The Role of Triterpenoids in Gastric Ulcer: Mechanisms and Therapeutic Potentials

Abstract

Gastric ulcer (GU) is a prevalent gastrointestinal disorder impacting millions worldwide, with complex pathogenic mechanisms that may progress to severe illnesses. Conventional therapies relying on anti-secretory agents and antibiotics are constrained by drug abuse and increased bacterial resistance, highlighting the urgent need for safer therapeutic alternatives. Natural medicinal compounds, particularly triterpenoids derived from plants and herbs, have gained significant attention in recent years due to their favorable efficacy and reduced toxicity profiles. Emerging evidence indicates that triterpenoids exhibit potent anti-ulcer properties across various experimental models, modulating key pathways involved in inflammation, oxidative stress, apoptosis, and mucosal protection. Integrating current knowledge of these bioactive compounds facilitates the development of natural triterpenoids, addresses challenges in their clinical translation, deepens mechanistic understanding of GU pathogenesis, and drives innovation of therapeutic strategies for GU. This review comprehensively evaluates the progress of research on triterpenoids in GU treatment since 2000, discussing their biological sources, structural characteristics, pharmacological activities, and mechanisms of action, the animal models employed in the studies, current limitations, and the challenges associated with their clinical application.

1. Introduction

Gastric ulcer (GU) is an injury of mucosal integrity resulting from diverse invasive factors traversing the muscularis mucosae layer [1]. This widespread condition impacts nearly 10% of individuals globally, with potential progression to severe bleeding, perforation, and obstruction that collectively threaten patient well-being [2]. The causes of the emergence and development of GU are diverse. Recent studies highlight the disrupted equilibrium between invasive factors (e.g., smoking habit, alcohol consumption, pepsin, and gastric acid) and protective factors (e.g., mucus, bicarbonate, tight junction, and prostaglandins) as the pivotal determinant underlying ulcer progression [3,4,5,6]. In the past, GU was commonly attributed to excessive gastric acid secretion, stress, and poor dietary habits. Nowadays, Helicobacter pylori (H. pylori) infection and the extensive use of non-steroidal anti-inflammatory drugs (NSAIDs) have become the main triggers of GU [7] (Figure 1). The presence of GU suggests that there is inflammation in the gastric mucosa, and the severity of inflammation is related to the proximity of the ulcer center. A persistent inflammatory environment will eventually lead to gastric cancer [8,9].

Treatment of GU is usually aimed at healing the ulcer, preventing the development of complications, and inhibiting recurrence of the ulcer. Current treatment of GU is based on the use of anti-secretory agents and antibiotics that eradicate H. pylori. Anti-secretory agents encompass antiacids, histamine H2 receptor antagonists, and proton pump inhibitors. Proton pump inhibitors are the most rapid and potent, establishing them as first-line therapeutic agents for GU [10,11]. However, with the extensive clinical use of these drugs, several problems have ensued. Proton pump inhibitors demonstrate excessive utilization in clinical settings, with persistent post-discharge administration for nonessential therapeutic indications correlating with elevated risks of acute kidney injury, chronic kidney disease, and fractures [12]. Furthermore, the extensive utilization of antibiotics not only enhances H. pylori resistance but also increases the prevalence of diseases that are negatively associated with H. pylori, such as gastroesophageal reflux and obesity [13]. The search for anti-ulcer drug candidates from natural medicines represents an effective approach to addressing GU.

Natural medicines have demonstrated their safety and efficacy in both traditional and modern medicine, making them an ideal source of compounds with anti-ulcer potential. In recent years, bioactive compounds derived from natural sources, such as polysaccharides [14], flavonoids [15], coumarin [16], and alkaloids [17], have demonstrated significant anti-ulcer activities. In addition to these compounds, natural terpenoids have garnered considerable attention in the treatment of GU due to their unique structural characteristics and diverse biological activities.

Terpenoids originate through the mevalonate pathway biosynthesis and are characterized by isoprene units, which constitute the core backbone architecture of these specialized metabolites. Terpenoids demonstrate remarkable architectural diversity in molecular frameworks, underpinning their extensive bioactive potential. Particularly, triterpenoid derivatives exhibit the most therapeutically significant pharmacological profiles within all terpenoids. Triterpenoids are made up of six isoprene units with a skeleton containing 30 carbon atoms. Most of the natural triterpenoids are ring-forming, with tetracyclic and pentacyclic derivatives predominating. Depending on the number of rings and the manner of ring condensation, triterpenoids can be categorized into dammarane-type, cycloartane-type, tirucallane-type, oleanane-type, ursane-type, lupane-type, and friedelane-type. Oxidation, methylation, and acylation at varying positions on the skeleton further enrich the structure of triterpenoids, resulting in a wide range of pharmacological properties, such as anti-inflammatory, antioxidant, antimicrobial, anti-cancer, and cardioprotective effects [18,19,20,21,22].

In recent years, numerous triterpenoids isolated from natural medicines have been demonstrated to possess gastroprotective efficacy within a diverse array of GU models. However, this area remains critically under-reviewed. Our search identified only one paper in 1998 focusing on the synthesis and anti-ulcer activities of glycyrrhizin, oleanolic acid, and ursolic acid derivatives, specifically examining these particular derivatives rather than triterpenoids as a broader class [23]. With advancing research, scholars have made remarkable progress in exploring triterpenoids for GU treatment, yet no comprehensive review has analyzed or synthesized findings in this field over the past two decades. Therefore, this review consolidates research on triterpenoids in GU treatment since 2000, using studies retrieved from reference databases such as PubMed, Science Direct, Scopus, and Google Scholar. Specifically, it includes (1) the natural origins, chemical structures, and biological activities of gastroprotective triterpenoids; (2) proposed pharmacological mechanisms with graphical schematics; (3) a summary table that integrates information on compounds, sources, models, activities, and mechanisms; (4) evaluation of GU animal models employed in the reviewed studies; and (5) current limitations and future challenges in clinical implementation. This review aims to provide a reference for the development and utilization of triterpenoids in medicinal plants as well as the improvement and updating of therapeutic regimens for GU.

2. The Activity of Triterpenoids in GU

2.1. Dammarane-Type Triterpenoids

2.1.1. Ginsenoside Rb1, Ginsenoside Rd, and Ginsenoside Rg3

Ginsenosides are the main active components of ginseng (Panax ginseng C. A. Meyer), San-Qi (Panax notoginseng (Burkill) F. H. Chen ex C. H. Chow), and American ginseng (Panax quinquefolius L.). They are structurally categorized into four chemotypes based on sapogenin skeletal frameworks: protopanaxadiol (ginsenosides Rb1, Rd, and Rg3) (Figure 2), protopanaxatriol (ginsenoside Rh4), ocotillol (pseudoginsenoside F11), and oleanane-type derivatives exemplified by Ro [24]. The first three of these types are all tetracyclic triterpenes of the dammarane type.

A substantial body of evidence from numerous studies indicates that ginsenoside Rb1, ginsenoside Rd, and ginsenoside Rg3 are capable of treating malignant tumors through multiple pathways [25]. Beyond that, the rich pharmacological properties they possess also make them exert a beneficial effect on the treatment of GU. In the hydrochloric acid/ethanol (HCl/EtOH)-induced GU model in rats, ginsenoside Rb1, isolated from the active fraction of ginseng head, exhibited a significant inhibitory effect on gastric mucosal damage by promoting gastric mucus secretion [26]. Ginsenoside Rd was isolated from ginseng flower buds through methanol extraction followed by successive normal-phase and reversed-phase silica gel column chromatography. In ethanol and indomethacin-induced gastric mucosal injury models, this compound exhibited ulcer inhibition rates of 57.6% and 52.1% (100 mg/kg, p.o.), respectively, and its efficacy was comparable to the reference agent cetraxate hydrochloride [27]. It has been shown that ginsenoside Rg3 (5, 10, and 20 mg/kg, p.o.) exhibited a dose-dependent reduction in the ulcer index in ethanol, pylorus ligation, and acetic acid-induced GU in rats. This effect was associated with a reduction in the levels of inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1), as well as an increase in the expression of superoxide dismutase (SOD), epidermal growth factor (EGF), and epidermal growth factor receptor (EGFR) [28].

