A comprehensive review of the effects of Panax ginseng and its constituents against inflammatory diseases

Abstract

Unresolved inflammation can progress into severe diseases that need safer and more effective therapeutic strategies. The adverse effects of conventional anti-inflammatory agents have evoked interest in natural products as alternatives. Panax ginseng is a traditional medical herb famous for its diverse pharmacological properties. This review comprehensively discusses the anti-inflammatory effects of P. ginseng and its constituents against inflammatory bowel disease, hepatitis, sepsis, gastritis, atopic dermatitis, acute lung disease, and rheumatoid arthritis. We summarize the therapeutic effects and underlying molecular mechanisms of P. ginseng reported in studies published as of February 2025. Our review highlights the potential of P. ginseng as an anti-inflammatory agent or functional food that affects the interconnected disease network.

Graphical abstract

1. Introduction

Inflammation is a host defense mechanism against external stimuli such as pathogens, physical stress, and toxic chemicals. It induces a local immunological response at the infected or injured spot to remove the triggers and cure the damage. This process involves leukocyte recruitment and the release of inflammatory mediators, resulting in redness, swelling, heat, pain, and loss of function [1]. To immediately remove the threatening stimulus and recover the disrupted homeostasis, the inflammatory mechanism takes priority over homeostatic controls [2]. Therefore, when acute inflammation fails to resolve the infection or injury, the dysregulated homeostasis mechanism loses its ability to manage the production of inflammatory mediators, resulting in uncontrolled and excessive responses [1]. Over time, that cycle results in systemic chronic inflammation, which impairs immune functioning and causes diseases such as cancer, obesity, and diabetes [3]. The functional contribution of inflammation to disease has been studied using bioinformatic approaches. Systemic studies report that the inflammation network underlies cancer, metabolic, and neurodegenerative disorders [4]. In addition, inflammation has been associated with the correlation of pairs of conditions, such as immune/infection, cardiovascular/metabolic, cardiovascular/immune, and aging/cancer [5]. For instance, NFKB1 and RELA in the nuclear factor-κB (NF-κB) pathway critically link infection and cancer. Moreover, in single-cell sequencing of colon cancer cell types, diabetes- and cancer-related genes were most activated in macrophages, suggesting relationships among macrophage-driven inflammation, diabetes, and cancer [6]. Those findings suggest that targeting inflammation could be an effective pharmacological strategy.

Therefore, anti-inflammatory agents are frequently prescribed for many diseases. The most used medications include non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and immunosuppressants. Aspirin, one of the most famous NSAIDs, suppresses inflammation by inhibiting the cyclooxygenase (COX) enzyme, which releases prostaglandin and thromboxane [7]. However, NSAIDs are reported to have adverse effects on the lower gastrointestinal tract, liver, brain, lung, kidneys, and cardiovascular system by suppressing the COX enzyme [8,9]. Corticosteroids, such as prednisone, bind to inflammatory transcription factors and glucocorticoid response elements, inhibiting anti-inflammatory gene expression and the mitogen-activated protein kinase (MAPK) pathway [10]. However, they can adversely affect the musculoskeletal, metabolic, and endocrine systems [11]. Immunosuppressants are used for chronic inflammatory diseases, but long-term use can weaken the protective effects of the immune system [12]. The unwanted side effects of existing anti-inflammatory agents highlight the need for alternative approaches. In this regard, natural products with immunomodulatory and anti-inflammatory properties have gained attention as potential therapeutic agents [13]. Traditionally, herbs have been used as medicine, and some of them, rich in phytochemicals, enhance immunity by activating the lymphocytes, phagocytosis, and interferon production [14]. Several plants, including ginseng, Ganoderma lucidum, and chlorella, have been studied to determine their immune-modulating capabilities, and they are often commercialized as health-functional foods [15].

Ginseng is a traditional medicinal herb that belongs to the genus Panax, family Araliaceae. The Greek word “pan”, which means “all,” and “Akos,” which means “cure,” combine to form the term “Panax,” that is “all healing” [16]. Indeed, its significant medicinal and adaptogenic properties have led to its wide use in medicine for several decades. Recently, its various phytochemical properties, including anti-inflammation, antioxidation, immunomodulation, and anti-cancer, have been studied using modern scientific research methods [[17], [18], [19], [20]]. Among the 17 ginseng species, Panax ginseng Meyer (P. ginseng), also known as Korean ginseng or Asian ginseng, is used medicinally and called “king of the herbs” in East Asia [21]. There are 3 processed forms of P. ginseng: white ginseng, red ginseng, and black ginseng [22]. White ginseng is dried fresh with sunlight. Red ginseng (or Korean red ginseng, KRG) is made by steaming 6-year grown fresh ginseng at 90–98 °C and drying it in hot air and sunlight until its moisture content reaches 15–18 % [23]. Black ginseng is made by repeating the steaming and drying process 9 times [24]. It is known that steaming fresh ginseng modulates its phytochemical composition, resulting in better biological effects and fewer adverse effects [22,25]. Recently developed separation and purification technologies have helped in understanding the individual components of P. ginseng and their pharmacological effects.

