral bioavailability of ginseng and its hydrolysates [90]. Another study reported that oral ginsenoside Re did not improve β-cell function or insulin sensitivity in overweight/obese individuals with impaired glucose tolerance or newly diagnosed diabetes [91]. Similarly, the ginsenoside Rb1 did not affect insulin secretion or blood glucose levels in healthy individuals [92].

Multiple pharmacological activities of ginseng and its bioactive components, which are important natural medicinal agents, have been demonstrated in cellular and animal models [93]. However, despite promising preclinical findings, clinical evidence for their efficacy in modulating glucose–lipid metabolism and managing metabolic disorders in humans remains limited, underscoring the need for high-quality clinical trials. The clinical translation of the metabolic benefits of ginseng is hampered by the intrinsic limitations of its active constituents, including low aqueous solubility, poor membrane permeability, and rapid in vivo metabolism, resulting in low bioavailability [94]. Therefore, strengthening the design of high-quality, multicenter, large-scale clinical trials combined with innovative drug delivery technologies and formulation improvements is urgently needed. In-depth investigation of the in vivo metabolic pathways and mechanisms of ginseng active components, alongside optimization of formulation development and administration strategies, is essential to facilitate their clinical translation and practical application, thereby providing a robust scientific foundation for subsequent clinical research and implementation.

7. Recent advances in the extraction of active components of P. ginseng and extraction technologies

Naturally derived bioactive molecules are increasingly recognized as valuable sources of novel therapeutic agents due to their low toxicity and high medicinal potential. This therapeutic promise has driven extensive efforts to isolate and characterize bioactive compounds. With growing understanding of disease-related mechanisms, optimizing extraction techniques has become critical, as the pharmacological activity of natural products is highly dependent on the method employed. Numerous studies have demonstrated that different extraction approaches can markedly influence the yield, structural characteristics, and biological activity of the obtained compounds. Therefore, the choice of extraction method not only affects efficiency but also directly impacts the functional potential of natural products and provides a foundation for subsequent mechanistic and activity-based studies.

P. ginseng contains a variety of bioactive components, such as ginsenosides, polysaccharides, and glycopeptides, which have distinct biological effects, including antioxidant, antiaging, antitumor, and metabolic regulatory activities. With the global prevalence of metabolic disorders, particularly those involving glucose‒lipid metabolism, increasing attention has been given to the therapeutic efficacy of P. ginseng-derived compounds in managing diabetes, dyslipidemia, and obesity. These compounds exert their effects through well-defined mechanisms. Therefore, optimizing the extraction of highly active P. ginseng constituents not only increases their yield but also enhances their biological efficacy and facilitates mechanistic studies, thereby improving their translational potential in the intervention of metabolic disorders.

Ultrahigh-pressure extraction has emerged as one of the most advanced and efficient techniques for isolating ginsenosides, not only drastically reducing extraction time to just a few minutes but also better preserving the structural integrity and biological activity of the active components. In one study, microwave-assisted extraction and conventional hot water extraction were used to isolate P. ginseng polysaccharides. The chemical composition and structural characteristics of the extracted polysaccharides were preliminarily analyzed, their biological activities were assessed, and differences in structural features and antioxidant capacities were compared between the two extraction methods [95]. The results showed that polysaccharides obtained via microwave-assisted extraction (MPPG) exhibited superior antioxidant activity compared with those obtained through hot water extraction (WPPG), highlighting the impact of extraction techniques on the bioactivity of P. ginseng components.

Another study utilized a specialized processing method in which peeled P. ginseng roots were dried and heat-treated in an 80 °C oven for 14 days to produce aged P. ginseng. WG and RG were used as controls to evaluate the effects of aged P. ginseng on glucose‒lipid metabolism in HFD-fed mice. The findings demonstrated that compared with white ginseng, aged P. ginseng processed via this technique exhibited more pronounced antihypertensive and hypoglycemic effects. These benefits are likely attributed to the higher levels of ginsenosides present in aged P. ginseng [96].