2.1.2. Ginsenoside Rh4 and Protopanaxatriol

Ginsenoside Rh4 (Figure 3A) is a dammarane-type tetracyclic triterpenoid saponin that, in addition to its anti-tumor effects [29,30], has been shown to protect gastric tissues through a variety of pathways. Pretreatment with ginsenoside Rh4 (60 mg/kg) for a period of seven days was observed to significantly improve gastric mucosal histomorphology in ethanol-induced mucosal damage in rats. This therapeutic effect involves a multimodal mechanism: upregulating nitric oxide (NO) and prostaglandin E2 (PGE2) synthesis, concomitant with COX-2 expression downregulation and NF-κB transduction suppression, collectively attenuating mucosal oxidative damage and pro-inflammatory cascades. Additionally, the compound was shown to elevate B-cell lymphoma-2 (Bcl-2) levels and reduce Bcl-2-associated X protein (Bax) and Factor-related Apoptosis (Fas), which in turn inhibits apoptosis [31].

Protopanaxatriol (Figure 3B) is a sapogenin and a metabolite of ginsenoside Rh4, exhibiting significant anti-inflammatory and antioxidant activity [32,33]. The gastroprotective effects of protopanaxatriol were examined in an acetic acid-induced GU model. The pharmacodynamic evaluation revealed that medium and high doses of protopanaxatriol (10 and 20 mg/kg, p.o.) mitigated the loss of body weight and the expansion of ulcerated areas induced by acetic acid. Additionally, the levels of interleukin-6 (IL-6), malondialdehyde (MDA), tumor necrosis factor α (TNF-α), ET-1, EGF, and SOD were dose-dependently regulated. It is noteworthy that the modulatory effects of protopanaxatriol at a high dose were comparable to those of the positive control omeprazole [34].

2.1.3. Ocotillol

Ocotillol-type saponins represent a distinctive class of dammarane-type saponins, characterized by the presence of a tetrahydrofuran ring. They are widely distributed in various ginseng species, including American ginseng and Vietnamese ginseng, serving as a key marker of American ginseng [35]. Ocotillol-type saponins demonstrate multifaceted therapeutic potential, such as anti-inflammatory, antibacterial, and anti-tumor effects [36]. Ocotillol (Figure 4) is the sapogenin of ocotillol-type saponins and their main metabolic component after oral administration. Ocotillol can reduce the level of ET-1 in serum and increase the level of NO in serum and gastric mucosa, as well as enhance the level of SOD, EGF, and EGFR in gastric mucosa. This ultimately leads to an improvement in the morphology of gastric tissues in model rats, which becomes similar to that of normal rats [37].

2.2. Cycloartane-Type Triterpenoid

Astragalus membranaceus (Fisch.) Bunge, a key medicinal plant in traditional Chinese medicine, has been widely utilized in clinical applications. Astragaloside IV (Figure 5) is a cycloartane-type tetracyclic triterpenoid saponin present in the aqueous extracts of Astragalus membranaceus and is the primary active component of the plant [38]. It exhibits a number of therapeutic profiles, mechanistically encompassing anti-inflammatory, antioxidant, anti-tumor, and neuroprotective effects [39]. In an ethanol-induced GU rat model, the protective effect of astragaloside IV was reversed by the NO synthase inhibitor L-NAME, indicating the involvement of NO in the anti-ulcer mechanism of astragaloside IV [40]. In addition, astragaloside IV (1, 10 and 50 mg/kg, p.o.) dose-dependently decreased gastric injury induced by water immersion and restraint stress in rats, with ulcer inhibition of 70.79% at a dose of 50 mg/kg. Besides enhancing the gastric mucosal barrier (increasing gastric pH and gastric mucus volume), anti-inflammatory (decreasing the levels of TNF-α and monocyte chemoattractant protein-1 (MCP-1)), and antioxidant (enhancing the activity of SOD and reducing the level of MDA) functions, astragaloside IV also upregulated the expression of heat shock protein 70 (HSP70) and thus inhibited the activation of Bax, showing an anti-apoptotic effect [41]. The administration of astragaloside IV (50 mg/kg, p.o.) inhibited an aspirin-induced decrease in cyclooxygenase-1 (COX-1) expression, thereby increasing the PGE2 level, enhanced the activity of SOD and the level of NO in the stomach, and attenuated the degree of aspirin-induced pathological damage to gastric mucosa. In vitro, aspirin-induced apoptosis was significantly inhibited by astragaloside IV (50 μg/mL). Notably, astragaloside IV did not interfere with aspirin’s effects on COX-2, suggesting its potential for concurrent administration with aspirin to mitigate the gastrointestinal side effects associated with long-term aspirin therapy [42].

2.3. Tirucallane-Type Triterpenoid

Amphipterygium adstringens (Schltdl.) Schiede ex Standl is a medicinal plant native to Mexico that is considered an important anti-ulcer drug in local traditional medicine, and its stem bark is often used in treating various conditions like GU and gastritis [43]. 3α-Hydroxymasticadienoic acid (Figure 6), a tirucallane-type tetracyclic triterpenoid, was isolated from the dichloromethane fraction of the hexane extract of Amphipterygium adstringens stem bark via silica gel column chromatography. This compound exhibited a significant protective effect on gastric mucosa in the ethanol-induced GU model. This effect was inhibited by the sulfhydryl blocker N-ethylmaleimide, indicating that the anti-ulcer activity of 3α-hydroxymasticadienoic acid is dependent on endogenous sulfhydryl groups [44]. In addition, 3α-hydroxymasticadienoic acid has been shown to increase PGE2 levels and SOD activity while decreasing TNF-α and leukotriene B4 (LTB4) levels, exhibiting anti-inflammatory and antioxidant effects, as well as elevating the levels of gaseous mediators NO and hydrogen sulfide (H₂S) in rat gastric tissue, which functions to safeguard the stomach mucosa against indomethacin injury [45].

2.4. Oleanane-Type Triterpenoids

2.4.1. Oleanolic Acid

Oleanolic acid (Figure 7A) is an oleanane-type pentacyclic triterpenoid, widely present in nature and isolated from more than 1600 plant species, many of which serve as food and medicine. It is most prevalent in Oleaceae plants [46]. Oleanolic acid has attracted significant scientific attention because of its wide range of pharmacological effects, including gastroprotective, anti-inflammatory, antibacterial, antiviral, and anti-tumor properties [47]. The anti-ulcer effects of oleanolic acid (50, 100, and 200 mg/kg, p.o.) were shown in ethanol, aspirin, and pylorus ligation-induced GU models. In the last two models, its therapeutic effectiveness was similar to that of ranitidine at a dose of 50 mg/kg orally [48]. Specifically, it was observed that oleanolic acid (100 mg/kg, p.o.) markedly diminished the area of acetic acid-induced gastric lesions. In oleanolic acid-treated rats, the thickness of the gastric mucus layer increased to 540 μm, compared with 342 μm in control rats. These findings suggest that oleanolic acid exerts therapeutic effects on acetic acid-induced chronic GU in rats [49]. In vitro, oleanolic acid and its derivatives significantly reduced the damage caused by sodium taurocholate to human gastric adenocarcinoma cells (AGS), increased the content of PGE2 in AGS cell cultures, and substantially stimulated the proliferation of human lung fibroblasts. These gastroprotective activities of oleanolic acid and its derivatives were successfully validated in the HCl/EtOH-induced gastric injury model in mice. These activities attenuated gastric injury in mice to varying degrees [50].