2. Phytochemical properties of Panax ginseng

The composition of P. ginseng can be largely divided into the saponin and non-saponin fractions. Ginsenosides, the major saponins in P. ginseng, are unique and characteristic components of the genus Panax and are considered the main active phytochemical components. These components consist of hydrophobic aglycone and hydrophilic sugar groups, and their physiological activity can differ depending on the sugar-binding forms and aglycone structure. Ginsenosides are classified into 6 groups: protopanaxatriol type (PPT), protopanaxadiol type (PPD), oleanolic acid type, ocotillo type, C17 side-chain varied, and miscellaneous subtypes [26]. PPDs and PPTs are the major ginsenosides in KRG and have four rings of (Dammarane)-triterpene aglycone. They are structurally similar, but PPTs have a hydroxyl group at C-6 [27]. The classification of ginsenosides is summarized in Table 1. Rb1, Rb2, Rc, Rd, Re, and Rg1 account for over 90 % of P. ginseng's total ginsenoside concentration [28]. Compound K is a bio-transformed secondary ginsenoside metabolized from PPDs by gut bacteria [29]. It is absorbed better than the other ginsenosides, so its bioactivity is the focus of ginseng research [30].

Table 1.

Saponin and non-saponin components of P. ginseng, KRG, and black ginseng.

Saponin
PPDs	Major ginsenosides	Rb1, Rb2, Rc, Rd
	Minor ginsenosides	Rb3, Rh2, Rg3, Rg5, Rk1, Rz1
	Bio-transformed ginsenoside	Compound K
PPTs	Major ginsenosides	Re, Rg1
	Minor ginsenosides	Rh1, Rg2, Rf, Rh4, F4, Rg6
Non-saponin
Carbohydrates		Saccharides (mono-, di-, tri-, and poly-), fiber, pectin
Nitrogenous substances		Protein, peptides, amino acids, nucleic acids, alkaloids
Maillard reaction products		AFG (arginine-fructose-glucose), FG (fructose-arginine), maltol
Fats		Lipids, phenolic compounds (p-coumaric acid et al.), essential oils, phytosterols, organic acids, polyacetylenic alcohols
Vitamins and minerals		Vitamin B1, B2, B12, biotin, K, Ca, Mg, Zn, Cu

The types and amounts of ginsenosides change during the heating and drying processes. Unstable malonyl ginsenosides, such as Mal-Rb2 and Mal-Re, lose their malonyl residues [31]. During processing, the natural ginsenosides are chemically transformed into rare synthetic ginsenosides: [Rb1, Rb2, Rc, Rd] → [Rg3] → [Rg5, Rk1, Rs3, Rz1]/[Re] → [Rg2] → [F4, Rg6]/[Rg1] → [Rh1] → [Rh4, Rk3] [32,33]. As these rare ginsenosides are not abundant in fresh ginseng, their chemical formation and enrichment during processing could be a key factor for enhancing the therapeutic efficacy of processed products.

Though the ginsenosides are regarded as the primary bioactive components of P. ginseng, the non-saponin fractions have also been reported to have various physiological effects. These include polysaccharides, amino acids, vitamins, minerals, and flavonoids (Table 1) [34]. The composition of the non-saponin fractions is also altered during the heating process. Polysaccharides undergo starch gelatinization, which enhances the storability of KRG and black ginseng [34]. Also, arginine-fructose-glucose and maltol are generated through the Maillard reaction during steaming and drying [31]. They are also important phytochemical components with anti-inflammatory and antioxidant properties [[35], [36], [37]]. Given the biological significance of both the saponin and non-saponin fractions, a comprehensive evaluation of P. ginseng's anti-inflammatory effects should consider both fractions.

3. Panax ginseng and its components against inflammatory diseases

3.1. Inflammatory bowel disease

Inflammatory bowel disease (IBD), comprising ulcerative colitis and Crohn's disease, is a chronic intestinal autoimmune inflammatory disease affecting the gastrointestinal tract. It is characterized by immune cell infiltration, gut microbiome dysbiosis, and intestinal epithelial barrier dysfunction [38]. Several studies have demonstrated the anti-inflammatory effects of P. ginseng in IBD models (Table 2). In an animal model, KRG and its saponin and non-saponin fractions alleviated the clinical symptoms of colitis caused by dextran sodium sulfate (DSS) and reduced myeloperoxidase (MPO) activity [39]. Similarly, KRG relieved epithelial damage, inflammation, and impaired mucus secretion while modulating the gut microbiota, increasing probiotic bacteria and decreasing harmful bacteria, in a DSS-induced colitis model [40]. A computational study also suggested that ginsenosides might regulate the gut microbiota and its metabolites by targeting EGFR, STAT3, and AKT1 [41]. In the same model, fermented wild ginseng was shown to inhibit macrophage infiltration and NF-κB translocation [42].

