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Academic Editors: Gabriella Calviello and Simona Serini Received: 26 November 2025 Revised: 17 January 2026 Accepted: 23 January 2026 Published: 29 January 2026 Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. Review Natural Products Targeting Key Molecular Hallmarks in Gastric Cancer: Focus on Apoptosis, Inflammation, and Chemoresistance Daniel Simancas-Racines 1,2,* , Jaen Cagua-Ordoñez 3,4 , Jaime Angamarca-Iguago 3,4, Juan Marcos Parise-Vasco 2,3 and Claudia Reytor-González 1,4,* 1 Facultad de Ciencias de la Salud y Bienestar Humano, Universidad Tecnológica Indoamérica, Ambato 180150, Ecuador 2 Facultad de Salud y Bienestar, Pontificia Universidad Católica del Ecuador, Quito 170143, Ecuador 3 Facultad de Ciencias de la Salud y Bienestar Humano, Universidad Tecnológica Indoamérica, Quito 170103, Ecuador 4 Escuela de Medicina, Pontificia Universidad Católica del Ecuador, Santo Domingo 230203, Ecuador * Correspondence: danielsimancas10@gmail.com (D.S.-R.); claudiareytor@gmail.com (C.R.-G.) Abstract Natural products have emerged as promising multi-target agents for addressing the com- plex biology of gastric cancer, a malignancy characterized by marked molecular heterogene- ity, late clinical presentation, and frequent resistance to systemic therapies. This narrative synthesis integrates primarily preclinical evidence, with emerging clinical data, on how naturally derived compounds modulate three central molecular processes that drive gastric tumor progression and therapeutic failure: evasion of programmed cell death, persistent tumor-promoting inflammation, and chemoresistance. Compounds such as curcumin, resveratrol, berberine, ginsenosides, quercetin, and epigallocatechin gallate restore apop- totic competence by shifting the balance between pro-survival and pro-death proteins, destabilizing mitochondrial membranes, promoting cytochrome c release, and activating caspase-dependent pathways. These agents also exert potent anti-inflammatory effects by inhibiting nuclear factor kappa B and signal transducer and activator of transcription signaling, suppressing pro-inflammatory cytokine production, reducing cyclooxygenase activity, and modulating the tumor microenvironment through changes in immune cell be- havior. In parallel, multiple natural compounds function as chemo-sensitizers by inhibiting drug efflux transporters, reversing epithelial–mesenchymal transition, attenuating cancer stem cell-associated traits, and suppressing pro-survival signaling pathways that sustain resistance. Collectively, these mechanistic actions highlight the capacity of natural products to simultaneously target interconnected hallmarks of gastric cancer biology. Ongoing ad- vances in formulation strategies may help overcome pharmacokinetic limitations; however, rigorous biomarker-guided studies and well-designed clinical trials remain essential to define the translational relevance of these compounds. Keywords: gastric cancer; natural products; apoptosis; inflammation; chemoresistance; tumor microenvironment; ABC transporters; phytochemicals 1. Introduction Gastric cancer (GC) remains one of the most challenging oncologic diseases worldwide, ranking as the fifth most frequently diagnosed malignancy and the fifth leading cause of cancer-related mortality [1,2]. According to the latest GLOBOCAN 2022 estimates, approximately 968,784 new cases are reported annually, with a markedly elevated burden Int. J. Mol. Sci. 2026, 27, 1347 https://doi.org/10.3390/ijms27031347 https://crossmark.crossref.org/dialog?doi=10.3390/ijms27031347&domain=pdf&date_stamp=2026-01-31 https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ https://www.mdpi.com/journal/ijms https://www.mdpi.com https://orcid.org/0000-0002-3641-1501 https://orcid.org/0000-0002-1684-5206 https://orcid.org/0009-0007-4234-5524 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 2 of 25 in East Asian regions such as