2.4.2. Araloside A

Araloside A (Figure 7B), an oleanane-type pentacyclic triterpenoid commonly present in Aralia plants, is nontoxic and has shown some antioxidant effects [51]. It is the primary anti-ulcer constituent of Aralia elata (Miq.) Seem. and demonstrated considerable inhibitory effects on HCl/EtOH, aspirin, pylorus ligation, and stress-induced GU in four distinct rat models. In the last model, araloside A (100 mg/kg, p.o.) showed a stronger anti-ulcer effect than cimetidine (100 mg/kg, p.o.), which was related to the inhibition of gastric acid secretion [52]. Similarly, in ethanol and aspirin-induced GU in mice, araloside A (40 mg/kg, p.o.) improved gastric blood flow, enhanced gastric mucosal defenses, and inhibited H⁺/K⁺-ATPase, thereby increasing gastric juice pH. It is noteworthy that araloside A exhibited a more potent anti-apoptotic effect compared to the positive control omeprazole by elevating the Bcl-2/Bax ratio, inhibiting cytochrome c release, and downregulating caspase-3 and caspase-9 activity as well as related mRNA expression [53].

2.4.3. 18β-Glycyrrhetinic Acid

Licorice, which is derived from the dried roots and rhizomes of Glycyrrhiza uralensis Fisch., Glycyrrhiza glabra L., and Glycyrrhiza inflata Bat., has been utilized in traditional medicine worldwide for a long time. It is often used to treat GU and respiratory problems [54]. 18β-glycyrrhetinic acid (Figure 7C) is an oleanane-type pentacyclic triterpenoid, primarily derived from licorice, and it demonstrates various pharmacological activities, including anti-inflammatory, antioxidant, antimicrobial, and anti-tumor effects [55]. Previous research has shown that 18β-glycyrrhetinic acid exhibits significant anti-ulcer activity in a variety of GU models [56,57]. Furthermore, 18β-glycyrrhetinic acid showed inhibitory effects on H. pylori in vitro and in vivo. Among various licorice extracts, 18β-glycyrrhetinic acid demonstrated the most powerful inhibition of H. pylori strains derived from gastric biopsies of patients with GU, with the effect being both rapid and dose-dependent [58]. The administration of 18β-glycyrrhetinic acid significantly reduced ulcer scores, improved gastric histomorphometry, inhibited H. pylori-induced gastric juice pH elevation, and decreased the expression levels of COX-2, interleukin-1β (IL-1β), iNOS, and TNF-α in H. pylori-infected Mongolian gerbils, protecting the gastric mucosa from H. pylori and the inflammation it causes [59].

2.4.4. Soyasaponin Bb

Soyasaponin Bb (Figure 7D) is an oleanane-type pentacyclic triterpenoid saponin present in soybeans and other Fabaceae plants. As a principal component of soybean saponins in soybean seeds and processed products, soyasaponin Bb shows significant pharmacological effects including anti-inflammatory and anti-tumor properties [60]. In a diclofenac-induced rat GU model, soyasaponin Bb exhibited comparable protective effects as the positive control drug ranitidine. It elevated the levels of SOD and catalase (CAT), reduced the levels of MDA, TNF-α, and IL-6, while increasing the levels of PGE2 and gastric mucus secretion in the stomach. The reduction in inflammation by Soyasaponin Bb was connected to the inhibition of NF-κB-mediated regulation of COX-2 expression [61].

2.4.5. δ-Amyrone

δ-Amyrone (Figure 7E), an oleanane-type pentacyclic triterpenoid from Sedum lineare Thunb., exhibits specific inhibitory activity against COX-2 and has no effect on COX-1, while also showing anti-inflammatory activity both in vitro and in vivo [62]. Pharmacological evaluation of δ-amyrone (4 and 8 mg/kg, p.o.) in ethanol-induced GU models revealed dose-dependent suppression of the expression of NF-κB, with subsequent attenuation of pro-inflammatory mediators (TNF-α, IL-6) and NO overproduction in gastric tissue. In addition, δ-amyrone elevated the gastric pH and gastric mucus content, inhibited the ethanol-induced increase in myeloperoxidase (MPO) levels, and significantly reduced gastric injury in mice [63].

2.4.6. Maslinic Acid

Maslinic acid (Figure 7F) is an oleanane-type pentacyclic triterpenoid that is present in various medicinal and edible plants like loquat, patchouli, hawthorn, spinach, and eggplant. It exhibits a diverse range of biological activities, including antioxidant, anti-inflammatory, anti-diabetic, and anti-tumor [64]. Maslinic acid (10 mg/kg, p.o.), isolated from the methanol extract of Plinia edulis (Vell.) Sobral fruits through chromatographic column separation, demonstrated significant gastroprotective effects in both HCl/EtOH and indomethacin-induced GU models in mice. The ulcer area was reduced by 97.12% and 96.28%, respectively, in comparison to the control group. This anti-ulcer effect of maslinic acid is partially attributed to its prominent inhibitory effect on H⁺/K⁺-ATPase [65].

2.4.7. α-Boswellic Acid

α-Boswellic acid (Figure 7G) is an oleanane-type pentacyclic triterpenoid mainly present in the resins secreted by plants of the Boswellia genus [66]. In an ethanol-induced GU model in rats, α-boswellic acid (200 mg/kg, p.o.) exerts gastroprotective effects by activating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) antioxidant pathway. Pretreatment with α-boswellic acid raised the pH of gastric juice, elevated gastric mucus secretion, increased the levels of PGE2 and NO as well as the activities of SOD and CAT, reduced MDA production and leukocyte infiltration, and markedly improved the morphology of gastric tissues in rats [67].

2.5. Ursane-Type Triterpenoids

2.5.1. Ursolic Acid

Ursane-type compounds structurally derived from ursolic acid (Figure 8A), a phytochemical with common occurrence across the plant kingdom, can be found in apple peel, rosemary, and lavender [68]. Due to its multiple intracellular and extracellular targets, ursolic acid exhibits a wealth of pharmacological activities including antimetastatic, antioxidant, anti-inflammatory, and antimicrobial properties [69]. Aganosma dichotoma K. Schum is a plant traditionally utilized in Indian medicine for its anti-ulcer properties. Ursolic acid (50 mg/kg, p.o.) isolated from the ethanolic extract of its roots via high-performance thin-layer chromatography demonstrated a significant reduction in gastric juice volume and an elevation in gastric pH in pylorus-ligated rats. Additionally, ursolic acid exhibited anti-ulcer effects in both pylorus-ligated and ethanol-induced GU models in rats [70]. Pharmacological evaluation of ursolic acid derived from Ochrosia elliptica Labill. buds in an ethanol-induced GU model revealed that pretreatment with 100 mg/kg significantly reduced MDA levels and suppressed caspase-3 activity in gastric tissues compared to controls. These results indicate that the compound provides gastroprotective effects through dual mechanisms: attenuating mucosal oxidative stress and modulating apoptotic signaling pathways. Furthermore, the molecular docking results revealed that ursolic acid exhibits preferential binding affinity toward H⁺/K⁺-ATPase, demonstrating stronger molecular interactions than omeprazole and ranitidine, thereby highlighting its potential as a novel acid-suppressive therapeutic candidate [71].

2.5.2. Tormentic Acid

Tormentic acid (Figure 8B) is a naturally occurring ursane-type pentacyclic triterpenoid, mainly extracted from the leaves and the whole herb of plants belonging to the Rosaceae family, though it is also present in the Labiatae and Urticaceae families. Tormentic acid has a multitude of pharmacological activities, including anti-inflammatory, anti-cancer, anti-diabetic, hepatoprotective, and neuroprotective [72]. The effects of tormentic acid on indomethacin-induced gastric injury were examined in vitro and in vivo. Tormentic acid (4 mg/kg) increased the levels of glutathione peroxidase (GSH-Px), SOD, and CAT, decreased the levels of MDA, TNF-α, IL-1β, and IL-6, elevated the expression of anti-inflammatory cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10), and significantly reduced the area of ulcers in indomethacin-induced GU in rats. Additionally, tormentic acid inhibited indomethacin-induced apoptosis in human gastric mucosal epithelial cells (GES-1), while promoting cell proliferation and cell migration. The findings indicated that the gastric mucosal protective mechanism of tormentic acid was linked to the promotion of epithelial cell regeneration and migration, as well as the acceleration of gastric mucosal barrier remodeling [73].