Table 2.

Anti-inflammatory effects of P. ginseng against inflammatory bowel disease.

Components	Models	Activities	Ref.
KRG	DSS-treated mice	Increase COX-1, ZO-1, and occludin levels	[39]
		Reduce MPO activity	[39,40]
		(1)Modulate gut microbiota (2)Reduce PI3K/AKT-mediated β-catenin/TCF-4 expression (3)Reduce IL-1β, IL-6, and IFN-γ levels	[40]
Ginsenosides	Acetic acid–treated rats	(1)Modulate gut microbiota (2)Modulate EGFR-TKI resistance and the PI3K/AKT pathway (3)Reduce IL-1β and TNF-α levels (4)Increase IL-10 levels	[41]
Fermented wild ginseng	DSS-treated mice	(1)Reduce IL-1β, IL-6, IL-12p40, TNF-α, and IFN-γ mRNA levels by inhibiting the NF-κB pathway (2)Reduce intestinal macrophage infiltration (3)Increase ZO-1 levels	[42]
	LPS-treated RAW 264.7 cells/peritoneal macrophages	Reduce pro-inflammatory cytokines such as TNF-α and IL-12p40 by inhibiting the NF-κB pathway	[42]
Saponin, Non-saponin	DSS-treated mice	(1)Reduce MPO activity (2)Increase COX-1, ZO-1, and occludin levels	[39]
Rg2	DSS-treated mice	(1)Increase claudin-3, mucin 2, ZO-1, and occludin mRNA levels (2)Reduce IL-1β, IL-6, and TNF-α levels by inhibiting the NF-κB/NLRP3 pathway	[43]
	LPS/Nig-treated iBMDM	Reduce IL-1β and TNF-α levels by inhibiting the NF-κB/NLRP3 pathway	[43]
Rb1	DSS-, TNBS-treated mice	(1)Reduce MPO activity (2)Reduce IL-1β, IL-6, TNF-α, p65, and cleaved-caspase 3 levels (3)Reduce ER stress by stimulating the Hrd1 signaling pathway	[44]
Rg1	DSS-treated mice	Reduce IL-2 and TNF-α levels by modulating gut microbiota	[45]

KRG, Korean red ginseng; DSS, dextran sodium sulfate; COX, cyclooxygenase; ZO-1, zonula occludens-1; MPO, myeloperoxidase; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; IL-1β, interleukin-1β, IL-6, interleukin-6; IFN-γ, interferon-γ; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor; TNF-α, tumor necrosis factor-α; IL-10, interleukin-10; NF-κB, nuclear factor-κB; LPS, lipopolysaccharide; Nig, nigericin; iBMDM, immortalized bone marrow–derived macrophage; NLRP3, NLR family pyrin domain containing 3; iNOS, inducible nitric oxide synthase; TNBS, 2,4,6-trinitrobenzene sulfonic acid; ER, endoplasmic reticulum; IL-2, interleukin-2.

Among the individual ginsenosides, Rg2 decreased colon inflammation by suppressing the p65 subunit of NF-κB and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation [43]. Rb1 reduced inflammation and apoptosis in mice treated with DSS or 2,4,6-trinitrobenzene sulfonic acid [44]. It was associated with endoplasmic reticulum (ER) stress, which co-stimulates IBD pathogenesis, and Hrd1, the ER-resident E3 ubiquitin ligase that activates the T cell immune response and resolves ER stress by degrading misfolded proteins. Rb1 normalized Hrd1 expression and decreased ER stress markers such as GRP78 and CHOP. Rg1 reduced interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α) protein levels and modulated the gut microbiome and tryptophan metabolism [45]. These findings show that P. ginseng might modulate the NF-κB-associated inflammation, gut microbiota, and ER stress induced by IBD.

3.2. Hepatitis

Hepatitis is a form of liver inflammation that results from viruses, alcohol, toxic substances, or autoimmune attacks. The anti-inflammatory effects of P. ginseng against hepatitis are summarized in Table 3. Hepatitis B viruses (HBV) contribute to acute and chronic hepatitis and can trigger severe lung diseases. In HepG2.2.15 cells (HBV-transfected cell line), Rg3 suppressed the myeloid differentiation primary response 88 (MyD88)-dependent pathway by downregulating the TRAF6/TAK1 pathway, and it reduced the expression of IL-8 and TNF-α by inhibiting JNK/AP-1 signaling, implying its potential to relieve chronic hepatitis B [46]. Rg1 boosted the Th1 and Th2 lymphocyte responses by upregulating the interferon-γ (IFN-γ) and IL-4 via toll-like receptor 4 (TLR4) signaling pathways in HBV antigen–infected mice [47].

Table 3.

Anti-inflammatory effects of P. ginseng against hepatitis.