Similarly, heat-processed P. ginseng pectic polysaccharides have been investigated. One research group focused on evaluating the effects of thermal processing on P. ginseng pectins and examining changes in 74 chemical constituents and the induction of antihyperglycemic activity. In vivo experiments in animals revealed that heat-treated P. ginseng pectins (GPs) significantly reduced blood glucose levels and strongly promoted antioxidant effects in alloxan-induced diabetic mice. Notably, the effects intensified with increasing processing temperature [97]. These findings suggest that thermal processing alters the properties of P. ginseng pectins, thereby enhancing their physiological activity in regulating glucose‒lipid metabolism. Therefore, heat processing enhances the bioactivity of P. ginseng by increasing the ginsenoside content and by modifying the structural properties of pectic polysaccharides, leading to improved hypoglycemic and antioxidant effects.

Fermentation has been validated as an effective strategy for enhancing the extraction of the bioactive components of P. ginseng. Various fermentation approaches, including solid-state fermentation, lactic acid bacterial fermentation, Monascus fermentation, and microbial fermentation, have been widely studied. One study investigated the biochemical changes in wild P. ginseng subjected to fermentation by Rhizopus oligosporus [98]. Specifically, the research team fermented wild P. ginseng at 30 °C for durations ranging from 1 to 14 days. The 14 types of L-carnitine and ginsenosides identified in the products of the fermented samples were subsequently analyzed using UPLC‒MS. The results confirmed that the fermentation process significantly increased the levels of ginsenosides while reducing the potential for cell toxicity from wild P. ginseng to RAW264.7 murine macrophage-derived cells. Both raw and fermentation-treated wild P. ginseng suppressed nitric oxide (NO) production in RAW264.7 murine macrophages, indicating notable anti-inflammatory properties.

Additionally, hydroponically grown P. ginseng fermented with Lactobacillus brevis B7 presented increased concentrations of phenolic and flavonoid compounds and increased antioxidant capacity and NO-scavenging activity, thereby resulting in greater bioactivity. Fermented hydroponic P. ginseng also demonstrated superior redox-balancing and anti-inflammatory effects, significantly mitigating elevated levels of inflammatory mediators [99]. These findings suggest that fermentation may offer a promising route for extracting P. ginseng bioactives with enhanced therapeutic potential, particularly in the context of regulating glucose‒lipid metabolic disorders.

In summary, recent advances in extraction and processing technologies for P. ginseng, including ultrahigh-pressure extraction, microwave-assisted extraction, heat processing, and fermentation, demonstrate that the choice and optimization of extraction methods can directly influence both the yield and structural integrity of bioactive components. These methodological improvements not only enhance antioxidant, antihyperglycemic, and anti-inflammatory activities, but also provide a solid basis for mechanistic studies of glucose‒lipid metabolism regulation. Overall, optimizing the extraction and processing techniques of P. ginseng is crucial for enhancing the biological efficacy of its active components and advancing their application in the intervention of metabolic disorders.

8. Conclusion

With the continuous improvement in living standards in modern society, dietary patterns have become increasingly diverse, and the frequency of HFD consumption has risen significantly. Combined with a lack of regular physical activity, the incidence of glucose‒lipid metabolism disorders is increasing annually, resulting in chronic noncommunicable diseases [3]. Recent studies have gradually confirmed that Panax species have significant potential in regulating glucose–lipid homeostasis. P. ginseng contains various bioactive compounds, including ginsenosides, polysaccharides, and peptides (oligopeptides), which act at the molecular and cellular levels through multiple pathways and signaling cascades to modulate metabolic processes. These compounds increase insulin sensitivity, inhibit fat accumulation, and increase lipid catabolism, underscoring their promise for preventing and treating glucose‒lipid metabolic disorders. This review summarizes the current research on the effects of P. ginseng bioactive components on disorders of glucose–lipid metabolism, with a focus on their multitarget mechanisms of action, with the goal of establishing a scientific rationale for guiding the clinical use of P. ginseng and its extracts in the management of metabolic diseases.