2.5.3. Asiaticoside

Centella asiatica (L.) Urban, a herbaceous perennial with pantropical distribution, holds dual ethnomedicinal significance in Ayurvedic and traditional Chinese medicine, particularly valued for its antipyretic properties and therapeutic efficacy in managing dermatological pathologies [74]. Asiaticoside (Figure 8C) is a natural ursane-type pentacyclic triterpenoid and a principal active ingredient of Centella asiatica. It has gained widespread attention in dermatological research due to its efficacy in wound healing and skin care. Moreover, asiaticoside possesses a variety of biological activities involving anti-inflammatory, neuroprotective, and anti-tumor activities [75]. In an acetic acid-induced GU model in rats, asiaticoside demonstrated the capacity to reduce MPO activity in ulcerated tissues, promote microangiogenesis at the base of the ulcer, and facilitate cell proliferation at the ulcer site, exhibiting anti-inflammatory, angiogenic, and cell proliferative properties [76]. In addition, asiaticoside dose-dependently attenuated the activity and protein expression of iNOS in the ulcerated tissues of rats with acetic acid-induced gastric injury, thereby inhibiting the overproduction of NO, which could aggravate the ulcers, and showing gastroprotective activity [77].

2.5.4. Niga-Ichigoside F1

Niga-ichigoside F1(Figure 8D) is a natural ursane-type pentacyclic triterpenoid, predominantly distributed in the Rubus genus, which has been shown to have antioxidant, anti-inflammatory, and wound-healing properties [78,79]. In addition to these biological activities, there is a therapeutic effect of niga-ichigoside F1 on different types of GU. Niga-ichigoside F1 was isolated from the methanol extract of dried roots of Rubus coreanus Miq. via silica gel column chromatography. This compound significantly inhibited ethanol-salicylate-induced GU in rats and reduced gastric secretion, total acid excretion, and gastric juice acidity, while enhancing the activities of GSH-Px and SOD [80]. In a GU model in mice induced by HCl/EtOH, niga-ichigoside F1 (30 mg/kg) demonstrated anti-ulcer effects comparable to the positive control drug omeprazole, with an ulcer inhibition rate of 98.45%. This activity of niga-ichigoside F1 may be partly attributed to its anti-secretory effect [81].

2.6. Lupane-Type Triterpenoids

2.6.1. Lupeol

Lupeol (Figure 9A), a lupane-type pentacyclic triterpenoid widely distributed in nature, exhibits significant therapeutic potential across multiple domains. This compound exerts its effects through the modulation of critical pathological pathways including oxidative stress, inflammatory responses, and apoptotic regulation via diverse mechanisms. Consequently, it holds clinical relevance in the fields of oncology, metabolic disorders, cardiovascular diseases, and renal pathologies [82]. In an ethanol-induced GU model in mice, lupeol (30 mg/kg, p.o.) restored ethanol-depleted non-protein sulfhydryl groups (NP-SH) and exhibited stronger gastroprotective effects than the positive control drug N-acetylcysteine. This protective effect of lupeol was found to be attenuated by indomethacin and L-NAME, indicating that prostaglandins (PGs) and NO may play a role in its treatment [83]. Molecular interaction results revealed van der Waals interactions between lupeol and key amino acid residues of gastric H⁺/K⁺-ATPase, suggesting that this compound has great potential as an anti-ulcer agent through anti-secretory effects [84].

2.6.2. Betulinic Acid

Betulinic acid (Figure 9B) is a lupane-type pentacyclic triterpenoid commonly found in the bark of Betula platyphylla Suk. and has therapeutic effects on tumors, inflammation, and diabetes [85]. In an indomethacin-induced GU model, the ulcer index of rats pretreated with betulinic acid for seven consecutive days was significantly reduced in a dose-dependent manner compared with the control group. This anti-ulcer effect of betulinic acid is attributed to an increase in the number of gastric mucus cells and gastric mucus secretion, as well as a decrease in gastric acid secretion and MDA level in the stomach [86].

2.7. Friedelane-Type Triterpenoid

Friedelin (Figure 10), a friedelane-type pentacyclic triterpenoid, is commonly identified in the bark and leaves of diverse plant species. In addition to being used as an insecticide and herbicide, friedelin has applications in the treatment of cancer, diabetes, inflammation, and neurological disorders [87]. Friedelin (35 mg/kg, p.o.) significantly inhibited indomethacin-induced GU in rats. Apart from exerting anti-inflammatory and antioxidant effects by regulating the levels of glutathione (GSH), MPO, MDA, TNF-α, and IL-10, friedelin can also increase the volume of gastric mucus and raise the pH of gastric juice, as well as downregulate the level of caspase-3 [88].

2.8. Other Triterpenoids

Azadiradione (Figure 11) belongs to the limonoids and serves as an active ingredient in the insecticidal plant Azadirachta indica A. Juss., which is mainly distributed in the tropical region of southeastern Asia [89]. In addition to its insecticidal properties, azadiradione (20 and 40 mg/kg, p.o.) isolated from the ethanol extract of Azadirachta indica seeds via silica gel column chromatography demonstrated significant protective effects in cold restraint stress, ethanol, pyloric ligation, and aspirin-induced GU in rats. The anti-ulcer effect of azadiradione was superior to that of the positive control drug sucralfate in an ethanol-induced ulcer model. This anti-ulcer property is related to the promotion of gastric mucin secretion, the inhibition of H⁺/K⁺-ATPase, and the increase in PGE2 levels in the stomach [90].

The effects of the above triterpenoids on GU are summarized and shown in

Table 1. Triterpenoids with anti-ulcer activity.