Mongolia, Japan, and South Korea [3]. Despite advances in early detection and therapeutic innovation, overall 5-year survival remains poor in most regions, typically ranging between 20% and 30%, largely due to late-stage presentation, aggressive tumor behavior, and limited durable treatment options [4]. The molecular heterogeneity of GC has been extensively characterized through large-scale genomic efforts, most notably by The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) [5,6]. TCGA defines four principal molec- ular subtypes—Epstein–Barr virus (EBV)-positive (~9%), microsatellite instability (MSI; 21–23%), genomically stable (GS; ~20%), and chromosomal instability (CIN; ~50%)—each associated with distinct genomic alterations, therapeutic vulnerabilities, and clinical out- comes [7]. Concordance analyses further indicate that TCGA GS, EBV, and CIN subtypes broadly correspond to the ACRG MSS/EMT, MSS/TP53+, and MSS/TP53− categories, respectively [8,9]. EBV-positive tumors are characterized by frequent PIK3CA mutations and extensive DNA hypermethylation, often accompanied by overexpression of immune checkpoint ligands PD-L1 and PD-L2 [10], MSI tumors display a high mutational burden and robust immune activation signatures, which have been associated with favorable responses to immune checkpoint inhibition [7]. In contrast, GS tumors are enriched for CDH1 and RHOA mutations and commonly exhibit diffuse-type histology, while CIN tumors are marked by extensive copy-number alterations, TP53 mutations, and amplification of receptor tyrosine kinases that may be amenable to targeted therapeutic strategies [5]. From a clinical standpoint, more than 70% of patients present with advanced or metastatic disease, substantially limiting opportunities for curative treatment [11–13]. Therapeutic resistance further compromises outcomes and is driven by a convergence of mechanisms, including overexpression of multidrug efflux transporters, activation of epithelial–mesenchymal transition (EMT) programs, persistence of cancer stem cell popu- lations, and upregulation of DNA damage repair pathways [14–18]. Although standard treatments—such as platinum-based chemotherapy, trastuzumab in HER2-positive disease, and immune checkpoint inhibitors in selected molecular subsets—have improved outcomes in specific contexts, median survival in metastatic GC rarely exceeds 12 months [11,19,20]. Treatment-related toxicity leading to dose reductions or discontinuation further contributes to suboptimal therapeutic efficacy [21,22]. A defining feature of gastric carcinogenesis is the progressive acquisition of molec- ular hallmarks that promote malignant transformation, invasion, and resistance to ther- apy [23]. Among these, dysregulation of programmed cell death—driven by TP53 in- activation, overexpression of anti-apoptotic Bcl-2 family proteins, and impaired death receptor signaling—plays a central role in tumor survival and chemoresistance [5,24–29]. In parallel, chronic inflammation constitutes a major etiological and promotional factor in GC, mediated by sustained activation of NF-κB, STAT3, and COX-2 signaling pathways, frequently initiated and perpetuated by Helicobacter pylori infection [30,31]. In addition, multifactorial chemoresistance emerges through ABC transporter upregulation, metabolic rewiring, cancer stemness, and enhanced DNA repair capacity [18,32–36]. Additional pro- cesses, including redox imbalance and aberrant activation of oncogenic signaling cascades such as PI3K/AKT/mTOR and Wnt/β-catenin, further contribute to disease progression and therapeutic failure. 