Components	Models	Activities	Ref.
KRG	Alcohol-treated mice	(1)Reduce hepatic steatosis (2)Reduce TNF-α and IL-1β levels by inhibiting the TLR4 pathway	[52]
Rg3	HepG2.2.15 cells	(1)Suppress the MyD88-dependent pathway by downregulating the TRAF6/TAK1 pathway (2)Reduce IL-8 and TNF-α levels by inhibiting the JNK/AP-1 pathway	[46]
Rg1	HBV antigen-infected mice	Boost Th1 and Th2 responses and modulate the TLR4 pathway	[47]
	Alcohol-treated mice	Reduce TNF-α and IL-6 levels	[49,51]
		Inhibit the NF-κB pathway	[[49], [50], [51]]
		Reduce oxidative stress	[50,51]
		Protect the gut by modulating gut microbiota	[50]
	Alcohol-treated L-O2 cells	(1)Reduce TNF-α, IL-1β, and IL-6 levels by inhibiting the NF-κB pathway (2)Reduce inflammasome activation and ROS	[51]
	ConA-treated mice	(1)Reduce TNF-α, IFN-γ, and IL-6 levels by inhibiting the NF-κB pathway (2)Reduce CD4+ and CD8+ T cell infiltration into the liver	[57]
Rb1	Alcohol-treated zebrafish larvae and L-O2 cells	(1)Reduce hepatic steatosis (2)Reduce ROS (3)Reduce TNF-α levels by inhibiting the NF-κB pathway	[53]
Compound K	ConA-treated mice	(1)Reduce TNF-α, IL-6, and IL-1β levels by inhibiting the TLR4/NF-κB pathway (2)Reduce CD4+ T cell infiltration into the liver (3)Recover antioxidant activity and reduce MDA levels by activating the Sirt1/Nrf2 pathway	[58]
Maltol	Alcohol-treated mice	(1)Recover antioxidant activity and reduce MDA levels (2)Reduce TNF-α and IL-1β levels	[36]
LGP	ConA-treated mice and RAW 264.7 cells	Reduce IL-1β, IL-6, IL-18, and TNF-α levels by inhibiting the PI3K/AKT and TLR/NF-κB pathways	[59]

KRG, Korean red ginseng; MyD88, myeloid differentiation primary response 88; TRAF6, TNF receptor associated factor 6; TAK1, transforming growth factor β-activated kinase 1; IL-8, interleukin-8; TNF-α, tumor necrosis factor-α; JNK, Jun N-terminal kinase; AP-1, activating protein-1; IL-1β, interleukin-1β; IL-6, interleukin-6; NF-κB, necrosis factor-κB; ROS, reactive oxygen species; ConA, concanavalin A; TBK1, TANK-binding kinase 1; IRF-3, interferon regulatory factor 3; ATF2, activating transcription factor 2; TLR4, toll-like receptor 4; MDA, malondialdehyde; Sirt1, sirtuin 1; Nrf2, nuclear factor erythroid-2-related factor 2; LGP, low molecular weight ginseng polysaccharides; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B.

Alcohol is a major cause of deadly liver diseases. Excessive and prolonged alcohol intake harms the innate immune system via the TLR4 signaling pathway, which increases pro-inflammatory cytokine expression and produces reactive oxygen species (ROS) [48]. Rg1 was shown to suppress NF-κB activation, thereby reducing pro-inflammatory cytokine production and ROS, while maintaining gut integrity by modulating the gut microbiota [[49], [50], [51]]. Gao et al. suggested that Rg1 modulation of the NF-κB pathway might be associated with the glucocorticoid receptor [49]. Additionally, KRG and Rb1 lowered steatosis in liver tissues and reduced TNF-α and IL-1β levels by inhibiting the TLR4 pathway [52,53]. Maltol, a product of the Maillard reaction in heat-processed ginseng, exhibited hepatoprotective effects by reducing TNF-α and IL-1β levels while elevating the expression of antioxidative enzymes such as catalase and superoxide dismutase [36].

Autoimmune hepatitis (AIH) is a chronic, severe, and progressive liver disease characterized by inflammatory infiltration, autoantibody production, and an auto-reactive T cell response [54]. Though the precise mechanism of AIH remains unclear, the concanavalin A (ConA)-induced liver injury mouse model mimics the histological and serological characteristics of human AIH patients [55,56]. The anti-inflammatory properties of KRG were shown in ConA-induced AIH model animals. Rg1 was shown to decrease CD4⁺ and CD8⁺ T cell infiltration into the liver and suppress the release of inflammatory cytokines such as TNF-α and IFN-γ [57]. Compound K further alleviated inflammation and hepatocyte apoptosis by inhibiting TLR4/NF-κB, and it suppressed oxidative stress via sirtuin 1/nuclear factor erythroid-2-related factor 2 (Sirt1/Nrf2) pathways [58]. The non-saponin fraction also exhibited hepatoprotective effects. Qi et al. purified low molecular weight polysaccharides from ginseng and discovered that they suppress inflammation and hepatocyte apoptosis by targeting the PI3K/AKT and TLRs/NF-κB signaling pathways in both in vitro and in vivo ConA-induced AIH models [59].