Compound	Plant Source	Type	Model	Efficacy	Effect or Mechanism	Ref.
Ginsenoside Rb1	Panax ginseng C. A. Mey.	Dammarane	Male SD rats (oral EtOH/HCl (60%/150 mM, 5 mL/kg))	60.6% 1 (300 mg/kg)	↑ mucus	[26]
Ginsenoside Rd	Panax ginseng C. A. Mey.	Dammarane	Rats (oral ethanol (20 mg/kg))	57.6% 2 (100 mg/kg)		[27]
			Rats (oral indomethacin (20 mg/kg))	52.1% 2 (100 mg/kg)
Ginsenoside Rg3	Panax ginseng C. A. Mey.	Dammarane	Male Wistar rats (oral ethanol (5 mg/kg))	63.1% 1 (20 mg/kg)	↑ SOD, NO, EGF, EGFR ↓ iNOS, ET-1	[28]
			Male Wistar rats (pyloric ligation)	64.8% 1 (20 mg/kg)
			Male Wistar rats (inject 0.3 mL indomethacin)	62.7% 1 (20 mg/kg)
Ginsenoside Rh4	Panax notoginsen (Burkill) F. H. Chen ex C. Y. Wu & K. M. Feng	Dammarane	Male SD rats (absolute ethanol (5 mg/kg))	92.57% 2 (60 mg/kg)	↑ NO, PGE2, COX-2, Bcl-2 ↓ MAPK/NF-κB signaling pathway, Bax, Fas	[31]
Protopanaxatriol	Panax ginseng C. A. Mey.	Dammarane	Male Wistar rats (inject 0.3 mL indomethacin)		↑ SOD, EGF, EGFR ↓ TNF-α, IL-6, ET-1, MDA	[34]
Ocotillol	Panax plants	Ocotillol	Male Wistar rats (inject 0.3 mL indomethacin)		↑ NO, SOD, EGF, EGFR ↓ ET-1	[37]
Astragaloside IV	Astragalus membranaceus (Fisch.) Bunge	Cycloartane	Male Wistar rats (oral absolute ethanol (1 mg/rat))	52.3% 2 (30 mg/kg)	↑ NO	[40]
			Male SD rats (water immersion and restraint stress)	70.79% 2 (50 mg/kg)	↑ PH, mucus, SOD, HSP70 ↓ MDA, TNF-α, MCP1	[41]
			Wistar rats (oral aspirin (150 mg/kg))		↑ COX-1, PGE2, NO, SOD	[42]
3α-Hydroxymasticadienoic acid	Amphipterygium adstringens (Schltdl.) Schiede ex Standl	Tirucallane	Male Wistar rats (oral indomethacin (30 mg/kg))	70% 2 (30 mg/kg)	↑ SOD, PGE2, NO, H2S ↓ TNF-α, LTB4	[45]
Oleanolic acid	Oleaceae plants	Oleanane	Male SD rats (inject 0.05 mL of 30% acetic acid)	76.0% 2 (100 mg/kg)	↑ mucus	[49]
			AGS (10 mM NaT for 30 min)		↑ PGE2	[50]
Araloside A	Aralia plants	Oleanane	Male SD rats (oral EtOH/HCl (60%/150 mM, 1.5 mL/rat))	51.4% 1 (100 mg/kg)	↑ pH	[52]
			Male SD rats (aspirin (100 mg/kg))	80.7% 1 (100 mg/kg)
			Male SD rats (water immersion stress)	84.3% 1 (100 mg/kg)
			Male SD rats (pyloric ligation)	73.9% 1 (100 mg/kg)
			Male Kunming mice (oral 80% ethanol containing 15 mg/mL aspirin (10.0 mL/kg))	About 40% 1 (40 mg/kg)	↑ pH, mucus, Bcl-2 ↓ H+/K+-ATPase, cytochrome c, caspase-3, caspase-9, Bax	[53]
Soyasaponin Bb	Fabaceae plants	Oleanane	Male Wistar albino rats (diclofenac sodium (5 mg/mL))		↑ PGE2, mucus, CAT, SOD ↓ COX-2, MDA, TNF-α, IL-6, NF-κB	[61]
δ-Amyrone	Sedum lineare Thunb.	Oleanane	Male Kunming mice (oral 75% ethanol (0.5 mL/100 g))		↑ pH, mucus ↓ MPO, TNF-α, IL-6, NO, NF-κB	[63]
Maslinic acid	Loquat, patchouli, hawthorn, spinach, and eggplant	Oleanane	Female Swiss mice (oral EtOH/HCl (60%/0.3 M, 10 mL/kg))	97.12% 2 (10 mg/kg)	↓ H+/K+-ATPase	[65]
			Female Swiss mice (oral indomethacin (80 mg/kg))	96.28% 2 (10 mg/kg)
α-Boswellic acid	Boswellia plants	Oleanane	Male SD rats (oral absolute ethanol (5 mL/kg))	42.45% 1 (200 mg/kg)	↑ pH, mucus, PGE2, NO, CAT, SOD, Nrf 2/HO-1 ↓ MDA	[67]
Ursolic acid	Apple peel, rosemary, and lavender	Ursane	Female Wistar albino rats (oral 95% ethanol (1 mL/rat))	96.9% 1 (100 mg/kg)	↓ MDA, caspase-3, H+/K+-ATPase	[71]
Tormentic acid	Rosaceae plants	Ursane	Male SD rats (oral indomethacin (100 mg/kg))		↑ GSH-Px, SOD, CAT, IL-10 ↓ MDA, TNF-a, IL-1b, IL-6, IL-4	[73]
			GES-1 (700 μM indomethacin for 18 h)		↑ cell migration ↓ cell apoptosis	[73]
Asiaticoside	Centella asiatica (L.) Urban	Ursane	Male SD rats (inject 60% acetic acid (0.12 mL/rat))		↓ MPO	[76]
			Male SD rats (inject 60% acetic acid (0.12 mL/rat))		↓ iNOS	[77]
Niga-ichigoside F1	Rubus plants	Ursane	Male SD rats (oral ethanol (4 mL/kg) and sodium salicylate (200 mg/kg)		↑ SOD, GSH-Px	[80]
			Male Swiss mice (oral EtOH/HCl (60%/0.3 M, 0.5 mL/rat))	98.45% 2 (30 mg/kg)		[81]
Lupeol	Cucumber, carrot, mango, strawberries, and olive	Lupane	Male Swiss albino mice (oral absolute ethanol (0.2 mL/mice))	69.3% 2 (30 mg/kg)	↑ NP-SH	[83]
Betulinic acid	Betula platyphylla Sukaczev	Lupane	Male Wistar albino rats (indomethacin (40 mg/kg))		↑ mucus, pH ↓ MDA	[86]
Friedelin	Celastraceae, Asteraceae, Fabaceae, and Myrtaceous plants	Friedelane	Wistar albino rats (oral 96% ethanol (5 mL/kg))	88.21% 1 (35 mg/kg)	↑ PGE2, NO, SOD, GSH-px, CAT, GSH, IL-10, mucus, pH ↓ MPO, MDA, TNF-α, IL-6, caspase-3	[88]
Azadiradione	Azadirachta indica A. Juss.	limonoids	SD rats (cold restraint)	58.5% 1 (40 mg/kg)	↑ pH, mucus, PGE2 ↓ H+/K+-ATPase	[90]
			SD rats (oral absolute ethanol (5 mL/kg))	71.67% 1 (20 mg/kg)
			SD rats (pyloric ligation)	50.0% 1 (20 mg/kg)
			SD rats (aspirin (150 mg/kg))	55.53% 1 (20 mg/kg)

¹ Reduction in ulcer index; ² Reduction in ulcer area; ↓ indicates a decrease in expression and ↑ indicates an increase in expression.

.

3. The Pharmacological Mechanisms of Triterpenoids in GU

3.1. Regulation of Redox Balance

The equilibrium between oxidative stress and antioxidant defenses within the gastric mucosa governs both the initiation and progression of GU fundamentally. Reactive Oxygen Species (ROS) are a group of unstable molecules produced by various cells, which include hydrogen peroxide (H₂O₂), hydroxyl radicals (OH⁻), singlet oxygen (¹O₂), and superoxide (O₂⁻). These substances are generally considered to be harmful to the body [91]. Excessive ROS are generated when the body is exposed to stimuli such as ischemia, hypoxia, and radiation. These ROS can damage membranes and cellular macromolecules, induce apoptosis, and lead to gastric injury [92]. Furthermore, MPO located in neutrophils will also produce excessive ROS when neutrophils are activated. Subsequently, ROS react with H₂O₂ to produce large quantities of HOCl. HOCl will react vigorously with sulfhydryl groups and deplete GSH in significant quantities, thereby reducing the body’s antioxidant capacity [93]. GSH contains a readily oxidizable sulfhydryl group that reacts with ROS to eliminate it. GSH also assists GSH-Px in reducing H₂O₂ to H₂O. The antioxidant enzyme system in cells is composed of GSH-Px, CAT, and SOD. This system can effectively scavenge ROS while modulating systemic redox homeostasis [94]. These bioactive components coordinately regulate redox equilibrium through synergistic interactions. The balance is disrupted when there is a significant alteration in the levels of these substances in the stomach, thereby leading to oxidative stress. Triterpenoids such as tormentic acid [73], asiaticoside [76], and niga-ichigoside F1 [80] can enhance the activities of GSH-Px, CAT, and SOD, increase the level of GSH, and reduce the activity of MPO, suggesting that they are able to protect the gastric mucosa from oxidative damage.

GSH, as a key constituent of NP-SH, critically orchestrates GU pathophysiology through mucosal defense mechanisms. Because of its reduced sulfhydryl group, NP-SH is capable of binding to free radicals produced by ulcerogenic agents, thereby exhibiting antioxidant effects [95]. Meanwhile, NP-SH enhances the disulfide bonds between gastric mucus subunits, thus reinforcing the gastric mucus barrier and safeguarding the gastric mucosa from invasive factors [96,97]. Lupeol [83] restores ethanol-depleted NP-SH levels that prevent the exacerbation of GU.

