The Efficiency of Plant Extracts in the Prevention of Gastric Cancer: A Systematic Review

ABSTRACT

Background and Aims

Gastric cancer is a global health concern with high morbidity and mortality. This systematic review evaluates the potential of plant extracts in the prevention of gastric cancer by analyzing their bioactive mechanisms.

Methods

A total of 62 studies—including in vitro, in vivo, and clinical trials—were analyzed, focusing on their antiproliferative, proapoptotic, antiangiogenic, and anti‐inflammatory properties.

Results

Extracts such as Marsdenia tenacissima, Curcuma longa, and Rhus verniciflua showed significant promise.

Conclusion

Despite these findings, issues surrounding bioavailability, dosing standardization, and long‐term safety require further investigation before clinical translation.

Summary

• Across 62 included studies, plant extracts—particularly Curcuma longa, Marsdenia tenacissima, and Rhus verniciflua—exhibited consistent antiproliferative, proapoptotic, antiangiogenic, and antimetastatic effects against gastric cancer, with in vivo and clinical data supporting their therapeutic potential.

• Despite promising efficacy, key compounds like curcumin and resveratrol suffer from poor bioavailability, necessitating advanced delivery methods (e.g., nanoformulations). Safety concerns such as gastrointestinal side effects and hepatotoxicity were noted, especially with high doses or prolonged use.

• Garlic and curcumin had the strongest clinical evidence for reducing gastric cancer incidence and enhancing chemotherapy outcomes, with recommended daily doses of 200–1000 mg. However, variability in study design and methodological limitations (e.g., blinding, dosage inconsistency) moderate the overall strength of evidence.

Abbreviations

GRADE

Grading of Recommendations Assessment, Development, and Evaluation

MTE

Marsdenia tenacissima extract

NF‐κB

nuclear factor kappa B

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta‐Analyses

RoB

risk of bias

SYRCLE

Systematic Review Centre for Laboratory Animal Experimentation

1. Introduction

Gastric cancer remains a significant cause of cancer‐related deaths globally [1, 2]. Despite advances in medical treatments, including surgery, chemotherapy, and radiation therapy, or a combination of these methods, patient outcomes remain suboptimal due to tumor recurrence, drug resistance, and severe side effects [3, 4, 5, 6, 7, 8].

Efforts have been made in cancer treatment, but treatment responses remain suboptimal, with side effects occurring in the majority of cases [5, 6]. Recent interest has focused on natural compounds derived from medicinal plants, which exhibit multiple pharmacological activities, including antioxidant, anti‐inflammatory, and anticancer properties. Several plant extracts have demonstrated chemopreventive properties [9]. Plant extracts contain bioactive compounds such as polyphenols, flavonoids, terpenoids, and alkaloids, which influence various cellular pathways involved in cancer progression [10, 11]. Epidemiological studies suggest that populations consuming plant‐based diets have a lower incidence of gastric cancer, further supporting the role of plant‐derived compounds in chemoprevention [9, 10].

The interest in using plant extracts as chemopreventive agents against gastric cancer stems from their ability to modulate multiple cellular pathways involved in carcinogenesis. These compounds have been reported to inhibit tumor initiation, suppress tumor growth, induce apoptosis, and reduce the progression of precancerous lesions in preclinical studies [12]. Moreover, epidemiological evidence suggests that populations that consume high amounts of plant‐based diets have lower incidences of gastric cancer [13, 14].

Recent studies have provided evidence supporting medicinal plants' role in reducing gastric cancer risk [15, 16]. However, despite the increasing number of studies evaluating plant extracts against gastric cancer, variability in study design, dosage, and patient characteristics has prevented a consensus on their clinical efficacy.

This systematic review aims to assess the anticancer mechanisms of plant extracts against gastric cancer, evaluate pharmacokinetic properties and strategies to improve bioavailability, and limitations in current research. This review summarizes available evidence and highlights areas requiring further research.

2. Methods

2.1. Search Strategy

A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, and Embase up to January 2024. Boolean operators used were: (“plant extract” OR “phytochemical” OR “herbal medicine”) AND (“gastric cancer” OR “stomach cancer”) AND (“prevention” OR “chemoprevention”). The complete search syntax for each database is included in Table S1.