Taking those results together, P. ginseng and its components appear to regulate hepatitis via various signaling pathways, including TLR4/NF-κB, PI3K/AKT, and Sirt1/Nrf2. Understanding the effects of ginseng components on hepatitis mechanisms would broaden the possibility of using P. ginseng in clinical and complementary applications.

3.3. Sepsis

Sepsis is a systemic inflammatory response with an initial phase of acute inflammation and prolonged immunosuppression [60]. In the early stage of sepsis, excessive inflammation affects multiple organs, leading to shock, fever, and potential fatality or immunosuppression [61]. During the immunosuppressive phase, septic patients show increased anti-inflammatory cytokine release, T and B lymphocyte apoptosis, immune checkpoint upregulation, and immunosuppressant cell proliferation [60,62]. Twenty to thirty percent of septic patients die due to the reactivation of excessive inflammation or immunosuppression [62]. Table 4 shows the therapeutic effects of P. ginseng against sepsis.

Table 4.

Anti-inflammatory effects of P. ginseng against sepsis.

Components	Models	Activities	Ref.
KRG saponin	LPS-treated RAW 264.7 cells	Reduce NO level and inhibit iNOS, TNF-α, IL-6, GMCSF, and MCP-1 expression	[63]
	LPS-treated mice	Reduce serum TNF-α levels	[63]
Ginseng leaf extract	LPS-treated RAW 264.7 cells, mice	Reduce HMGB1 release by inhibiting JAK2/STAT1-dependent NO production	[66]
Rg3	LPS-treated peritoneal macrophages	(1)Reduce S-nitrosylation of the NLRP3 inflammasome and AKT by inhibiting NO production (2)Reduce ROS and apoptosis	[64]
	LPS-treated mice	Reduce splenic apoptosis and NO levels	[64]
		(1)Reduce IL-1β and TNF-α levels (2)Reduce immune cell accumulation in the spleen	[65]
Rb1	LPS-treated RAW 264.7 cells	(1)Reduce NO levels and COX-2 and iNOS expression (2)Reduce Ca2+ and ROS production (3)Reduce TNF-α, IL-6, and IL-1β levels by inhibiting the TLR4-MyD88-NF-κB/MAPK pathway	[67]
Re	LPS-treated mice	Reduce iNOS levels and NF-κB activation by inhibiting estrogen receptors, the PI3K/AKT pathway, and the MAPK pathway	[68]
Compound K	LPS-treated BMDMs	Inhibit MAPK and NF-κB activation	[70]
	LPS-treated RAW 264.7 cells	(1)Reduce TNF-α and NO levels as a ligand of the glucocorticoid receptor (2)Inhibit p65/IRF3 complex in TLR4-dependent transcriptional activation	[70]
	LPS-treated mice	Reduce TNF-α, IL-6, and NO levels	[70]
Rg1	CLP mice	Reduce IL-6 and TNF-α levels	[60,71]
		Reduce ER stress by upregulating Sirt1	[71]
	LPS-treated A549 cells	(1)Reduce apoptosis and ROS (2)Reduce TNF-α, IL-1β, and IL-6 by inhibiting NF-κB (3)Reduce ER stress by upregulating Sirt1	[71]
Rk1, Rg5	LPS-treated HUVECs	(1)Reduce HMBG1 release by Sirt1-mediated HMGB1 deacetylation (2)Reduce p38MAPK activation	[72]
	HMBG1-treated HUVECs	(1)Reduce TNF-α and IL-6 levels by inhibiting the NF-κB and MAPK pathways (2)Reduce leukocyte migration	[72]
	CLP mice	(1)Reduce HMBG1 release (2)Reduce TNF-α and IL-6 levels	[72]
Rh1	HMBG1-treated HUVECs	Reduce TNF-α and IL-6 by inhibiting NF-κB and ERK 1/2 activation	[73]
	CLP mice	Reduce HMGB1 release	[73]

LPS, lipopolysaccharide; NO, nitric oxide; iNOS, inducible nitric oxide synthase; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; GMCSF, granulocyte monocyte colony stimulating factor; MCP-1, macrophage chemo-attractant protein-1; NLRP3, NLR family pyrin domain containing 3; ROS, reactive oxygen species; IL-1β, interleukin-1β; HMGB1, high mobility group box 1; JAK2, Janus kinase 2; STAT1, signal transducer and activator of transcription 1; COX-2, cyclooxygenase-2; TLR4, toll-like receptor 4; MyD88, myeloid differentiation primary response 88; NF-κB, necrosis factor-κB; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; BMDM, bone marrow–derived macrophage; IRF3, interferon regulatory factor 3; CLP, cecal ligation and puncture; ER, endoplasmic reticulum; Sirt1, sirtuin 1; HUVEC, human umbilical vein endothelial cell; ERK, extracellular signal–regulated kinase.