P. ginseng bioactives play multifaceted roles in regulating glucose metabolism, primarily through three mechanisms: enhancing glucose uptake, promoting glycogen synthesis, and inhibiting gluconeogenesis, thereby contributing to glycemic homeostasis. Ingested carbohydrates are digested and absorbed into the bloodstream by the gut. The glucose transporter GLUT4 on adipocytes and skeletal muscle membranes facilitates the transport of glucose into cells, thereby lowering blood glucose levels [100]. GSK3β is a key enzyme that regulates glycogen synthase, which converts hepatic glucose into glycogen, thus increasing hepatic glycogen storage [30]. On the other hand, hepatic gluconeogenesis is a primary source of endogenous glucose and a critical target for glycemic control [101]. Both the PI3K/AKT signaling pathway and the AMPK signaling pathway are involved in these processes. P. ginseng bioactivities involve multitarget regulation of glucose metabolism. For instance, ginsenoside Rg1 facilitates GLUT4 translocation to the plasma membrane in C2C12 skeletal muscle cells [65]and protects HFD-induced obese mice by activating AMPK. CK not only enhances intestinal glucose absorption but also reduces blood glucose levels by inhibiting hepatic gluconeogenesis and promoting GLUT4-mediated glucose uptake in adipose and muscle tissues [102]. GRd and Rb1 have been shown to promote hepatic glycogen synthesis and inhibit gluconeogenesis, thereby improving hepatic glucose metabolism. Moreover, glucose metabolism disorders often induce inflammation, oxidative stress, and ER stress, which can further exacerbate metabolic dysfunction. P. ginseng bioactives can interrupt this vicious cycle. For example, GRg1 has been shown to suppress the nuclear translocation of NF-κB and reduce inflammatory cytokine release [46], while enhancing PI3K/AKT signaling, increasing AMPK expression, and inhibiting FOXO1 activity to alleviate IR. Ginseng Polypeptide (GPs) also reduce oxidative stress and inflammation [103], restoring insulin signaling and improving outcomes in patients with T2DM.

Lipid metabolic homeostasis is maintained through several mechanisms: (1) regulation of the differentiation of preadipocytes into healthy, mature adipocytes for precise lipid storage and mobilization; (2) positive modulation of multiple aspects of lipid metabolism, including lipid uptake, storage, β-oxidation, synthesis, and lipophagy, which may prevent or reverse lipid dysregulation; and (3) induction of the browning of white adipose tissue to increase thermogenesis and energy expenditure, thereby sustaining lipid balance. Among the regulatory mechanisms through which P. ginseng bioactives modulate lipid metabolism, the PPARγ and AMPK pathways play pivotal roles in adipocyte differentiation. Studies have shown that GRb1 and Rg3 can inhibit 3T3-L1 cell differentiation by enhancing PPARγ signaling. AMPK, a key regulator of metabolic balance, is involved in switching between catabolic (energy-generating) and anabolic (energy-storing) processes. Through the AMPK pathway, Rb1 promotes fatty acid oxidation and reduces lipid accumulation, whereas GRg1 and Rb2 [104] upregulate PGC1α and PRDM16, thereby inducing browning of white adipocytes and increasing thermogenic capacity. These findings underscore the diverse mechanisms through which P. ginseng bioactives intervene in lipid dysregulation.

Additionally, recent studies indicate that ginseng-derived bioactive components, for example, active components derived from ginseng, such as GABAFG, can significantly improve the disorder of glucose and lipid metabolism in type 2 diabetes models by regulating the autophagy-lysosomal pathway and intestinal flora [105]. This provides new mechanistic insights into how ginseng-derived bioactive components coordinate the regulation of glucose and lipid metabolism through multiple pathways.