Nrf2 also plays a significant role in clearing the oxidative stress state of gastric tissues. Under oxidative stress, cytoplasmic Nrf2 translocates to the nucleus, which in turn upregulates the expression of key antioxidant enzymes including SOD, CAT, and GSH-Px. The activation of Nrf2 also protects tight junctions, promotes gastric mucus secretion, and downregulates NF-κB to reduce inflammatory response [98,99]. In addition, HO-1, an antioxidant factor regulated by Nrf2, protects cells and inhibits ROS production, thereby protecting the gastrointestinal tract from oxidative stress damage [4,100]. The triterpenoid α-boswellic acid [67] can upregulate the expression of Nrf2, which exhibits antioxidant effects.

3.2. Regulation of Inflammatory Cytokines

The inflammatory reaction of gastric mucosa caused by various stimuli is a major cause of the occurrence and development of GU. Macrophages, as key cells in human innate immunity, are pivotal in mediating the inflammatory response. Once activated by different stimuli, macrophages form two phenotypes, M1 and M2, with pro-inflammatory and anti-inflammatory activities, respectively [101]. Macrophage activation by lipopolysaccharide and Th1 cytokines (including TNF-α) leads to the formation of M1 macrophages, which are capable of releasing cytokines such as TNF-α, IL-1β, and IL-6. In contrast, M2 macrophages activated by Th2 cytokines release cytokines such as IL-10 [102]. Thus, the pro-inflammatory factors TNF-α, IL-1β, and IL-6 contribute to the progression of GU, whereas the anti-inflammatory factor IL-10 reduces the severity of inflammation in GU [103]. Tormentic acid [73] and friedelin [88] are able to modulate the levels of these cytokines in different ulcer models to protect the gastric mucosa from inflammatory damage.

As a member of the CC chemokine family, MCP-1, alternatively designated C-C motif chemokine ligand 2, functions as a low-molecular-weight cytokine involved in immune regulation. It serves a pivotal function in the process of inflammation by regulating the migration and infiltration of inflammatory cells at the site of inflammation [104]. Previous research has indicated the involvement of MCP-1 in the formation of ulcers. The administration of TNF-α results in an increase in MCP-1 expression, which in turn regulates leukocyte recruitment and ultimately contributes to the recurrence of GU [105]. Astragaloside IV [41] reduced the levels of TNF-α and MCP-1 and exhibited anti-inflammatory effects in an acute GU model in rats. LTB4 is also associated with the promotion of leukocyte migration into inflamed tissues. When LTB4 is overproduced, it becomes involved in the production and persistence of inflammation [106]. A previous study demonstrated that indomethacin resulted in a significant elevation in gastric LTB4 levels and leukocyte infiltration in mice, which subsequently triggered an inflammatory response and gastric damage [107], whereas 3α-hydroxymasticadienoic acid [45] can reduce the level of LTB4 in the stomach and leukocyte infiltration, thereby inhibiting the inflammation of gastric mucosa.

NF-κB can activate the expression of genes associated with inflammation, thereby exerting a vital influence on the inflammatory process [108]. In response to stimulation by pro-inflammatory factors or ROS, activation of the transcriptional regulator NF-κB triggers downstream inflammatory pathways, elevating levels of cytokines including TNF-α, IL-1β, and IL-6, which collectively amplify GU progression [109,110]. The NF-κB pathway was inhibited and the levels of inflammation-associated cytokines were modulated in different ulcer models by ginsenoside Rh4 [31], soyasaponin B [61], and δ-amyrone [63]. This indicates that these triterpenoids protect gastric tissue by reducing the inflammation associated with ulcerative lesions.

ET-1, a powerful vasoconstrictor present in the gastrointestinal tract, is also a potent ulcerogenic agent. Excessive release of ET-1 due to various reasons can dramatically lower gastric blood flow and dysregulate microcirculation of the gastric mucosa, ultimately leading to gastric mucosal damage [111,112]. It has been shown that ET-1 significantly delays ulcer healing and scar formation in established GU [113]. ET-1 can also increase the expression of TNF-α, IL-6, and other inflammatory factors, which is a positive feedback process. As a result, these factors will in turn stimulate the synthesis and release of ET-1, worsening the inflammatory response [114]. Triterpenoids such as ginsenoside Rg3 [28], protopanaxatriol [34], and ocotillol [37] exhibit gastroprotective effects by decreasing ET-1 levels in a variety of GU models.

3.3. Regulation of Gastric Mucosal Cytoprotective Factor

In the presence of gastric acid, pepsin, and foreign invading factors, the maintenance of gastric mucosal tissue structure and normal physiological functions cannot be achieved without the support of cytoprotective factors. Cytoprotective factor enhances gastric mucus secretion while maintaining the integrity of the gastric epithelium, thereby reinforcing the defensive capabilities of the gastric mucosa and mitigating the damage associated with GU [115,116]. Among these protective factors, PGE2, NO, H₂S, and Hsp 70 play a pivotal role in the inhibition of GU by triterpenoids.

Endogenous PGs constitute a class of lipid mediators produced from arachidonic acid via prostaglandin synthase and two isomers of cyclooxygenase (COX-1 and COX-2). They possess potent gastrointestinal protective properties [117]. In normal gastric mucosa, COX-1 is highly expressed, while COX-2 is almost unexpressed. However, the expression level of COX-2 is increased in the presence of inflammation or tissue injury [118]. Among these endogenous PGs, the role of PGE2 is the most important. The classification of PGE2 receptors into four distinct subtypes provides further evidence that PGE2 exerts a multitude of effects on the gastrointestinal tract. Through the activation of various receptors, PGE2 is capable of increasing gastric mucus and HCO₃⁻ secretion, inhibiting gastric acid secretion and gastric motility, enhancing gastric mucosal blood flow, and impeding neutrophil migration [119,120]. A number of triterpenes, including ginsenoside Rh4 [31], astragaloside IV [42], and friedelin [88], have been demonstrated to enhance the gastric mucosal barrier by regulating the activity of COX and the level of PGs.

The balance of the gastric environment is influenced by the presence of certain gaseous media. NO is a small molecule gaseous mediator produced by the enzyme nitric oxide synthase (NOS). Its effects on the health of the gastric mucosa are double-edged. NOS is categorized into three subtypes, namely neuronal NOS (nNOS), endothelial (eNOS), and iNOS. eNOS and nNOS are integral to gastric homeostasis. NO produced by them can mediate gastric mucosal blood flow, decrease gastric acid secretion by regulating endogenous PGs, attenuate oxidative stress through free radical scavenging, and sustain goblet cell secretory activity for mucus barrier integrity [121,122]. Triterpenoids such as astragaloside IV [42] and α-boswellic acid [67] upregulate the NO level. Nevertheless, there is a strong correlation between iNOS and the severity of inflammation. Pro-inflammatory cytokines, including TNF-α and IL-1β, facilitate the expression of iNOS and consequently result in a significant increase in NO production. Excessive amounts of NO were found to disrupt mitochondrial respiration, damage DNA, promote mutation, and ultimately induce apoptosis and exacerbate inflammation [123,124]. Ginsenoside Rg3 [28] and asiaticoside [77] could protect gastric mucosa from the negative effects of NO by blocking iNOS.

In addition to upregulating NO levels, 3α-hydroxymasticadienoic acid [45] increased the levels of another gaseous mediator, H₂S, in the stomach. H₂S can activate mitogen-activated protein kinase and Nrf2, thereby enhancing cellular antioxidant capacity to counteract oxidative injury in the gastric mucosa. Furthermore, H₂S reduces gastric acid secretion and increases the level of HCO₃⁻ in the stomach, a process that is mediated by NO and PGs. This ultimately protects the gastric mucosa from damage [125].

External stimuli, such as oxidative stress, lead to an increase in the levels of Hsp 70, a member of the heat shock family of proteins that is widely found in mammalian cells. Hsp 70 removes damaged denatured proteins to preserve the functional structure of tissue proteins, thus preventing apoptosis [126]. In addition, Hsp 70 enhances the tightness of cell junctions, thereby safeguarding cells from injury [127]. Several studies have demonstrated that elevated levels of Hsp 70 exert a beneficial influence on gastric mucosal protection [128,129]. Astragaloside IV [41] can regulate the level of Hsp 70 in GU models, enhance the protective effect of gastric mucosa, and promote the healing of gastric mucosal injury.