Several studies have reported the anti-inflammatory effects of P. ginseng and its bioactive components in lipopolysaccharide (LPS)-induced septic models. The saponin fraction of KRG downregulated pro-inflammatory cytokines in both in vitro and in vivo LPS-stimulated models [63]. Rg3 inhibited NLRP3 inflammasome activation, lowered nitric oxide (NO) and ROS levels, and prevented spleen apoptosis and immune cell accumulation [64,65]. Ginseng leaf extract reduced the release of high mobility group box 1 (HMGB1) by inhibiting NO production in a JAK2/STAT1-dependent manner [66].

Some ginsenosides have been linked to MAPK pathway–related anti-inflammatory mechanisms in the LPS-induced model of sepsis. Rb1 downregulated inflammatory and oxidant genes and relieved splenic injuries via the TLR4-MyD88-NF-κB/MAPK pathways [67]. Re prevented cardiac inflammation, which was associated with estrogen receptors, phosphatidylinositol 3-kinase (PI3K)/AKT signaling, and the MAPK pathway [68]. That finding might correlate with its observed inhibitory activity on MAPK, NF-κB, and c-Fos in an LPS-induced model of acute lung injury (ALI) [69]. Compound K protected mice from sepsis in a dose-dependent manner, decreasing serum TNF-α, IL-6, and NO levels and inhibiting MAPK activation [70]. Further in vitro studies found that compound K acts as a glucocorticoid receptor ligand, interrupting the p65/interferon regulatory factor complex in TLR4 pathways.

Cecal ligation and puncture (CLP) is used as a clinical sepsis model, and HMGB1 also works as a mediator of sepsis. Rg1 reduced cell apoptosis, cytokine production, and liver and lung injuries in CLP-induced septic mice [60]. It also mitigated lung inflammation and ER stress through sirt1 regulation [71]. Rk1 and Rg5, the rare ginsenosides enriched in black ginseng, showed therapeutic effects in LPS-, CLP-, and HMGB1-induced septic models [72]. These compounds reduced SIRT1-mediated HMGB1 deacetylation, protected vascular integrity, and reduced NF-κB and ERK 1/2 activation and TNF-α/IL-6 production. Rh1 decreased leukocyte migration, tissue damage, and HMGB1 release in CLP-induced septic mice [73].

A significant number of septic patients exhibit resistance to glucocorticoid drugs, which can result from inherited glucocorticoid receptor mutations or an acquired inflammation-induced reduction in glucocorticoid receptor responsiveness [74]. Several studies have shown that ginsenosides suppress the release of inflammatory cytokines and inhibit the expression of the NF-κB, AP-1, and MAPK pathways. Notably, compound K and Rg1 have been identified as glucocorticoid receptor agonists [70,75,76]. Rg1 reduced NO levels and TNF-α production and upregulated glucocorticoid receptor expression in LPS-stimulated RAW 264.7 cells when it was co-treated with a low dose of corticosterone (1 μM) [76]. Further studies on the role of ginsenosides in glucocorticoid-resistant septic patients, as well as their comparative efficacy with conventional glucocorticoid agents, would broaden the therapeutic potential of P. ginseng in sepsis treatment.

3.4. Gastritis

Gastritis is one of the most common inflammatory diseases. The causes of gastritis include Helicobacter pylori infection, which can increase the risk of gastric cancer, and the use of NSAIDs such as indomethacin and acetylsalicylic acid (aspirin) [77]. KRG extract suppressed the gastritis induced by H. pylori by inhibiting inflammatory mediators, MPO activity, and lipid peroxide levels [77]. Ginseng berry juice containing Re, Rd, Rb3, Rc, and some non-saponin components such as p-coumaric acid modulated the expression of TNF-α, IL-6, IL-13, IL-10, and COX-2 by inhibiting the NF-κB pathway in mice with EtOH/HCl-induced gastritis [78]. Rg1 relieved oxidative stress and pyroptosis by modulating the NF-κB/NLRP3/Gasdermin D pathway in a chronic atrophic gastritis model [79]. Additionally, the non-saponin fraction of KRG protected against gastric damage by increasing COX-1 expression and alleviating MPO activity in indomethacin-, acetylsalicylic acid–, and cold stress–induced in vivo models [39]. These findings demonstrate that P. ginseng has the potential to treat gastritis induced by various causes (Supplementary Table 1).

3.5. Atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease with complex and heterogeneous pathology. Keratinocytes, the main cell type in the epidermis, play a crucial role in maintaining skin immunological hemostasis [80]. When allergens break the skin barrier, stimulated keratinocytes release chemokines, such as thymic and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), and thymic stromal lymphopoietin (TSLP), that recruit immune cells and promote Th2 differentiation [81]. Th2 cell cytokines (IL-4, IL-5, IL-13, and IL-31) and Th1 cell cytokines (IL-1β, IL-6, IL-10, and IFN-γ) work in the acute and chronic phases, respectively, and macrophages exacerbate skin barrier dysfunction [81]. The production of these cytokines and chemokines is regulated by the MAPK and NF-κB pathways [81]. P. ginseng has been shown to suppress AD via those signaling pathways (Supplementary Table 2).