P. ginseng, a traditional herbal medicine, has been widely used in both clinical practice and health maintenance and is generally considered to have a favorable safety profile. Multiple animal and clinical studies have reported that when administered at conventional doses, P. ginseng and its major active constituents do not induce serious adverse effects, and standardized oral extracts are generally well tolerated. For example, ginsenoside CK, a gut microbiota–derived metabolite of protopanaxadiol-type ginsenosides, exhibited low acute oral toxicity in rodents, with no mortality or overt toxic reactions observed even at high doses, suggesting a wide safety margin [106]. Clinically, standardized fermented ginseng powder (GBCK 25) administered for 12 weeks improved hepatic function and alleviated fatigue symptoms; low-dose supplementation significantly reduced the levels of γ-glutamyltransferase (GGT) and inflammatory markers, whereas high-dose supplementation reduced fatigue scores, without causing clinically significant safety concerns [107].

Nevertheless, P. ginseng is not entirely devoid of adverse effects. Excessive or high-dose intake may lead to headache, dizziness, palpitations, elevated blood pressure, pruritus, and erythematous rashes. Excessive intake has been associated with insomnia, tachyarrhythmia, hypertension, gastrointestinal disturbances, and nervousness [108]. However, in some trials, the incidence of treatment-related adverse events did not differ significantly between the intervention and placebo groups.

Drug–herb interactions also warrant attention. Coadministration of P. ginseng with antidiabetic agents may potentiate hypoglycemia, while American ginseng has been reported to reduce the anticoagulant effect of warfarin, potentially compromising therapeutic safety [109]. Taken together, the results of this study reveal that P. ginseng and its derivatives have a solid safety foundation, yet systematic toxicological and pharmacokinetic evaluations remain necessary—particularly regarding long-term administration and high-dose use—to guide rational and evidence-based clinical application.

Although P. ginseng and its bioactive constituents have demonstrated considerable potential in modulating glucose–lipid metabolism in vitro and in animal models, their clinical translation remains hindered by several critical challenges. First, these active compounds generally exhibit poor oral absorption, pronounced first-pass metabolism, and suboptimal aqueous and lipid solubility, making it difficult to maintain therapeutically effective concentrations in vivo and thereby compromising the stability and reproducibility of clinical efficacy [110]. Second, most clinical studies on ginseng are characterized by small sample sizes, single-center designs, short intervention periods, and considerable heterogeneity among participants, with a paucity of large-scale, multicenter, long-term randomized controlled trials, leading to relatively weak evidence levels. In addition, while animal and cell models provide valuable insights into mechanistic pathways, they cannot fully recapitulate the complexity of human metabolic environments, thus limiting the predictive accuracy of translational research. In terms of safety, although ginseng is generally well tolerated, systematic safety evaluations for individual ginsenosides remain insufficient, particularly in the context of long-term administration and potential interactions with other medications, warranting more rigorous monitoring. Finally, limitations in formulation technology, delivery routes, and dosage optimization further restrict the clinical utility of these compounds. Therefore, future research should focus on elucidating the molecular mechanisms of action, refining structure–activity relationships, and conducting comprehensive pharmacokinetic and safety evaluations, in addition to the development of efficient delivery systems, to advance the broad clinical translation and application of ginsenosides and other ginseng-derived natural products in the management of metabolic diseases.

In summary, the active components of the natural medicinal herb P. ginseng have therapeutic effects on disorders of glucose–lipid metabolism. Given the tight interconnection between glucose and lipid metabolism in maintaining systemic energy homeostasis—in which changes in blood glucose levels affect lipid synthesis and breakdown and lipid dysregulation in turn disrupts glycemic control—shared signaling pathways and hormonal regulation (e.g., insulin and AMPK) are critical for emergence. With advances in technology and increasing clinical application, future research should not be limited to the benefits of P. ginseng and its preparations but should further explore their molecular mechanisms of action and develop novel agents for the prophylaxis and therapy of glucose‒lipid metabolic abnormalities.

Author contributions

ZY and HR proposed the framework of this paper. ZY, HR, ZQ, HMD and ZS drafted the manuscript. SX and LJR made the figures and tables. TXL and LM reviewed the manuscript. All the authors were involved in revising the manuscript and reading and approving the submitted version.

Declaration of competing interest

The authors declare that they have no conflict of financial interests or personal relationships that could have appeared to influence the work reported in this manuscript.

Data availability

No data was used for the research described in the article.