3.4. Regulation of the Acidity and Viscosity of Gastric Juice

Digestion is one of the main functions of the stomach. The production of gastric acid is a crucial element of this process, yet it is also a contributing factor to the formation of GU [130]. Gastric parietal cells exchange H⁺ from the cytoplasm to the gastric lumen through H⁺/K⁺-ATPase, and H⁺ combines with Cl⁻ in the gastric lumen to form gastric acid. The secretion process of gastric acid is modulated through the nervous system, hormones, and paracrine secretion. Exogenous factors may induce the dysregulation of secretion, which triggers erosive effects on gastric mucosa [130,131]. Triterpenoids including maslinic acid [65] and ursolic acid [71] inhibit H⁺/K⁺-ATPase, which in turn exhibits anti-secretory effects.

The gastric mucus covering the gastric epithelial cells represents the initial line of defense for the gastric tissue. Gastric mucus is primarily composed of water, glycolipids, proteoglycans, and glycoproteins. Among these components, mucin, a highly glycosylated glycoprotein secreted by goblet cells, serves as a crucial component of the mucus layer [132]. Mucus is hydrophilic, and its capacity to bind water serves as a diffusion barrier that protects gastric epithelial cells from gastric acid and proteases, thereby preventing self-digestion [133]. Gastric mucus plays an indispensable role in gastric healing by acting as a barrier between the stomach and the external environment during the regeneration of epithelial cells [134]. The level of gastric mucus and mucin is closely related to the generation and healing of GU. Ginsenoside Rb1 [26], oleanolic acid [49], and betulinic acid [86] all increase gastric mucus or mucin levels, suggesting that these triterpenoids may exert gastroprotective and ulcer healing effects by enhancing the gastric mucosal barrier.

3.5. Inhibition of Apoptosis

Apoptosis constitutes a core pathomechanism in GU development. In mammalian cells, apoptosis is subdivided into two canonical pathways: the intrinsic or mitochondrial pathway and the extrinsic or death receptor pathway [135]. Stimuli such as ROS can trigger the intrinsic pathway of apoptosis, which activates the pro-apoptotic protein Bax of the Bcl-2 family. Bax inhibits the expression of the anti-apoptotic protein Bcl-2 on the mitochondrial membrane, resulting in the opening of the mitochondrial membrane channels. Subsequently, the pro-apoptotic factor cytochrome c is released, which then activates caspase-9 to interact with caspase-3, ultimately leading to apoptotic cell death [4,136,137]. The induction of apoptosis through Fas, on the other hand, belongs to the extrinsic or death receptor pathway. Fas is a death receptor that is situated on the cell surface. When it is combined with the Fas ligand (FasL), a transmembrane protein belonging to the TNF family, Fas activates caspase-8 to interact with caspase-3, thereby inducing cell apoptosis [137,138]. Some members of the caspase family, such as caspase-1, contribute to the process of inflammation. Apoptosis or inflammatory factors can activate caspase-1, and activated caspase-1 can exacerbate inflammation through a positive feedback mechanism [137]. Triterpenoids, including ginsenoside Rh4 [31], araloside A [53], and friedelin [88], have been demonstrated to regulate the levels of the aforementioned factors, thereby protecting gastric tissue from apoptosis and inflammatory destruction.

3.6. Inhibition of Helicobacter Pylori

H. pylori is a Gram-negative bacterium that can be transmitted via fecal–oral and oral–oral routes. In numerous developing countries, the infection rate exceeds 50%, making it a major epidemiological driver of the prevalence and progression of GU [139]. H. pylori can produce a substantial quantity of urease, which catalyzes the hydrolysis of urea to ammonia and carbonic acid. As a result, gastric acid is neutralized, creating a nearly neutral microenvironment that supports the survival of Helicobacter pylori in the stomach. Simultaneously, this process alters the gastric mucus layer from a gel to a viscous solution, thereby enabling H. pylori to utilize its flagella to traverse the gastric mucus layer and attach to gastric epithelial cells [140]. H. pylori can induce morphological changes in host cells by expressing virulence genes, resulting in an inflammatory response and the promotion of apoptosis [141,142]. 18β-Glycyrrhetinic acid [59] demonstrates inhibitory effects on H. pylori, elevates gastric juice pH, and attenuates the inflammatory response induced by H. pylori. These findings suggest that triterpenoids may protect gastric tissues via the inhibition of H. pylori.

3.7. Promotion of GU Healing

The promotion of ulcer healing represents a crucial aspect of the mechanism through which triterpenoids exert their anti-ulcer effects. These effects are linked to a multitude of growth factors, including epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR). EGF is a polypeptide that inhibits gastric acid secretion and promotes the proliferation and differentiation of mucosal epithelial cells [143]. In addition to its direct interaction with EGFR, EGF can also activate COX-2 to produce PGE2, which indirectly activates EGFR through matrix metalloproteinases, thereby accelerating the healing of GU [144]. Triterpenoids, including ginsenoside Rg3 [28], protopanaxatriol [34], and ocotillol [37], are capable of elevating the levels of EGF and EGFR in diverse GU models, exhibiting a significant effect on the promotion of ulcer healing. The pharmacological mechanisms of triterpenoids in the prevention and treatment of GU are shown in Figure 12.

4. The Animal Models Employed in Research on Triterpenoids in GU

Triterpenoids isolated from natural medicines can protect gastric mucosa from both endogenous and exogenous invasive factors. This is achieved through a range of complex and diverse mechanisms of action. The discovery of these triterpenoids with pronounced pharmacological effects could not be achieved without the support of animal models. The utilization of experimental animal models has facilitated a more profound comprehension of the etiology, pathology, and overall characteristics of GU in humans. Previous studies have used a variety of GU models, including ethanol, NSAIDs, pylorus ligation, and acetic acid-induced GU models. These models are inextricably linked to the triggers that produce GU in humans (Figure 13). Understanding the pathophysiological mechanisms by which they induce ulcers can help to better address the challenges posed by GU.

Alcohol is one of the most widely used addictive substances. The excessive intake of alcohol may result in the development of GU. Consequently, ethanol has been extensively employed as an ulcerogenic agent in ulcer models [145]. Ethanol exposure induces structural and functional perturbations in the gastric mucosal barrier, characterized by the depletion of endogenous antioxidant systems (SOD and GSH) coupled with the enhanced generation of ROS. This impairs the antioxidant capacity of the organism and ultimately gives rise to oxidative stress and apoptosis [145,146]. The levels of pro-inflammatory factors such as NF-κB, TNF-α, and IL-6, which trigger inflammation and slow ulcer healing, also increase with ethanol consumption [145,147]. Ethanol inhibits the activity of acetaldehyde dehydrogenase, leading to the accumulation of acetaldehyde in the stomach. This accumulation of acetaldehyde induces the death of gastric mucosal cells and destroys mitochondria, resulting in the release of ROS and subsequent oxidative stress [148,149]. Furthermore, ethanol can also impede the secretion of PG in the stomach, which in turn damages the microcirculation of the gastric mucosa and inhibits gastric mucosal regeneration [146]. Ginsenoside Rd [27], astragaloside IV [40], and α-boswellic acid [67] have been demonstrated to inhibit the development of ethanol-induced GU in rats. The effects of these triterpenoids can be attributed to the attenuation of ethanol-induced oxidative stress and inflammation.