KRG reduced the release of inflammatory cytokines and chemokines, including IL-8, TARC, and MDC, by suppressing the MAPK and NF-κB pathways in HaCaT keratinocytes, HMC-1 mast cells, and 2,4-dinitrofluorobenzene (DNFB)-induced AD model mice [82]. Ahn et al. studied the anti-inflammatory properties of an Rg5:Rk1 mixture using two in vitro AD models: TNF-α/IFN-γ-stimulated HaCaT cells and LPS-stimulated RAW 264.7 cells [83]. Rg5:Rk1 reduced the release of Th2-associated chemokines and cytokines by inhibiting NF-κB and STAT1 signaling through the p38 MAPK pathway in HaCaT cells. It also attenuated NO production and downregulated AD-related genes such as MDC. BIOGF1K, a fraction of P. ginseng rich in compound K, reduced AD-related cytokines by suppressing MAPK pathways in A2187-treated RBL-2H3 cells and MHC-1 cells [84]. In addition, short-term hydroponic-cultured ginseng containing optimized contents of chlorogenic acid, Re, Rg1, Rb1, and Rd inhibited TNF-α/IFN-γ-induced TARC expression in HaCaT cells, which implies its AD treatment potential [85]. p-Coumaric acid, an active phytochemical in P. ginseng, suppressed the expression of TSLP, TNF-α, IL-6, and IL-1β in HMC-1 cells by downregulating the MAPK and NF-κB pathways [86]. It also relieved pathological symptoms and reduced serum levels of histamine, IgE, and inflammation in the DNFB-induced AD mouse model.

3.6. Acute lung disease

ALI is acute lung inflammation with alveolar–capillary barrier dysfunction and hypoxia. Although ALI was not defined in the Berlin Classification in 2012, which clarified the definition of acute respiratory distress syndrome (ARDS), it is now widely regarded as a milder form of ARDS and is commonly used in animal studies that can't fulfill the clinical criteria of ARDS [87]. ALI can be triggered by viral or bacterial infection, radiation, or chemicals, and it is marked by an accumulation of neutrophils and fluid into the alveoli and the expression of inflammatory cytokines, including IL-1β, IL-6, and TNF-α [87].

Qi et al. analyzed the mechanism of P. ginseng on ALI/ARDS via network pharmacology [88]. They suggested STAT3, VEGFA, FGF2, PIK3CA, MAPK1, and IL-2 associated with the PI3K-AKT and MAPK pathways as the potential targets of P. ginseng. They also experimentally suppressed immune cell infiltration and pro-inflammatory cytokine release in an LPS-induced ALI mouse model by inhibiting those suggested potential targets. Other studies have also shown the anti-inflammatory effects of P. ginseng in the lungs (Supplementary Table 3). Inhalation of nebulized ginsenosides recovered lung injuries by reducing inflammatory cytokine levels and immune cell infiltration and exhibited a smad2-mediated anti-pulmonary fibrosis effect [89]. Ju et al. studied the effects of various ginsenosides on lung inflammation in an LPS-induced ALI model [69]. Rc, Re, Rg1, and Rh2 significantly reduced the cell counts in bronchoalveolar lavage fluid. In particular, Re (50 mg/kg) notably attenuated lung injury and immune cell infiltration into the lungs at a level comparable to that of dexamethasone (30 mg/kg), perhaps through its inhibition of MAPK, NF-κB, and c-FOS activation. Similar effects were also shown with the PPD fractions (20 μg/kg by inhalation and 50 mg/kg by intragastric administration), and those effects occurred by inhibiting TNFA/TNFAR and IL-7/IL-7R signaling [90]. Rg3 alleviated LPS-induced lung edema and neutrophil and macrophage infiltration by suppressing NF-κB and COX-2 [91].

3.7. Rheumatic arthritis

Rheumatic arthritis (RA) is a chronic autoimmune inflammatory disease in the joints. Collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) are widely used experimental models for RA that closely mimic its key pathogenic features, including synovitis, B and T lymphocyte involvement, and increased expression of pro-inflammatory cytokines such as TNF-α and IL-1β [92]. The effects of P. ginseng against RA are summarized in Supplementary Table 4. Rg1 was shown to alleviate the clinical symptoms of arthritis in a CIA model [75]. The saponin fraction of KRG, enriched in Rb1, Rc, and Rb2, downregulated immune cells (early T cell, CD8⁺ T cells, mature CD4⁺ T cells, B cells, activated dendritic cells, and neutrophils) and restored cytokine imbalances by decreasing serum levels of pro-inflammatory cytokines and increasing anti-inflammatory IL-10 levels in CIA mice [93]. Furthermore, Meng et al. demonstrated that Rg1, Rg3, Rg5, Rb1, Rh2, and compound K reduced IL-6 and TNF-α expression and modulated the CD4⁺ T cell population in RA [94]. Compound K further promoted the proliferation of CD8⁺ T cells and suppression of M1 macrophages, demonstrating the most potent therapeutic activity among the substances tested. It also protected joints by relieving TNF-α- and glucocorticoid receptor–associated synovitis and inhibiting the proliferation of B and T cells in the AIA and CIA model animals, respectively [95,96].