This systematic review was conducted following PRISMA guidelines [17]. A comprehensive search was performed across databases, including PubMed, Scopus, and Web of Science, to identify studies examining herbal therapies with anticancer effects. The search strategy incorporated terms such as “anticancer plants,” “herbal therapy gastric cancer,” “natural compounds in oncology,” and “botanical treatment cancer.” Boolean operators (e.g., “AND,” “OR”) were applied to refine results. The search was restricted to English‐language articles published within the last 10 years to capture recent advances. A detailed search strategy, including complete Boolean strings and operators, is provided in Table S1 to ensure reproducibility.

2.2. Inclusion and Exclusion Criteria

We included original in vitro, in vivo, and clinical studies evaluating plant extracts in gastric cancer prevention. Reviews, editorials, and studies lacking outcome data were excluded.

The selected documents met the following criteria: (a) published original studies or case reports, (b) studies evaluating medicinal plants for gastric cancer therapy or prevention, and (c) research reporting bioactive effects, dosages, or mechanisms of action.

Articles were excluded if they were: (a) review articles, editorials, or studies without original data, (b) did not report bioactive effects or dosages, (c) studies focusing on cancers other than gastric cancer.

2.3. Data Extraction

Data extraction included detailed information on each study's compounds, formulations, dosages, pharmacokinetics, including bioavailability, metabolism, and half‐life, and adverse events across studies. For each medicinal plant extract, specific active compounds (e.g., curcumin in turmeric, epigallocatechin gallate in green tea) were identified and categorized. Additionally, dosages and formulations (e.g., purified extract, essential oil, or powder form) were recorded whenever reported by the studies.

2.4. Study Selection and PRISMA Flowchart

The study selection process is outlined in the updated PRISMA 2020 flow diagram (Figure 1), with a clear rationale for exclusions at each stage.

Figure 1.

Flow diagram of study selection.

2.5. Synthesis of Results

In synthesizing results, we documented the exact dosages used in each included study, standardized in mg/kg or μg/mL as applicable, to ensure clarity for future research and potential clinical application.

2.6. Risk of Bias (RoB) Assessment

RoB in the included studies was evaluated using the Cochrane Risk of Bias 2.0 (RoB 2.0) tool for clinical trials and the SYRCLE RoB tool for preclinical animal studies. The Cochrane RoB 2.0 tool assesses domains including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting. The SYRCLE tool, tailored for animal studies, evaluates similar domains adapted to preclinical settings. Results were summarized in a color‐coded format (Table S2) and categorized into overall judgments of low risk, some concerns, or high risk.

3. Results

3.1. Analysis of the Included Literature

A total of 62 studies met the inclusion criteria (Figure 1). The included studies span various plant‐derived compounds and formulations tested in vitro, in vivo, and clinical settings, demonstrating diverse bioactive effects and mechanisms against gastric cancer.

3.2. Active Compounds, Formulations, and Dosages

The studies examined a range of bioactive compounds, including curcumin, resveratrol, green tea extract, and quercetin, with diverse dosages and formulations. For example, curcumin doses ranged from 200 mg/kg to 400 mg/kg in animal models, while green tea extract was tested at 300 mg/mL in vitro. Variations in efficacy were observed depending on dosage and formulation, highlighting the importance of optimizing these parameters for translational applications. Figure 2 illustrates the distribution of bioactive effects observed. Categorized results by study type, extract, and dosage are included in Table S3 [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73].

Figure 2.

Number of studies of bioactive effects observed in medicinal plants reported in the included studies.

3.3. Pharmacokinetics of Key Plant Extracts

Table 1 provides detailed pharmacokinetic and bioavailability data. Curcumin and resveratrol, two extensively studied plant extracts, have demonstrated limited bioavailability due to rapid metabolism and poor water solubility. Strategies such as nanoencapsulation and liposomal formulations have been developed to improve their pharmacokinetic profiles. Studies suggest that nano‐formulations enhance the systemic circulation time of these compounds, increasing their therapeutic potential.

Table 1.

Pharmacokinetics and bioavailability of curcumin and resveratrol.

Compound	Absorption	Half‐life	Bioavailability	Metabolism
Curcumin	Poor	~1–2 h	< 1%	Glucuronidation, sulfation (hepatic)
Resveratrol	Moderate	~9 h	~25%	Phase II metabolism (liver)

3.4. Synthesis of Findings

Subgroup analyses revealed patterns in the bioactive effects across studies. Antiproliferative and proapoptotic effects were the most frequently reported mechanisms, followed by antimetastatic and antiangiogenic properties (Table 2). Descriptive summaries of the effects grouped by mechanism and plant source provide insights into potential therapeutic strategies.

Table 2.

Bioactive effects observed in medicinal plants across various studies.

Bioactive effects	Medicinal plants	References
Antiproliferative effects	Camellia sinensis, Saussurea lappa, Euphorbia lunulata, Dioscorea bulbifera (ethanol extract), Coptis chinesis, Piper longum, Sophora spp.	[18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62]
Proapoptotic effects	Camellia sinensis, Cardiospermum halicacabum (water extract), Plumbago zeylanica, Chrysosplenium nudicaule (ethanol extract), Saussurea lappa, Nigella sativa, Euphorbia lunulata, Euphorbia esula (water extract), Coptis chinesis, Stephania tetrandra, Piper longum, Sophora spp.
Antimetastatic effects	Camellia sinensis, Plumbago zeylanica, Saussurea lappa, Nigella sativa, Coptis chinesis, Piper longum
Antiangiogenic effects	Camellia sinensis
Autophagic cell death induction	Plumbago zeylanica, Coptis chinesis, Stephania tetrandra, Sophora spp.
Sensitizing cancer cells to chemotherapeutics	Nigella sativa, Stephania tetrandra

3.5. Mechanism of Action of Marsdenia tenacissima Extract (MTE)

MTE has been identified as a potent anticancer agent with multiple mechanisms of action. Research indicates that MTE inhibits tumor growth by inducing apoptosis, blocking angiogenesis, and suppressing key oncogenic signaling pathways. Additionally, MTE has been shown to enhance the efficacy of chemotherapy by sensitizing cancer cells to chemotherapeutic agents.

3.6. Bias Assessment and Evidence Quality and GRADE Evidence Summary

A detailed evaluation of study quality using RoB domains revealed variability across studies. Common concerns included inadequate randomization, lack of blinding, and incomplete reporting. A GRADE evidence table was generated to assess the strength of evidence for key outcomes. Most outcomes were rated as moderate due to risks of bias and heterogeneity in study designs. Table S2 summarizes the bias domains evaluated and a GRADE Evidence summary.

3.7. RoB Results

RoB across the included studies varied considerably. Among clinical trials, the most frequent sources of bias were inadequate blinding and randomization procedures. In preclinical studies, many lacked clarity in allocation concealment and outcome assessment. Overall, 38% of studies were judged as low risk, 42% showed some concerns, and 20% were assessed as high RoB. A detailed summary is provided in Table S2, along with color‐coded risk judgments for transparency.

3.8. Addressing Variability in Study Design

Variability in study design (in vitro, in vivo, or clinical study) was a major challenge in synthesizing findings across studies. Differences in patient characteristics, extract formulations, and treatment protocols contributed to heterogeneity. Efforts were made to standardize adverse event reporting across studies with varying methodologies to ensure consistency.

3.9. Adverse Events and Long‐Term Toxicity, and Safety Concerns

Adverse events were inconsistently reported across studies. Where available, the most common events were mild gastrointestinal disturbances. Table 3 summarizes adverse events observed. Studies reported gastrointestinal disturbances as the most common adverse event and potential hepatotoxicity in high‐dose MTE treatments.

Table 3.

Adverse events summary.

Adverse events	Frequency	References
Gastrointestinal disturbances	Common	[18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62]
Mild allergic reactions	Rare	[18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62]

3.10. In Vivo Studies

Table 4 presents studies conducted in xenograft mice to assess the efficacy of medicinal plants against gastric cancer in vivo. Xenograft studies showed a significant reduction in tumor growth across nine medicinal plants. A total of nine plants were examined in vitro, with the primary mode of action observed being the inhibition of tumor growth and reduction in tumor volume for these medicinal plants.

Table 4.

In vivo studies on medicinal plants against gastric cancer in mice models.

Medicinal plants	Mode of action	References
Scutellaria spp.	Reduced tumor volume	[63]
Chaetomium spp.	Inhibited proliferation, induced cell cycle arrest (G2/M), and apoptosis	[64]
Cucurbita spp.	Reduced tumor volume	[65]
Cruciferous plants	Inhibited tumor growth	[66]
Dioscorea spp.	Inhibited tumor growth	[67]
Zanthoxylum nitidum	Reduced tumor volume, Induced apoptosis, cell arrest (S phase), inhibited tumor growth	[68]
Perilla frutescens	Inhibited tumor growth	[69]
Garlic	Inhibited tumor growth	[60]
Zingiber officinale	Inhibited tumor growth	[62]

3.11. Clinical Studies

Table 5 presents clinical studies on the activity of medicinal plant extracts against gastric cancer in humans. Five medicinal plants were studied in clinical settings, showing promising results in tumor regression, chemotherapy response enhancement, and reduced cancer incidence.