NSAIDs have become among the most widely used over-the-counter drugs globally due to their efficacious antipyretic, analgesic, and anti-inflammatory properties [150,151]. Nevertheless, the prolonged use of NSAIDs frequently results in gastric mucosal erosion, gastrointestinal bleeding, gastric perforation, and GU. Approximately 13% of patients with GU are associated with the use of NSAIDs, with indomethacin often employed in animal models of GU due to its propensity to induce gastric injury [151,152]. NSAIDs primarily exert anti-inflammatory effects by inhibiting the two subtypes of COX, COX-1 and COX-2. Unfortunately, this is also one of the mechanisms by which NSAIDs induce GU. This inhibition of COX reduces the body’s PG level, decreases mucosal blood flow, decreases gastric mucus and bicarbonate secretion, and ultimately leads to gastric mucosal damage [152,153,154]. NSAIDs combine with the phospholipids of gastric mucosal epithelial cells, destroying their hydrophobic properties and increasing the permeability of the gastric mucosa. This results in the diffusion of gastric acid into the gastric mucosal barrier, which in turn leads to cellular necrosis and the induction of GU [151,153]. The triterpenoids 3α-hydroxymasticadienoic acid [45], astragaloside IV [42], and betulinic acid [86] exhibit the ability to safeguard gastric mucosa from NSAID-induced damage. This is achieved through the upregulation of inhibited COX activity, the increase in prostaglandin secretion, and the enhancement of the gastric mucosal barrier function. Consequently, these triterpenoids can be employed in conjunction with NSAIDs to mitigate the gastrointestinal adverse effects associated with NSAID treatment and enhance therapeutic efficacy.

In addition to the utilization of pharmacological agents to induce GU, the pyloric ligation model represents a principal methodology in experimental gastroenterology research. This method results in the excessive accumulation of gastric acid and the destruction of the gastric mucosa, which ultimately leads to the formation of GU [155]. Following pyloric obstruction caused by pyloric ligation, the vago-vagal reflex is activated by mechanoreceptors within the pyloric region, which stimulates the secretion of gastric acid through the neuronal, endocrine, and paracrine pathways, leading to gastric acid accumulation [156,157]. The excessive production of gastric acid not only alters the permeability of the gastric mucosa but also stimulates the secretion of pepsin, which facilitates the self-digestion of the gastric mucosa. This process ultimately leads to the destruction of the gastric mucosa and the acceleration of the ulceration process [158,159]. Additionally, pyloric ligation-induced GU has been demonstrated to be linked to oxidative stress, a process that stimulates ROS production and ultimately results in decreased SOD and GSH levels and increased MDA levels [157,159]. Ginsenoside Rg3 [28], araloside A [52], and azadiradione [90] can exhibit inhibitory effects on pyloric ligation-induced GU by reducing gastric acid production and inhibiting oxidative stress.

Stress is a major cause of GU [160]. The use of stress models for research can better clarify the treatment direction of stress ulcers. Stress stimulates the sympathetic and parasympathetic nerves, increases gastric motility and the contraction of the gastric muscles, and constricts small arterial vessels. This results in the compression of gastric blood vessels and a reduction in gastric blood flow, which in turn causes mucosal hypoxia and ischemia. In this state, a substantial quantity of ROS is produced, which continues to activate the NF-κB-mediated inflammatory pathway. As a result, oxidative stress and inflammation are triggered, ultimately leading to the development of GU [161,162]. In addition, stress also results in the overproduction of NO within the body, leading to a reduction in the activity of antioxidant enzymes, thus weakening the defense of the gastric mucosa [163]. Triterpenoids, including astragaloside IV [41], araloside A [52], and azadiradione [90], demonstrated anti-ulcer effects in this model. The therapeutic efficacy may derive from multimodal actions involving inflammatory response modulation, oxidative stress attenuation, and the enhancement of the gastric mucosal defense.

In contrast to the acute ulcer model described above, the GU model induced by acetic acid is a chronic ulcer model. The acetic acid-induced GU model exhibits high clinical relevance by accurately mirroring both the histological architecture and healing process characteristic of human chronic ulcers. In consequence, this model is often used to assess the anti-ulcer properties of drugs [164]. Acetic acid reduces the levels of prostaglandins, growth factors, and NO in the stomach. Additionally, emerging evidence implicates it in the induction of pro-inflammatory cytokine upregulation alongside altering the microcirculation and adhesion patterns of gastric mucus, culminating in the structural and functional compromise of gastric mucosa. This damage penetrates deeply into the muscularis propria, leading to the formation of chronic GU within 2–3 days [164,165,166]. Ocotillol [37], oleanolic acid [49], and asiaticoside [76] exhibit anti-ulcer and healing-promoting properties in this model by enhancing gastric mucosal defenses, exerting anti-inflammatory effects and antioxidant effects.

5. The Current Limitations and Challenges of Triterpenoids in GU

Although triterpenoids demonstrate promising therapeutic potential for GU, several critical challenges limit their advancement as bioactive components. 18β-Glycyrrhetinic acid exhibits strong antibacterial effects against H. pylori, suggesting its value in protecting gastrointestinal health. However, a report reveals that prolonged high-dose oral administration may induce pseudoaldosteronism, manifesting as hypertension, hypokalemia, and metabolic alkalosis [167]. Ginseng, a widely used medicinal plant, contains triterpenoids as its primary active components with multiple gastroprotective properties. Notably, ginsenoside Rb1 demonstrates embryotoxicity and teratogenic effects in rodent whole-embryo culture experiments [168]. High oral doses (600 mg/kg) of rare ginsenosides like Rh4 altered gut microbiota composition and disrupted the metabolism pathways of vitamin B6, glutathione, arginine, and proline in rats, ultimately causing liver injury [169]. These compounds also face bioavailability challenges. Their lipophilic nature and large molecular size restrict absorption, and astragaloside IV shows bioavailability of only 7.4% and 3.66% in dogs and rats, respectively [38]. Most dammarane-type triterpenoids exhibit similarly low absorption rates. The mean half-lives of ginsenoside Rb1 and ginsenoside Rd in plasma were 17.96 h and 19.29 h, respectively, indicating that these triterpenoids could be rapidly metabolized [170]. Furthermore, clinical evidence remains insufficient. Current research predominantly relies on animal models and lacks large-scale human trials to comprehensively validate the safety and efficacy of triterpenoids for GU treatment. These combined limitations (safety concerns, pharmacokinetic challenges, and inadequate clinical verification) constrain their therapeutic application potential.

Nevertheless, emerging evidence highlights promising avenues for improvement. Certain triterpenoids exhibit effective anti-ulcer doses significantly below toxic thresholds. Ursolic acid shows a mouse acute LD50 of 9.26 g/kg [171], far surpassing its effective dose for GU treatment (100 mg/kg). Notably, this compound has been safely consumed as a dietary supplement without reported adverse events [172]. Friedelin exerts significant anti-ulcer effects at 35 mg/kg, with the oral administration of 80 mg/kg in rats showing no behavioral alterations or mortality within 24 h [88]. Bioavailability enhancement strategies show particular promise. Structural modifications of free triterpenoids can improve water solubility and biological activity [50,173], facilitating drug delivery. Advanced formulations like nano-formulations and gastroretentive delivery systems enhance gastric targeting and prolong therapeutic action [174]. Combination therapy with absorption enhancers (e.g., piperine) significantly increases triterpenoid permeability and bioavailability [175]. These findings emphasize the urgent need to prioritize translational research. Subsequent investigations should focus on comprehensive long-term toxicological evaluations to establish safety profiles for GU treatment applications. Such approaches will generate scientifically robust evidence to guide clinical development, ultimately bridging the gap between laboratory discoveries and practical therapeutic implementations.

6. Conclusions

In summary, triterpenoids isolated from natural medicines can treat and prevent GU induced by a variety of factors, including alcohol, NSAIDs, H. pylori, and stress. This is achieved through a range of mechanisms, including anti-inflammatory, antioxidant, cytoprotective, anti-secretory, anti-apoptotic, antibacterial, and ulcer-healing promotion. The rise in drug abuse and H. pylori resistance highlights the necessity of the development of more efficacious treatment options and superior pharmaceutical agents to address these challenges. With their recognized safety, reliability, and favorable biological activities, triterpenoids isolated from natural medicines have the potential to be utilized as dietary supplements or adjuvants to the prevention and treatment of GU as well as to lessen side effects that other medications may cause. It is anticipated that these compounds will emerge as one of the candidates for anti-ulcer drugs in the future.