4. Conclusion

This review focused on the anti-inflammatory effects and mechanisms of P. ginseng and its components against IBD, hepatitis, sepsis, gastritis, AD, ALI, and RA (Fig. 1). Ginsenosides, the non-saponin fraction, and KRG have all been shown to alleviate the pathogenesis of inflammation. Notably, they consistently inhibited key inflammatory signaling pathways, such as the NF-κB, MAPK, and PI3K-AKT pathways, which commonly regulate inflammation in various diseases. For example, the hyperactivation of the NF-κB pathway, a central hub in inflammatory signaling, is a shared pathogenic feature such as massive neutrophil infiltration in ALI, the mucosal damage in IBD, and the cytokine storm in sepsis [[97], [98], [99]]. The inhibition of this pathway by P. ginseng may imply its broad therapeutic potential across inflammatory diseases. The connections between diseases could provide opportunities to develop integrated therapeutic approaches. For example, sepsis can be an indirect causative factor in ALI/ARDS. A network pharmacology study reported that the PI3K-AKT and MAPK pathways are the main targets for ginseng in ALI/ARDS, and those pathways are also inhibited by ginseng in septic models [67,68,70,72,88]. Therefore, P. ginseng can potentially mitigate sepsis-induced ALI/ARDS by targeting shared inflammatory processes. Also, excessive alcohol intake can not only induce hepatitis but also disrupt gut microbiota, a factor implicated in IBD. Rg1 was found to modulate the gut microbiota in both IBD models and hepatitis models, highlighting that P. ginseng might affect disease networks rather than isolated pathologies [45,50]. The systemic effects of P. ginseng could result from diverse components that enable the simultaneous modulation of multiple inflammatory targets across different organs.

Fig. 1.

Summary of Panax ginseng's modulation of key components in inflammatory diseases.

Despite the verified therapeutic effects of P. ginseng, most research has focused on preclinical or cell-based fundamental studies [100]. Clinical trials are required to establish P. ginseng as agents or adjuvants and apply the existing preclinical findings to real-world applications. However, two major challenges hinder the bench-to-bedside translation. The first challenge is the standardization of P. ginseng extract. To ensure consistent therapeutic outcomes, various factors such as ginseng's age, processing methods, and component ratio should be controlled. However, the therapeutic effect of ginseng likely arises from a complex interaction of multiple components, highlighting the challenges of standardization. Though ginsenosides have been the main focus of current research, some studies have discovered that the non-saponin fractions also have anti-inflammatory and immunomodulatory properties that contribute to the therapeutic effects of P. ginseng both independently and synergistically with saponin. Therefore, the study of P. ginseng standardization should consider both the ginsenosides and non-saponins, along with their synergistic effects. Novel approaches, such as modulating the processing of P. ginseng to optimize the content ratios or cultivating P. ginseng in diverse ways, may offer new approaches for maximizing its efficacy. A thorough understanding of the synergistic mechanisms among ginseng components and their effects on disease networks is required to develop ginseng-based products with optimal bioactivity.

The second challenge is the low bioavailability of ginsenosides. The dammarane skeleton of ginsenoside is hydrophobic, limiting the solubility, while the glycosyl structure decreases the lipophilicity, hindering the ginsenosides from penetrating the biofilm layer of cells [101]. Strategies to improve the bioavailability of P. ginseng include the bioconversion process (eg., in vitro fermentation) and delivery system. The red ginseng-derived ginsenosides showed higher absorption extents in mouse tissue and plasma compared to those from white or fresh ginseng [102]. Also, delivery vehicles such as nano-formulation and liposome can improve the absorption of ginsenosides by increasing the surface areas and lipophilicity, making them promising tools for improving the clinical utility of P. ginseng.

Among these challenges remain, solving them would enhance the therapeutic potential of P. ginseng in clinical trials. Further studies should focus on well-designed clinical studies that investigate dose-response, long-term safety, and inflammatory biomarkers. Furthermore, modern technologies such as microbiome analyses and computational target predictions may provide insights into better and safer use of P. ginseng for inflammatory disease treatment. Through a systemic and technologically informed approach, the therapeutic potential of P. ginseng can be validated and progressed to an evidence-based therapeutic agent.

Appendix A. Supplementary data

The following is the supplementary data to this article: