Therapeutic effects and mechanisms of action of Baicalein on stomach cancer: a comprehensive systematic literature review

Abstract

Background

Stomach cancer, or gastric cancer (GC), is a major global health problem characterized by the malignant proliferation of cells in the gastrointestinal lining. Recent studies have highlighted the potential therapeutic effects of natural compounds, including baicalein (BC), a flavonoid derived from the roots of Scutellaria baicalensis. This systematic review aims to evaluate the effects and mechanisms of action of BC in stomach cancer.

Method

The study followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was performed in PubMed, Embase, Web of Science, and Scopus databases up to March 2025.

Results

The review demonstrated that BC exerts therapeutic effects on GC through multiple biochemical mechanisms. BC plays an important role in inducing apoptosis, inhibiting cell proliferation, and suppressing metastasis in GC cells. It also modulates several signaling pathways, including phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), mitogen-activated protein kinases (MAPKs), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), leading to the downregulation of oncogenes.

Conclusion

Given its effects on GC progression, BC may serve as a potential adjuvant therapy. However, to confirm its clinical benefits, well-designed human studies in GC patients are required.

Graphical abstract

Introduction

Gastric cancer (GC) is one of the leading causes of cancer-related mortality, accounting for over 700,000 deaths worldwide each year [1, 2]. Although primary GC often has a favorable prognosis, a substantial proportion of cases are diagnosed at an advanced or locally metastatic stage [3]. Chemotherapy remains a key therapeutic strategy for patients with advanced GC [4].

The response to traditional therapy is often inadequate in individuals with metastatic GC due to multidrug resistance and severe side effects [5]. The overall 5-year survival rate for patients with GC is approximately 20–25% [6]. The transformation of normal gastric epithelial cells into malignant cells is frequently triggered by chronic inflammation, most commonly caused by Helicobacter pylori infection, which can lead to atrophic gastritis [7]. In addition, genetic predispositions, including mutations in tumor suppressor genes (e.g., CDH1) and oncogenes (e.g., KRAS), play a significant role in cellular dysregulation and carcinogenesis [8, 9]. The activation of signaling pathways such as Wnt/β-catenin and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) further promotes uncontrolled cell growth and survival [8, 10]. The role of microRNAs in the post-transcriptional regulation of gene expression is increasingly recognized as a critical factor in the development of GC [11, 12]. Therefore, greater efforts are needed to develop novel therapeutic and preventive strategies, including drugs that specifically target cancer metastasis [13].

Baicalein (BC), a bioactive flavonoid derived from Scutellaria baicalensis, exhibits multiple biological activities, including anticancer, anti-inflammatory, anti-lipogenic, antibacterial, cardioprotective, neurogenic, hypoglycemic, and wound-healing properties [14, 15]. PHY906, a traditional Chinese medicine formulation containing Scutellaria baicalensis, has shown potential as an adjunct to chemotherapy, enhancing the efficacy of anticancer agents with promising results in clinical trials for pancreatic, colorectal, and hepatic malignancies [16]. Evidence indicates that BC exerts anticancer effects by inducing apoptosis in cancer cells through suppression of the PI3K/AKT pathway, particularly in breast and liver cancers [17, 18]. Moreover, BC may enhance the cisplatin sensitivity of GC cells by promoting apoptosis and autophagy via modulation of the AKT/mammalian target of rapamycin (mTOR) and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2–related factor 2 (Nrf2) pathways [19].

Despite these encouraging findings, detailed systematic reviews on the regulatory mechanisms of BC in GC remain limited. Therefore, the aim of this study is to comprehensively evaluate and summarize the molecular mechanisms by which BC influences GC progression, with a particular focus on its potential therapeutic and preventive applications.

Methods

Search methodology

This research followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [20]. The following electronic databases were searched without temporal restrictions up to March 2025: Embase, PubMed, Web of Science, and Scopus. Both Medical Subject Headings (MeSH) and non-MeSH terms were used in the search strategy. The keywords included: “baicalein [MeSH]” AND (“gastric carcinoma [MeSH]” OR “gastric cancer [MeSH]” OR “gastric neoplasm [MeSH]” OR “gastric malignancy [MeSH]” OR “gastric tumor [MeSH]” OR “stomach malignancy [MeSH]” OR “stomach cancer [MeSH]” OR “stomach carcinoma [MeSH]” OR “stomach neoplasm [MeSH]”). In addition, the reference lists of eligible publications were screened to ensure that no relevant studies were overlooked.

Study selection

The titles and abstracts of articles identified through the search strategy were independently screened by two authors to determine potentially eligible studies. Subsequently, the full texts of these articles were thoroughly reviewed to confirm their final inclusion based on predefined criteria.

Inclusion criteria: (a) studies reporting both in vivo and in vitro experiments to provide comprehensive mechanistic insights; (b) studies specifically investigating the effects of BC on GC, demonstrating direct relevance; (c) studies using BC as the sole intervention, without concurrent treatments or combination therapies, to ensure effect attribution; (d) articles published in peer-reviewed journals in English, ensuring scientific rigor and accessibility; and (e) studies reporting quantitative or qualitative outcomes related to the efficacy, safety, or molecular mechanisms of BC in GC.

Exclusion criteria: (a) studies examining interventions other than BC or combined interventions that could confound its effects; (b) studies lacking an appropriate control or comparison group necessary for evaluating treatment outcomes; (c) publication types such as reviews, conference abstracts, presentations, book chapters, or commentaries that do not provide original experimental data; (d) articles not published in English due to language limitations; and (e) studies with incomplete or unclear methodology or outcomes that prevent reliable assessment.

Data extraction

All relevant papers were independently evaluated by two authors. The extracted data included the first author’s name, research topic, study design, intervention duration, supplement dose, and primary outcomes. Any disagreements between the two reviewers during the selection process were resolved through discussion and, when necessary, consultation with a third author to reach consensus.

Risk of bias (RoB) assessment

Two authors independently assessed the potential RoB in both in vivo and in vitro studies. The overall RoB in in vivo trials was evaluated using the SYRCLE RoB tool, while the quality of in vitro studies was assessed using the OHAT RoB tool. These instruments evaluate potential biases related to selection, detection, performance, attrition, and reporting. Studies were classified as high risk if methodological flaws were present that could affect the results, low risk if no such issues were identified, or uncertain risk if the available evidence was insufficient to make a definitive judgment.

Results

A total of 205 articles were initially identified from several databases: 36 from PubMed, 52 from Web of Science, 29 from ScienceDirect, 48 from Embase, and 40 from Scopus. After removing duplicates, 56 papers were retained for title and abstract screening. Following a thorough evaluation, 13 publications were included in the current research. Figure 1 illustrates the main characteristics of the selected articles.

Fig. 1.

The present investigation assessment of the PRISMA flow diagram, employing a systematic review approach

In vitro studies

Table 1 summarizes the in vitro effects of BC on GC cell lines. The most frequently used models included AGS, MGC-803, HGC-27, and SGC-7901, with additional studies involving GES-1, MKN-74, and BGC-823. Li et al. [21] demonstrated that BC induced apoptosis and autophagy in MGC-803, SGC-7901, and HGC-27 cells, enhancing cisplatin sensitivity via suppression of the AKT/mTOR pathway and modulation of the Nrf2/Keap1 axis. Liu et al. [22] showed that BC activated pyroptosis in AGS cells through NF-κB-mediated upregulation of the NLRP3 inflammasome, leading to increased expression of Caspase-1, GSDMD-N, IL-1β, and LDH release in a dose-dependent manner. Qiao et al. [23] reported that BC suppressed proliferation, migration, and angiogenesis in HGC-27, SGC-7901, MGC-803, and BGC-823 cells by upregulating miR-7, which directly targets the 3′ untranslated region of focal adhesion kinase (FAK), thereby reducing FAK expression and inhibiting downstream PI3K/AKT/mTOR signaling.

Table 1.

Summary of in vitro studies on Baicalein (BC) in gastric cancer (GC)

Author, year	Cell line(s)	Dose	Assay(s)	Duration	Major findings
Shen et al. [24], 2023	HGC-27 and AGS	0, 15, 30, 60, and120 µM	MTT; colony formation; cell-cycle & apoptosis by flow cytometry (Annexin V/PI); Western blot; Fluo-3 AM Ca²⁺ assay	48 h	BC inhibited GC cell proliferation; induced G₀/G₁ arrest & apoptosis; triggered ER stress; activated BTG3 to repress PI3K/AKT, thereby promoting ER stress–mediated apoptosis
Qiao et al. [25], 2021	HGC-27 and SGC-7901	0, 10, 20, 30, 40, and 50 µM	MTT; wound healing; Western blot	72 h	BC inhibited proliferation and migration; reduced FAK expression and phosphorylation of PI3K/AKT/mTOR signaling components
Qiao et al. [23], 2022	HGC-27, SGC-7901, MGC-803, and BGC-823	0, 6.25, 12.5, 25, 50 µM	MTT; EdU incorporation; colony-formation; wound-healing; transwell migration/invasion; Matrigel tube-formation	MTT and EdU at 48 h; migration/invasion at 24 h; tube formation at 6–12 h	BC suppressed proliferation, migration/invasion, and angiogenesis in GC cells by upregulating miR-7, which binds FAK 3′UTR to inhibit FAK and downstream PI3K/AKT signaling
Chen et al. [26], 2008	AGS	BC: 40 µM; 12-HETE (control arm): 100 nM	MTT; flow cytometry (PI staining); Western blot	48 h for MTT and apoptosis measurements; Western blot and PKC assays at both 24 h and 48 h	BC decreased phospho-ERK1/2 levels and down-regulated Bcl-2; inhibited proliferation and induced apoptosis via ERK1/2–Bcl-2 blockade; also reduced PKC activity
Chen et al. [27], 2014	AGS	0, 25, and 50 µM	Wound-healing; Transwell migration/invasion; qPCR; Western blot	24 h	BC treatment inhibited AGS cell motility, migration and invasion by downregulating TGF-β and Smad4 mRNA/protein and reducing N-cadherin, vimentin, ZEB1 and ZEB2 levels
Ye et al. [28], 2024	GES-1 (normal); MKN-74, MGC-803 (GC)	5, 10, 25, and 50 µM	MTT; colony formation; wound healing; Transwell invasion; flow cytometry & Hoechst staining (apoptosis); immunofluorescence (EMT markers); Western blot	MTT up to 72 h; EMT/apoptosis & Western blot at 24 h; migration/invasion assays up to 48 h	BC decreased GC cell viability in a time- and dose-dependent manner, inhibited colony formation, induced apoptosis, suppressed migration/invasion, down-regulated p12-LOX, reversed EMT (↑E-cadherin/ZO-1; ↓Vimentin/Snail/MMP-2/GSK-3β), and blocked MEK/ERK signaling
Guo et al. [29], 2017	BGC-823	0, 5, 10, and 15 µg/mL	MTT; Transwell migration; Transwell invasion through Matrigel; Northern blot; Western blot	Proliferation at up to 48 h; migration/invasion at 24 h; EMT and NF-κB–Snail signaling analyzed after 24 h of BC treatment	BC dose-dependently suppressed BGC-823 proliferation; reduced invasion and migration; modulated MMP/TIMP mRNA (slight rise in MMP-2/9; marked increase in TIMP1/3); reversed TGF-β₁-induced EMT by upregulating E-cadherin and downregulating N-cadherin/vimentin; inhibited NF-κB activation (↑IκBα, cytosolic p65; ↓p-IκBα, nuclear p65) and reduced Snail expression, thereby blocking the NF-κB/Snail axis
Mu et al. [30], 2016	SGC-7901	0, 15, 30, 60, and 120 µM	MTT; colony formation; cell cycle (PI flow cytometry); apoptosis (Annexin V/PI flow cytometry and Hoechst 33342); mitochondrial membrane potential; Western blot	24, 48, 72 h; mechanistic assays: 48 h; colony formation	BC inhibited SGC-7901 proliferation in a time- and dose-dependent manner; induced S-phase arrest (↑S-phase fraction from 33.4% to 65.3%); triggered apoptosis via caspase-3 activation and PARP cleavage; downregulated Bcl-2 and upregulated Bax; disrupted mitochondrial membrane potential; suppressed colony formation
Liu et al. [22], 2024	AGS	6.25, 12.5, 25, 50, and 100 µM	CCK-8 viability; LDH release; ROS (flow cytometry); Western blot; qRT-PCR	24 h	BC activated NF-κB/NLRP3 inflammasome signaling, increasing pyroptosis markers (Caspase-1, GSDMD-N, IL-1β, LDH, ROS) dose-dependently
Li et al. [21], 2020	MGC-803, HGC-27, and SGC-7901	6.25, 12.5, 25, 50, and 100 µM	MTT and colony-formation assays; Transwell invasion assay; Annexin V/PI flow cytometry; confocal microscopy of LC3 puncta; qRT-PCR for autophagy-related genes; Western blot, Nrf2/Keap1, apoptosis and autophagy markers	Proliferation and invasion assays at 48 h; apoptosis measured at 24–48 h; autophagy markers assessed at 24 h; colony formation over 10–14 days	BC dose-dependently sensitized GC and SGC-7901/DDP cells to cisplatin: suppressed proliferation and invasion; increased apoptosis (↑cleaved-caspase-3, Bax/Bcl-2 ratio); induced autophagy (↑LC3-II, Beclin-1; ↓p62) via inhibition of Akt/mTOR and modulation of Nrf2/Keap1. Combined treatment was synergistic
Shao et al. [31], 2024	HGC-27 and oxaliplatin-resistant HGC-27/L	50, 100, 200, and 400 µM	Western blot, RT-qPCR, CCK-8, JC-1 (mitochondrial potential), MDA, GSH, Fe²⁺, ROS (flow cytometry), TEM imaging	24 h and 48 h depending on assay	BC induced ferroptosis by activating p53, downregulating SLC7A11/GPX4, increasing ROS, iron, and lipid peroxidation
Yan et al. [32], 2015	SGC-7901 and MGC-803	0, 10, 20 and 40 µM (MTT dose–response tested up to 400 µM; subsequent migration/invasion experiments used ≤ 40 µM)	MTT assay; Transwell migration and invasion; RT-qPCR; Western blot; gelatin zymography	24 h for MTT, RT-qPCR, Western blot and zymography; 16 h for migration; 24 h for invasion	BC inhibited GC cell migration and invasion in a dose-dependent manner; downregulated MMP-2/9 mRNA, protein levels and gelatinolytic activity; decreased phospho-p38; SB203580 synergized with BC to further block MMP-2/9 expression and invasion, whereas anisomycin reversed BC’s effects

PI3K/AKT phosphoinositide 3-kinase/protein kinase B, miR-7 MicroRNA-7, BTG3 B-cell translocation gene 3, FAK focal adhesion kinase, mTOR mammalian target of rapamycin, TGF transforming growth factor, RT-qPCR real-time quantitative polymerase chain reaction, ERK1/2 extracellular signal-regulated kinases 1 and 2, EMT epithelial-mesenchymal transition, MEK1/2 mitogen-activated protein kinase 1 and 2 (also called MAP2K1/2), NF-κB nuclear factor-kappa B, Bcl-2 B cell lymphoma 2, MMP-9 matrix metalloproteinase-9

In vivo studies

Table 2 summarizes in vivo investigations on the effects of BC in animal models of GC. Studies were conducted in mice, with BC administered orally or by injection at doses ranging from 10 to 100 mg/kg. Ribeiro et al. [33] reported that mice receiving 10, 30, or 100 mg/kg of BC showed gastroprotective effects against acidified ethanol-induced gastric lesions. At 30 mg/kg, this protection was reversed by α₂-adrenoceptor antagonists, nitric oxide synthase inhibitors, and cyclooxygenase inhibitors, indicating involvement of multiple protective pathways. BC at this dose increased glutathione (GSH) levels, reduced myeloperoxidase (MPO) activity, enhanced gastric mucus production, decreased gastric secretion volume, and elevated pH. Additionally, BC inhibited histamine-induced acid secretion and demonstrated direct anti-H⁺, K⁺-ATPase activity, supporting its role in ulcer prevention. Mu et al. [30] found that daily oral administration of BC at 15 or 50 mg/kg for one week significantly reduced tumor volume and weight in SGC-7901 xenograft-bearing nude mice. Although molecular markers were not assessed in vivo, in vitro data from the same study showed that BC downregulated anti-apoptotic proteins (e.g., Bcl-2) and upregulated pro-apoptotic Bax, promoting apoptosis and S-phase arrest. Qiao et al. [25] demonstrated that intraperitoneal injection of BC at 50 mg/kg for three weeks suppressed tumor growth in HGC-27 xenograft-bearing nude mice. This was accompanied by reduced expression of FAK and decreased phosphorylation of PI3K, AKT, and mTOR. Immunohistochemical analysis also revealed lower Ki-67 levels, indicating reduced cellular proliferation.

Table 2.

Summary of in vivo studies on Baicalein (BC) in gastric cancer (GC)

Author, year	Animal model	Dose	Assay(s)	Duration	Major findings
Ribeiro et al. [33], 2016	Mice (n = 18)	10, 30 and 100 mg/kg	Anti-ulcerogenic assay (lesion area measurement) in ethanol/HCl model; GSH and MPO assays; gastric secretion metrics in pylorus-ligated mice; gastric mucus quantification by Alcian blue binding; in vitro H⁺, K⁺-ATPase activity assay	Lesions evaluated 1 h after ethanol/HCl administration; pylorus-ligation conducted for 4 h post-ligature; in vitro ATPase assay run immediately after enzyme isolation	BC dose-dependently prevented ethanol/HCl-induced gastric lesions; its protection was reversed by α₂-adrenoceptor blockade, SH-compound depletion, NO synthase and cyclooxygenase inhibitors, or K_ATP channel blocker. BC elevated mucosal GSH, decreased MPO activity, increased gastric mucus output, reduced volume and acid secretion, raised pH, and directly inhibited H⁺, K⁺-ATPase in vitro
Shen et al. [24], 2023	BALB/c nude mice (n = 24) bearing subcutaneous AGS xenografts	15 and 50 mg/kg/day	Tumor volume & weight measurement; Ki67 immunohistochemistry; TUNEL staining; Western blot for Grp78, CHOP, BTG3, PI3K/p-PI3K, AKT/p-AKT	4 weeks	BC dose-dependently inhibited xenograft growth; decreased Ki67⁺ cells; increased TUNEL⁺ apoptotic cells; upregulated BTG3; repressed PI3K/AKT; enhanced ER stress–mediated apoptosis
Mu et al. [30], 2016	Male BALB/c nude mice (4 per group) bearing subcutaneous SGC-7901 xenografts	15 and 50 mg/kg	Tumor volume measured weekly; final tumor weight at sacrifice	4 weeks	BC significantly reduced xenograft tumor volume and weight with no overt toxicity
Qiao et al. [25], 2021	Nude mice (n = 3 per group) with GC xenografts	50 mg/kg	Tumor volume and weight measurements; Western blot and IHC for FAK and Ki-67	3 weeks	BC significantly reduced tumor size and weight; downregulated FAK and Ki-67 expression, indicating reduced proliferation and migration
Qiao et al. [23], 2022	BALB/c nude mice (n = 3 per group) bearing subcutaneous GC xenografts	50 mg/kg	Tumor-volume and weight measurements; immunofluorescence and Western blot; qRT-PCR; luciferase reporter assay	3 weeks	BC upregulated miR-7 in tumor tissues, reduced FAK protein levels, inhibited tumor growth, and confirmed direct miR-7–FAK interaction via luciferase reporter assay, alongside PI3K/AKT suppression
Ye et al. [28], 2024	BALB/c nude mice (4 per group)	50 mg/kg	Tumor volume & weight measurements; histology (H&E); immunohistochemistry for p-ERK1/2, Ki-67, ZO-1	3 weeks	BC markedly suppressed xenograft growth, did not affect body weight, decreased p-ERK1/2 and Ki-67 staining, increased ZO-1 expression, and showed no overt toxicity by H&E

GSH glutathione, MPO myeloperoxidase, TUNEL terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, PI3K/AKT phosphoinositide 3-kinase/protein kinase B, BTG3 B-cell translocation gene 3, FAK focal adhesion kinase, RT-qPCR real-time quantitative polymerase chain reaction

RoB

The OHAT RoB instrument was used to evaluate the quality of in vitro experiments. Most studies demonstrated a low RoB for key factors, including appropriate dose or exposure administration, proper allocation of experimental groups, consistency of experimental conditions across groups, completeness of outcome data, and confidence in exposure characterization. However, inadequate reporting of assessor blinding was a common limitation. Approximately 80% of studies clearly described their group allocation methods and ensured complete outcome reporting (Fig. 2).

Fig. 2.

Risk of bias assessment results for in vitro studies included in this systematic review

For animal studies, the SYRCLE RoB tool was applied to assess study quality. Most studies were rated as low risk for sequence generation (selection bias), selective outcome reporting, baseline group similarities, and other potential sources of bias. Allocation concealment was adequately reported in 75% of studies (Fig. 3). Performance bias was identified in 20% of studies, while detection bias was noted in 10%. Reporting of critical information—such as random outcome assessment, assessor blinding, and randomization related to animal housing and handling by investigators or caregivers—was frequently insufficient.

Fig. 3.

Risk of bias assessment for animal studies using the SYRCLE tool

Discussion

BC, a flavonoid derived from Scutellaria baicalensis, has attracted considerable attention for its anticancer potential, particularly in GC [27]. The findings of this systematic review indicate that BC exerts its effects through multiple, interconnected biochemical pathways that converge on the regulation of apoptosis, oxidative stress, and tumor progression.

Mechanistic insights

A consistent theme across studies is the ability of BC to promote apoptosis by shifting the balance between pro- and anti-apoptotic signals. BC downregulates anti-apoptotic proteins such as B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra-large (Bcl-xL), while upregulating Bcl-2-associated X protein (Bax), thereby facilitating mitochondrial outer membrane permeabilization and cytochrome c release [24, 34]. This cascade activates caspase-dependent apoptosis, underscoring the mitochondrial pathway as a central mechanism [24].

BC also interferes with major survival pathways. Inhibition of PI3K/AKT signaling reduces downstream activation of mTOR, suppressing cell proliferation and enhancing apoptosis [35]. Similarly, BC modulates the NF-κB pathway by preventing inhibitor of kappa B (IκB) degradation, thereby blocking NF-κB nuclear translocation and reducing transcription of genes linked to inflammation and survival [36].

Beyond apoptosis, BC influences additional forms of cell death and stress responses. It induces autophagy and ferroptosis, partly through p53 activation and suppression of SLC7A11/GPX4, and disrupts mitochondrial membrane potential via reactive oxygen species (ROS) generation [31, 37]. The Nrf2/Keap1 axis also emerges as a key target: BC stabilizes Nrf2, leading to the induction of antioxidant enzymes such as HO-1, GST, and NQO1, which mitigate oxidative stress and contribute to its antitumor effects [38]. Collectively, these mechanisms suggest that BC functions as a multi-target agent capable of modulating both pro-death and pro-survival pathways in GC.

Therapeutic implications

The convergence of BC’s effects on apoptosis, oxidative stress, and metastasis-related pathways underscores its potential as a complementary therapeutic strategy. Notably, several studies demonstrated that BC enhances cisplatin sensitivity, suggesting a role in overcoming chemoresistance [19, 22]. Its ability to inhibit angiogenesis and metastasis through FAK/miR-7 and epithelial-mesenchymal transition (EMT) suppression further supports its therapeutic promise [28].

Translational challenges

Despite its promising preclinical profile, the clinical translation of BC faces several significant challenges [39]. A major limitation is its poor oral bioavailability, primarily due to low aqueous solubility and extensive first-pass metabolism [40]. Pharmacokinetic studies have demonstrated rapid clearance and limited systemic exposure, which may compromise therapeutic efficacy [41]. To overcome these obstacles, various strategies—including nanoparticle encapsulation, prodrug design, and co-administration with absorption enhancers—are currently under investigation [42]. In addition, comprehensive toxicological evaluations and standardized regulatory guidelines remain insufficient, further hindering clinical advancement [43]. These challenges underscore the necessity for optimized formulations and rigorous pharmacological profiling before BC can be considered a viable therapeutic candidate [44].

Strengths and limitations

This systematic review is the first to consolidate mechanistic evidence for BC in GC across diverse preclinical models and dosing ranges, revealing consistent, convergent biological effects. However, the evidence is limited to in vitro and in vivo experiments, with heterogeneity in protocols and outcomes. Clinical relevance cannot be inferred directly; rigorous trials are required to establish efficacy, safety, and pharmacokinetic profiles in patients.

Future directions

Priorities include standardized experimental designs, dose-response characterization, and validation in clinically relevant models. Translational research should assess BC as an adjunct to standard chemotherapy, delineate biomarkers of response (e.g., Bcl-2/Bax ratios, PI3K/AKT activity), and evaluate long-term safety. Addressing pharmacokinetic limitations and regulatory requirements will be essential for clinical advancement. Ultimately, well-controlled clinical trials are needed to determine BC’s therapeutic utility in GC.

Conclusion

This systematic review indicates that BC exhibits promising anticancer activity against GC in both in vitro and in vivo models. Across diverse experimental systems, BC consistently inhibited tumor cell proliferation and progression through multiple mechanisms, including the induction of apoptosis, modulation of tumor suppressor genes, regulation of oxidative stress, and suppression of pro-survival signaling pathways. These findings underscore BC’s potential as a multi-target agent with antitumor, anti-inflammatory, and antioxidant properties.

However, it is important to note that the current body of evidence is limited to preclinical studies. While these results offer valuable mechanistic insights and a strong experimental rationale, they cannot be directly translated into clinical practice. Translational research—including well-designed pharmacokinetic studies and rigorously controlled clinical trials—is essential to establish the efficacy, safety, and therapeutic applicability of BC in human patients with GC.

Author contributions

Conceptualization of the study: MC and JC; Regulatory affairs: YT and RAF; Preparation of paper-based questionnaire: MC, YT, and JC; Manuscript draft and generation of table/figures: MC and RAF; Critical revisions to the manuscript: MC and JC. All authors read and approved the final manuscript.

Funding

None.

Data availability

Data included in article/supplementary material/referenced in the article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.