Table 5.

Clinical studies on medicinal plant extracts against gastric cancer in humans.

Medicinal plants	Study group	Dosage	Observation	References
Garlic extract and oil	3365 residents with high risk of gastric cancer	200 mg aged garlic extract and 1 mg steam distilled garlic oil for 7 years	Decrease in the incidence of developing gastric cancer and mortality	[35]
Rhus verniciflua extract rich in flavonoids	An 82‐year‐old woman	900 mg of extract for 5 months	Reduction in tumor polyploidy mass and diminished lesions in the prepyloric antrum	[70]
Marsdenia tenacissima extract	1329 patients (51–68 years old)	Injection: 40–80 mL/dose, 7–21 doses/session orally: 6–7.2 g/dose, 30 doses/session	Enhancement of chemotherapy response and decrease occurrences of thrombocytopenia, anemia, nausea, peripheral neurotoxicity, and hepatic injury	[71]
Curcuma longa	25 patients	500 mg/day, 3 months	Histologic improvement of lesions	[72]
Aloe arborescens	240 patients (58–79 years old)	10 mL/three times daily orally (300 g of leaves in 500 g of honey in 40 mL of 40% alcohol) 6 days before and during chemotherapy	Increased tumor regression	[73]

3.12. Comparative Summary

Table 6 presents a comparative table that outlines various herbs and their active compounds, therapeutic uses, mechanisms of action, and potential adverse effects, designed to capture key aspects of herbal therapies in disease management [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73].

Table 6.

Outlines various herbs and their active compounds, therapeutic uses, mechanisms of action, and potential adverse effects.

Herb/compound	Therapeutic use	Mechanism of action	Potential adverse effects
Curcumin (Turmeric)	Anti‐inflammatory, anticancer	Inhibits NF‐κB pathway, antioxidant effects	Gastrointestinal discomfort, low bioavailability
Resveratrol (Grapes)	Cardiovascular protection, anticancer	Activates SIRT1, antioxidant, anti‐inflammatory	Low bioavailability, possible headache
Garlic (Allicin)	Antimicrobial, anticancer	Induces apoptosis, inhibits cell proliferation	Gastrointestinal irritation, bleeding risk
Green Tea (EGCG)	Antioxidant, anticancer	Scavenges free radicals, inhibits tumor growth	Mild GI upset, insomnia in sensitive individuals
Ginger (6‐Shogaol)	Antiemetic, anti‐inflammatory	Inhibits COX and LOX pathways, antioxidant	Heartburn, increased bleeding risk
Aloe Vera	Skin healing, anti‐inflammatory	Stimulates wound healing, modulates immune response	Skin irritation, potential GI upset
Ginseng	Cognitive enhancement, immune support	Modulates immune cells, antioxidant	Headache, sleep disturbances
Milk Thistle (Silymarin)	Liver protection, antioxidant	Stabilizes cell membranes, antioxidant	GI upset, mild laxative effect
Chamomile	Anxiety relief, sleep aid	Binds to GABA receptors, anti‐inflammatory	Allergic reactions, especially in those with ragweed allergy
Cranberry	Urinary tract infections	Prevents bacterial adhesion to bladder wall	GI upset, potential kidney stone formation
Licorice (Glycyrrhizin)	Respiratory and GI support	Anti‐inflammatory, inhibits viral replication	Hypertension, hypokalemia with long‐term use
Ashwagandha	Stress relief, immune support	Modulates cortisol, enhances immune activity	GI upset, drowsiness in high doses
Echinacea	Immune booster, anti‐inflammatory	Increases white blood cell activity	Allergic reactions, especially in those with daisy allergies
Peppermint (Menthol)	Digestive aid, antispasmodic	Relaxes GI muscles, anti‐inflammatory	Acid reflux, skin irritation

3.13. Clinical Implications

The findings underscore the potential for incorporating herbal therapies into clinical practice. Herbal therapies demonstrate promise in gastric cancer prevention and treatment, with specific evidence supporting the use of curcumin at doses of 500–1000 mg/day. Table 7 provides evidence‐based dosing recommendations.

Table 7.

Dosing recommendations for clinical use.

Medicinal plant	Recommended dose	Evidence level
Green tea extract	300 mg/day	Moderate (animal/in vitro studies)
Curcumin (Turmeric)	500–1000 mg/day	High (clinical trials)
Garlic (Allicin)	200 mg/day	High (longitudinal cohort studies)

3.14. Summary Interpretation

In vitro studies predominantly focused on mechanistic insights and used purified active compounds. Dosages ranged from 10 to 300 µM. In vivo studies demonstrated tumor growth inhibition and modulation of immune/inflammatory responses, with oral doses mostly between 100 and 400 mg/kg. Clinical studies showed reduced incidence or improved outcomes when plant extracts were given consistently at moderate dosages over weeks to months. Garlic and curcumin were the most evidence‐supported (Table S3).

4. Discussion

Gastric cancer is a major global health issue due to its high incidence and mortality rates [74]. Herbal medicine represents a significant domain in the search for novel cancer‐fighting drugs, with growing emphasis on exploring plant compounds as potential remedies against cancer [75]. Recently, interest has surged in exploring plant‐based compounds as potential treatments for cancer, with numerous preclinical studies on dietary agents, medicinal plants, and phytochemicals showing promise in cancer prevention [76, 77]. This review assesses the chemopreventive potential of plant extracts against gastric cancer, with a focus on key bioactive effects and mechanisms, such as antiproliferative activity, induction of autophagic cell death, and enhancement of chemotherapy sensitivity. Overall, the reviewed studies showed low to moderate RoB, supporting their reliability.

Our analysis included 62 studies detailing the in vitro bioactive effects of various medicinal plants. These findings underscore diverse anticancer activities, such as antiproliferative, proapoptotic, antimetastatic, and antiangiogenic effects, as well as the ability to sensitize cancer cells to chemotherapy. Among these, 15 plants displayed at least one bioactive effect, with 8 demonstrating multiple effects. This variety of actions highlights the multifaceted potential of medicinal plants in cancer prevention. Chemo preventive agents act by preventing, suppressing, or reversing cancer stages through mechanisms that impact hormonal activity, cell proliferation, DNA repair, and apoptosis [78]. For instance, polyphenols from these plants exhibit antioxidant and prooxidant effects, which are dose‐dependent and may influence DNA integrity [78].

4.1. Preclinical Models

In preclinical models, herbal therapies frequently show notable biological effects, such as anti‐inflammatory and anticancer properties. Compounds like curcumin, for example, demonstrate strong anti‐inflammatory effects by inhibiting NF‐kB pathways. Despite these encouraging results in animal studies, translating these findings into human applications is complex. Animal models and human systems often differ in metabolism, bioavailability, and safe dosage, leading to inconsistent outcomes in clinical trials. Curcumin, for example, has exhibited varying efficacy in clinical settings due to its low bioavailability. To bridge these gaps, researchers are developing advanced formulations to improve bioavailability and conducting pilot clinical studies with standardized dosages [79, 80, 81]. This study emphasizes the need for detailed pharmacokinetic studies, molecular pathway exploration, and biomarker validation in clinical trials to make herbal treatments more effective and reliable for human use.

This systematic review demonstrates the potential of plant‐derived compounds in gastric cancer prevention and therapy. Antiproliferative and proapoptotic effects were consistently observed, though significant heterogeneity in study designs and formulations was noted. Preclinical studies highlight promising bioactivity; however, bioavailability remains a key limitation.

Studies with xenograft mouse models further demonstrated that medicinal plants could inhibit gastric tumor growth [82]. Several extracts were observed in vitro to inhibit the proliferation of human gastric cancer cell lines [83].

Additionally, ramson extract arrested AGS human gastric cancer cells in the G2/M phase by downregulating cyclin B expression, while diallyl disulfide from garlic induced G2/M arrest in MGC803 cells by activating checkpoint kinases and suppressing cell cycle regulators. Furthermore, compounds such as diallyl trisulfide, latcripin 1, myricetin, S‐allylmercaptocysteine, 6‐shogaol, and (‐)‐epigallocatechin gallate demonstrated antiproliferative effects in gastric cancer cells and inhibited tumor growth in mouse models through various mechanisms, including cell cycle arrest, microtubule damage, and modulation of signaling pathways like Wnt/β‐catenin [84, 85, 86].

4.2. Clinical Implications and Future Research Directions

Table S4 provides human equivalent dose estimations and clinical recommendations.

The clinical relevance of preclinical findings is limited by bioavailability issues and the lack of rigorous pharmacokinetic and pharmacodynamic studies. Compounds like curcumin and resveratrol, despite their promising mechanisms of action, exhibit low bioavailability, raising questions about their practical application in human therapies. Recent advancements in formulation technologies, such as nanoencapsulation and conjugation, show potential to overcome these challenges but require validation through high‐quality clinical trials [79, 80, 81].

Preclinical and clinical evidence suggest curcumin has potential for inflammation reduction at doses of 500–1000 mg/day. However, enhanced formulations like liposomal or nano‐curcumin are critical for clinical translation.

The transition from preclinical to clinical research also highlights the need for standardized dosing and formulation protocols. How doses and bioactive compounds were standardized in the included studies remains unclear. For instance, preclinical models often employed doses that may not be achievable or safe in humans, complicating the translation of findings. Addressing this gap requires studies focused on establishing equivalency between preclinical and clinical dosages.

Moreover, the review identified a lack of clinical studies exploring the efficacy of natural products in gastric cancer. While some promising results were noted, such as reductions in gastric cancer incidence and enhanced chemotherapy responses, these findings are based on limited trials. High‐impact clinical studies, such as randomized controlled trials, are urgently needed to substantiate these preliminary observations.

Standardized RCTs are needed to evaluate bioavailability‐enhanced formulations. Larger trials should address heterogeneity in extract formulations and dosing protocols.

Future research should integrate pharmacokinetics, toxicity data, and clinical efficacy for better translation into medical practice.

4.3. Summary of Reported Adverse Events From Included Studies

Table S5 provides comparative summary of delivery systems for plant extracts. Most adverse events were mild and gastrointestinal in nature. M. tenacissima showed the greatest risk of systemic toxicity at high doses but was generally well‐tolerated at therapeutic levels. Garlic and green tea extracts were generally safe but could cause gastrointestinal discomfort. Rare but serious events (e.g., hepatotoxicity, bleeding) emphasize the need for clinical monitoring, especially in long‐term or high‐dose use.

4.3.1. Formulation Strategies to Improve Bioavailability

A major barrier to clinical translation of plant extracts is poor bioavailability, often due to low water solubility, chemical instability, and rapid metabolism. Multiple delivery systems have been developed to address these limitations:

• Nanoencapsulation: Uses nanocarriers to encapsulate bioactives, protecting them from degradation and enhancing gastrointestinal absorption.

• Liposomes: Spherical vesicles composed of lipid bilayers that improve solubility and promote controlled release.

• Solid Lipid Nanoparticles: Combine the advantages of polymeric nanoparticles and liposomes with enhanced stability and bioactive protection.

• Phytosomes: Complexes of bioactives with phospholipids that enhance absorption by increasing membrane permeability.

These systems have shown promise in increasing the half‐life, systemic availability, and therapeutic activity of compounds like curcumin, resveratrol, and EGCG. Comparative features and applications are summarized in Table S5, and an overview mechanism is presented in Figure 3.

Figure 3.

Mechanistic diagram of how these systems improve bioavailability.

4.4. Expanded Molecular Mechanism Discussion

Several plant‐derived compounds target critical oncogenic pathways involved in gastric cancer progression:

• Nuclear Factor Kappa B (NF‐κB) Pathway: This transcription factor is frequently activated in gastric cancer and promotes cell proliferation, invasion, and inflammation. Phytochemicals such as curcumin and resveratrol inhibit NF‐κB activation by suppressing IκB kinase and preventing nuclear translocation of p65.

• PI3K/Akt Pathway: Dysregulation of this pathway promotes survival and resistance to apoptosis. Curcumin, EGCG, and quercetin have demonstrated inhibitory effects on PI3K phosphorylation and downstream Akt signaling, restoring apoptotic sensitivity.

• STAT3 Pathway: STAT3 activation drives tumor cell growth, angiogenesis, and immune evasion. Plant extracts like resveratrol, baicalin, and thymoquinone inhibit STAT3 phosphorylation and nuclear translocation, thereby blocking gene transcription linked to tumor progression.

Figure 4 illustrates these signaling cascades and the specific points of phytochemical interference, enhancing clarity for therapeutic mapping.

Figure 4.

Molecular signaling pathways and their points of inhibition by various phytochemicals.

Mechanistically, compounds such as curcumin, resveratrol, and green tea catechins exhibit diverse anticancer activities, including inhibition of NF‐κB signaling, activation of antioxidant pathways, and modulation of pro‐inflammatory cytokines. These findings underscore the potential of phytochemicals to target multiple pathways, offering a complementary approach to conventional therapies. However, the clinical application of these findings remains constrained by issues such as variability in bioactive compound content and the lack of robust biomarkers for treatment efficacy. Chemopreventive agents act by preventing, suppressing, or reversing cancer stages through mechanisms that impact hormonal activity, cell proliferation, DNA repair, and apoptosis [78]. For instance, polyphenols from these plants exhibit antioxidant and prooxidant effects, which are dose‐dependent and may influence DNA integrity [78].

4.5. Bioavailability Enhancement Strategies

To overcome bioavailability challenges, recent advancements have focused on nanoencapsulation, cyclodextrin inclusion complexes, and phospholipid‐based formulations. Nanoencapsulation has improved the solubility and stability of plant‐based compounds, increasing their absorption and therapeutic efficacy. Cyclodextrin inclusion complexes enhance water solubility, while phospholipid‐based formulations improve gastrointestinal absorption.

4.6. Limitations and Opportunities

This review has several limitations. The exclusion of non‐English studies introduces potential language bias, which may have led to the omission of valuable data. Additionally, the focus on published studies raises concerns about selective reporting. Studies used varying doses and bioactive formulations, making cross‐comparison challenging. Standardized protocols are needed. Adverse events were inconsistently reported. Where available, the most common events were mild GI disturbances. Despite these limitations, the review highlights significant gaps in knowledge, including the need for:

• 1.Comprehensive pharmacokinetic and pharmacodynamic studies.
• 2.Standardized methodologies for assessing bioactive effects and mechanisms.
• 3.Exploration of long‐term safety and toxicity of herbal compounds.
• 4.Integration of preclinical and clinical data to guide translational research.

4.7. Research Gaps and Future Directions

To bridge safety data gaps, future studies should focus on:

• Standardizing plant extract formulations to reduce heterogeneity.

• Conducting long‐term toxicity assessments of key plant extracts and adverse events in clinical settings.

• Investigating dose–response relationships through standardized clinical trials.

• Conducting larger RCTs with bioavailability‐enhanced formulations.

• Exploring novel drug delivery systems, such as nanoencapsulation, to improve bioavailability.

• Expanding research on MTE's molecular mechanisms.

• Investigating mechanisms underlying the observed bioactive effects.

4.8. Practical Implications for Clinical Practice

Clinicians should consider evidence‐based dosing recommendations for plant‐derived compounds while accounting for formulation differences. For example, curcumin and green tea extracts show promise but require bioavailability enhancements for optimal efficacy.

5. Conclusions

Medicinal plants show strong potential in gastric cancer prevention, particularly M. tenacissima, Curcuma longa, and Rhus verniciflua. This review highlights the potential of medicinal plants in gastric cancer prevention and treatment, emphasizing the need for: standardized clinical trials for dosage optimization, advanced delivery systems to improve pharmacokinetics, and long‐term safety studies to ensure clinical viability. However, future research should integrate pharmacokinetics, toxicity data, optimize bioavailability, assess long‐term safety, standardize treatment protocols, and clinical efficacy for better translation into medical practice.

Author Contributions

Mahsa Rezvan: writing – original draft, validation. Seyed Erfan Hossini: formal analysis, investigation. Kimia Sarmast: visualization, methodology. Faham Khamesipour: writing – review and editing, conceptualization, supervision.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Transparency Statement

The lead author, Mahsa Rezvan, affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Supporting information

Supplementary Table 1: Full Search Strategy for Each Database. Supplementary Table 2. Risk of Bias Assessment Summary. Supplementary Table 3: Categorized Results by Study Type, Extract, and Dosage. Supplementary Table 4: Human Equivalent Dose (HED) Estimations and Clinical Recommendations. Supplementary Table 5: Comparative Summary of Delivery Systems for Plant Extracts.

Data Availability Statement

No data sets were generated or analyses during the current study. The authors confirm that the data supporting the findings of this study are available within the article.