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MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. https://doi.org/10.3390/ijms27031347 https://doi.org/10.1016/j.jconrel.2025.113991 https://doi.org/10.1111/cas.15377 https://doi.org/10.20892/j.issn.2095-3941.2024.0386 https://doi.org/10.1517/14656560902781907 https://doi.org/10.5539/jfr.v3n4p18 https://doi.org/10.1007/s00432-022-04408-0 https://doi.org/10.37349/eds.2025.1008106 https://doi.org/10.1002/hsr2.71251 https://doi.org/10.4251/wjgo.v17.i4.100484 https://www.ncbi.nlm.nih.gov/pubmed/40235887 https://doi.org/10.3390/molecules27103047 https://doi.org/10.1002/fsn3.4744 https://www.ncbi.nlm.nih.gov/pubmed/39834553 https://doi.org/10.3892/ol.2019.11104 https://www.ncbi.nlm.nih.gov/pubmed/31897137 https://doi.org/10.3892/ijo.2023.5567 https://doi.org/10.1186/1471-2407-13-421 https://www.ncbi.nlm.nih.gov/pubmed/24044575 https://doi.org/10.3390/ijms27031347 Introduction The Molecular Underpinnings of Gastric Carcinogenesis Evasion of Apoptosis: Bcl-2 Family Imbalance and Caspase Disruption The Inflammatory Milieu: NF-B, Cytokine Networks, and Helicobacter pylori The Challenge of Chemoresistance: ABC Transporters, Hypoxia, and EMT Intersecting Oncogenic Drivers: PI3K/AKT/mTOR and Wnt/-Catenin Signaling Natural Products as Modulators of Apoptosis in Gastric Cancer Curcumin: Targeting Mitochondrial Vulnerabilities Resveratrol: Dual Engagement of p53 and Mitochondrial Pathways Betulinic Acid and Ginsenosides: Direct Mitochondrial Initiators Oridonin: Threshold-Dependent Cell Death Induction Countering the Inflammatory Tumor Microenvironment with Natural Compounds Curcumin and Berberine: Targeting the NF-B-Driven Inflammatory and Immunosuppressive Axis Flavonoids (Quercetin, EGCG): Immunomodulatory Reprogramming of the Tumor Microenvironment Celastrol: Disrupting Cytokine Networks and the Inflammatory–Immune Interface Overcoming Chemoresistance: The Role of Natural Products as Chemo-SensitizersMechanisms of Action: Disrupting the Architecture of Chemoresistance Synergistic Interactions: Enhancing Conventional Chemotherapy Translational Barriers and Future Directions Persistent Barriers to Clinical Translation Delivery-Related Challenges: A Brief Perspective Integrating Natural Products into Precision Oncology Frameworks From Preclinical Promise to Clinical Validation Conclusions Appendix A Appendix B Appendix C Referencesidative DNA damage, epigenetic alterations, and progressive mucosal remodeling along the Correa cascade [30,31]. Importantly, several natural products have demonstrated the https://doi.org/10.3390/ijms27031347 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 3 of 25 capacity to modulate H. pylori-associated pathogenic mechanisms, either by exerting direct antibacterial effects or by attenuating inflammation-driven signaling pathways such as NF-κB and STAT3. These properties position natural compounds as potential modulators of early carcinogenic events as well as downstream tumor-promoting processes. Natural products have historically served as a cornerstone of anticancer drug discov- ery, with nearly half of currently approved oncologic agents derived from or inspired by natural sources [37,38]. Their intrinsic multi-target activity, relative biological selectivity, and capacity to modulate complex signaling networks confer advantages over single- target synthetic agents, particularly in heterogeneous and adaptive malignancies such as GC [39,40]. In this context, naturally derived compounds have demonstrated promising activity across multiple GC-relevant hallmarks, including restoration of apoptotic signaling, suppression of tumor-promoting inflammation, modulation of oncogenic pathways, and reversal of chemoresistance [41–44]. The structural diversity of these compounds—shaped by evolutionary selection—enables interactions with molecular targets often inaccessi- ble to conventional medicinal chemistry [45–47], while their preferential toxicity toward malignant cells reflects exploitation of cancer-specific metabolic and signaling vulnerabili- ties [48–51]. This review provides a comprehensive evaluation of natural products relevant to GC therapeutics, focusing on their ability to modulate three core molecular hallmarks—apoptosis, inflammation, and chemoresistance. It integrates mechanistic evidence from preclinical and clinical studies, examines next-generation delivery systems that enhance bioavailability and tumor targeting, and highlights translational barriers to clinical application. Finally, it outlines future directions including precision medicine strategies and rational combination therapy approaches to accelerate the integration of natural products into evidence-based gastric cancer treatment. 2. The Molecular Underpinnings of Gastric Carcinogenesis Gastric carcinogenesis is a multi-step, multi-factorial process driven by the progres- sive accumulation of genetic and epigenetic alterations that dysregulate essential cellular programs. These alterations enable the acquisition of core malignant capabilities described as the hallmarks of cancer [52]. In GC, three hallmarks are particularly central to dis- ease progression and therapeutic failure—apoptosis evasion, chronic inflammation, and chemoresistance—each orchestrated by tightly interconnected oncogenic signaling net- works. Understanding these molecular processes is essential to elucidating how natural products can modulate them and restore cellular vulnerability to treatment [53]. Table 1 summarizes key molecular targets involved in these hallmarks, highlighting their functional significance and relevance for therapeutic modulation. Table 1. Molecular Targets Implicated in Key Hallmarks of Gastric Cancer and Their Functional Roles. Molecular Target Protein Family/Type Primary Function in Gastric Cancer Associated Hallmark(s) Key References Bcl-2 Anti-apoptotic Bcl-2 family Sequesters pro-apoptotic proteins; maintains mitochondrial integrity; promotes survival and chemoresistance. Apoptosis evasion; chemoresistance Zhou et al. (2025) [54] Bax Pro-apoptotic Bcl-2 family Promotes mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release; often downregulated or inhibited. Apoptosis evasion Amjad et al. (2022) [55] https://doi.org/10.3390/ijms27031347 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 4 of 25 Table 1. Cont. Molecular Target Protein Family/Type Primary Function in Gastric Cancer Associated Hallmark(s) Key References Caspase- 9/Caspase-3 Initiator/executioner caspases Execute apoptotic cascade; their inactivation blocks programmed cell death and enhances resistance to therapy. Apoptosis evasion Amjad et al. (2022) [55] NF-κB Transcription factor Induces pro-inflammatory cytokines (IL-6, TNF-α), COX-2, and anti-apoptotic genes; central driver of tumor-promoting inflammation. Inflammation; apoptosis evasion; chemoresistance Chaithongyot et al. (2021) [31] COX-2 Cyclooxygenase enzyme Produces prostaglandins that promote inflammation, angiogenesis, and inhibit apoptosis; overexpressed in GC. Inflammation Xu et al. (2024) [56] IL-6 Cytokine Activates STAT3 and promotes proliferation, angiogenesis, and immune evasion. Inflammation; tumor progression Yu et al. (2024) [57] P-gp (MDR1/ABCB1) ABC transporter Effluxes chemotherapeutic agents, reducing intracellular drug accumulation; major mediator of multidrug resistance. Chemoresistance Li et al. (2024) [14] HIF-1α Transcription factor Mediates hypoxia response; upregulates genes promoting angiogenesis, glycolysis, and MDR1 expression. Chemoresistance; metastasis Albano et al. (2025) [58] PI3K/AKT Kinase signaling cascade Central survival pathway; inhibits apoptosis, enhances proliferation, and induces MDR1 expression. Apoptosis evasion; chemoresistance Morgos et al. (2024) [59] β-catenin Transcriptional co-activator Drives Wnt-mediated transcription promoting proliferation, EMT, and cancer stemness. Chemoresistance; apoptosis evasion Lei et al. (2022) [60] MOMP: mitochondrial outer membrane permeabilization; ABC transporters: ATP-binding cassette transporters; EMT: epithelial–mesenchymal transition. Molecular targets included were selected based on consistent evidence from peer-reviewed studies demonstrating reproducible involvement in at least one major hallmark of gastric cancer (apoptosis evasion, inflammation, or chemoresistance). Their functions are derived from experimental and translational studies in gastric cancer cell lines, xenograft models, and human tumor analyses. 2.1. Evasion of Apoptosis: Bcl-2 Family Imbalance and Caspase Disruption Apoptosis is a critical safeguard against malignant transformation, eliminating cells harboring oncogenic mutations or excessive proliferative stress [61]. In GC, the intrinsic (mitochondrial) apoptotic pathway is particularly relevant, as it integrates damage signals triggered by chemotherapy and cellular stress [62]. The Bcl-2 protein family acts as the central rheostat of this pathway: anti-apoptotic members (Bcl-2, Bcl-xL, Mcl-1) preserve mitochondrial integrity, while pro-apoptotic proteins (Bax, Bak, and BH3-only proteins such as Bid and Bim) promote mitochondrial permeabilization [61]. GC frequently exhibits overexpression of anti-apoptotic Bcl-2 proteins (up to 67% of tumors), which elevates the apoptotic threshold and contributes directly to chemore- sistance [63,64]. Conversely, downregulation or functional impairment of Bax and Bak prevents mitochondrial outer membrane permeabilization (MOMP), a pivotal step that allows cytochrome c release and apoptosome assembly. Once this process is blocked, https://doi.org/10.3390/ijms27031347 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 5 of 25 caspase-9 and downstream executioner caspases (caspase-3/7) remain inactive, effectively silencing programmed cell death [61]. MOMP is the point of no return in the apoptotic cascade. It allows for the release of intermembrane space proteins, most notably cytochrome c, into the cytosol. Cytosolic cytochrome c then binds to the apoptotic protease-activating factor 1 (Apaf-1), triggering the assembly of a large multiprotein complex called the apoptosome. This complex serves as an activation platform for the initiator caspase, caspase-9. Activated caspase-9 then initiates a proteolyticcascade, cleaving and activating the downstream executioner caspases, primarily caspase-3 and caspase-7. These executioner caspases are the final effectors of apoptosis, responsible for cleaving a multitude of cellular substrates, leading to the characteristic morphological and biochemical features of cell death [61]. This distorted Bax/Bcl-2 balance represents a highly actionable vulnerability, as its correction re-sensitizes cancer cells to intrinsic apoptosis. Importantly, a considerable number of natural compounds converge mechanistically on this pathway by increasing Bax expression and/or suppressing Bcl-2, thereby shifting the rheostat toward a pro-apoptotic state—a recurring and central theme in the natural product literature [65]. 2.2. The Inflammatory Milieu: NF-κB, Cytokine Networks, and Helicobacter pylori Chronic inflammation is a defining etiological driver of gastric carcinogenesis and a unifying mechanism linking environmental exposure to tumor initiation and progres- sion [66]. Helicobacter pylori infection—implicated in most non-cardia GC cases—initiates the Correa cascade and establishes a persistent inflammatory environment that promotes genomic instability, angiogenesis, and immune evasion [67]. NF-κB serves as the master transcriptional hub coordinating this response. Activation of upstream IκB kinase (IKK) pathways—via H. pylori, TNF-α, or IL-1β—leads to nuclear translocation of NF-κB and transcription of hundreds of pro-tumorigenic genes [31]. Key NF-κB targets include Cytokines, IL-6, IL-8, TNF-α, which reinforce inflammation through positive feedback loops [66]. Inflammatory enzymes, COX-2, which enhances prostaglandin production, promotes angiogenesis, and suppresses apoptosis [66]. Anti-apoptotic proteins, Bcl-2 family members, directly linking inflammation to cell survival [31]. This NF-κB-driven program creates a self-sustaining inflammatory loop that fuels malignant progression [68]. Because NF-κB is upstream of COX-2, cytokine expression, and anti-apoptotic signaling, targeting this axis has the potential to simultaneously mod- ulate several hallmarks [69]. This provides a strong mechanistic justification for the anti- inflammatory natural products explored later in the review. 2.3. The Challenge of Chemoresistance: ABC Transporters, Hypoxia, and EMT Chemoresistance is a major barrier to successful GC treatment and arises from an intricate network of adaptive mechanisms [70]. Among these, ATP-binding cassette (ABC) transporters are the best characterized. P-glycoprotein (P-gp/MDR1) and MRP1 actively efflux chemotherapeutic agents, lowering intracellular drug concentrations below cytotoxic thresholds. Their expression is frequently elevated in resistant GC cells and is further inducible by drug exposure, establishing a vicious cycle of acquired resistance [71]. The PI3K/AKT pathway is a key transcriptional regulator of MDR1, linking survival signaling with drug efflux capacity [24]. The tumor microenvironment adds an additional layer of complexity. Hypoxia—resulting from rapid tumor expansion and poor vascularization—stabilizes hypoxia-inducible factor 1α (HIF-1α), which drives the transcription of genes promoting angiogenesis, metabolic reprogramming, cell survival, and drug resistance [70]. HIF-1α directly increases P-gp https://doi.org/10.3390/ijms27031347 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 6 of 25 expression, creating a hypoxia–HIF-1α–ABC transporter axis that reinforces chemotherapy resistance [24]. Epithelial–mesenchymal transition (EMT) further exacerbates resistance. During EMT, epithelial markers are lost, and mesenchymal traits emerge, conferring motility, invasiveness, and a stem-like phenotype [24]. EMT cells exhibit heightened survival signaling, increased efflux pump expression, and diminished susceptibility to apoptosis. These mechanisms form an interconnected resistance network in which hypoxia in- duces HIF-1α, HIF-1α enhances EMT and ABC transporter expression, and EMT promotes further chemoresistance. Effective therapeutic approaches must therefore target multiple nodes within this system—precisely the type of multi-target activity that many natural products demonstrate. 2.4. Intersecting Oncogenic Drivers: PI3K/AKT/mTOR and Wnt/β-Catenin Signaling Two oncogenic signaling hubs—PI3K/AKT/mTOR and Wnt/β-catenin—play central roles in orchestrating GC progression and ensuring the persistence of multiple hallmarks. Activation of the PI3K/AKT/mTOR axis, commonly due to PIK3CA mutations or PTEN loss [72,73], enhances proliferation, suppresses apoptosis (e.g., via Bad phosphorylation), and upregulates MDR1 expression, directly promoting chemoresistance [24]. Meanwhile, aberrant Wnt/β-catenin signaling—present in up to 50% of GC cases—stabilizes β-catenin, enabling transcription of proliferative and stemness-associated genes such as c-MYC and CYCLIN D1 [74,75]. This pathway is a major driver of EMT and cancer stem cell maintenance, both strongly tied to metastatic potential and treatment failure. Importantly, these pathways exhibit substantial crosstalk: AKT inhibits GSK-3β, thereby stabilizing β-catenin and amplifying Wnt signaling [76]. Modulating either hub can therefore disrupt multiple malignant phenotypes simultaneously. This mechanistic architecture provides a strong rationale for natural compounds capable of modulating PI3K/AKT or Wnt/β-catenin, many of which are examined in subsequent sections. 3. Natural Products as Modulators of Apoptosis in Gastric Cancer The evasion of apoptosis represents a central survival strategy in gastric cancer (GC) and a major barrier to effective treatment. Natural products offer a diverse array of bioactive molecules capable of reactivating this suppressed cell death machinery through coordinated modulation of mitochondrial integrity, Bcl-2 family dynamics, caspase activation, and upstream tumor suppressor pathways (Figure 1) [23,77]. Collectively, these compounds act on key apoptotic checkpoints that are recurrently dysregulated in GC, complementing the molecular vulnerabilities described in the previous section (Table 2). Curcumin, resveratrol, berberine, quercetin, EGCG, and ginsenoside Rg3 represent the main natural products evaluated in gastric cancer, with their chemical structures summarized in Appendix A. Table 2. Representative Natural Products and Their Apoptosis-Modulating Mechanisms in Gastric Cancer. Natural Product Chemical Class Hallmarks Targeted Key Mechanistic Actions Key References Curcumin Polyphenol Apoptosis, Inflammation, Chemoresistance Bax/Bcl-2 modulation; MOMP induction; caspase-9/3 activation; NF-κB inhibition; MDR1 suppression Yang et al. (2024) [78]; W Liu (2024) [79]; Ren et al. (2025) [80] Resveratrol Stilbenoid Apoptosis, Inflammation, Chemoresistance p53 activation; Bax/Bcl-2 modulation; PI3K/AKT inhibition; NF-κB suppression Warias et al. (2024) [81] Betulinic Acid Triterpenoid Apoptosis Mitochondrial depolarization; cytochrome-c release; caspase-9/3 activation Chen et al. (2020) [82] https://doi.org/10.3390/ijms27031347 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 7 of 25 Table 2. Cont. Natural Product Chemical Class Hallmarks Targeted Key Mechanistic Actions Key References Ginsenosides Triterpenoid Saponins Apoptosis, Chemoresistance MMP loss; Bax translocation; cytochrome-c release; caspases activation; EMT attenuation Cui (2025) [83] Oridonin Diterpenoid Apoptosis, Cell Cycle Arrest Bax/Bcl-2 modulation; cytochrome-c release; caspase activation; G0/G1 or G2/M arrest Fakhri et al. (2022) [84] Berberine Alkaloid Apoptosis, Inflammation, Chemoresistance NF-κB inhibition; caspase-3/8/9 activation; MDR1 suppression Xu et al. (2022) [85]; Kou et al. (2020) [86] Quercetin Flavonoid Apoptosis, Inflammation, Chemoresistance Mitochondrial dysfunction; JNK/p38 activation; COX-2 reduction; HIF-1α inhibition Xie et al. (2025) [87] EGCG Flavonoid Apoptosis, Inflammation STAT3 inhibition;NF-κB suppression; decreased VEGF; mitochondrial ROS induction Cui (2025) [83] Celastrol Triterpenoid Apoptosis, Inflammation ROS–JNK activation; cytokine suppression (TNF-α, IL-8) Fakhri et al. (2022) [84] Figure 1. Integrated apoptotic pathways modulated by natural products in gastric cancer. The dia- gram illustrates the extrinsic apoptotic pathway (TRAIL–TRAIL-R1/R2, Fas–FasL, and TNF-α–TNFR signaling leading to DISC formation and caspase-8 activation) and the intrinsic mitochondrial path- way involving Bax/Bak activation, mitochondrial outer membrane permeabilization, cytochrome c release, apoptosome assembly, and caspase-9 activation. Effector caspases (caspase-3, -6, and -7) exe- cute the apoptotic program. Natural products—including curcumin, resveratrol, quercetin, berberine, and epigallocatechin gallate (EGCG)—modulate key regulatory nodes of these pathways by altering the Bax/Bcl-2 ratio, inhibiting NF-κB signaling, inducing reactive oxygen species (ROS), activating p53-dependent apoptotic programs, and promoting mitochondrial destabilization [88–90]. Color cod- ing: blue elements represent the extrinsic pathway, red elements indicate the intrinsic mitochondrial pathway, purple denotes p53-dependent signaling, green boxes represent natural products and their biological effects, and yellow denotes the mitochondrion. Solid arrows indicate activation, whereas T-bar connectors denote inhibitory interactions. Color variations at ligand–receptor binding sites (TRAIL–TRAIL-R1/R2, Fas–FasL, and TNF-α–TNFR) are used for illustrative purposes only and do not indicate distinct biological or signaling differences. Variations in color intensity are applied exclusively for visual clarity and do not imply different biological meanings. Created in BioRender. Reytor, C. (2026) https://BioRender.com/5qt1g8o. 3.1. Curcumin: Targeting Mitochondrial Vulnerabilities Curcumin, the main curcuminoid from Curcuma longa, is one of the most extensively studied apoptosis-modulating natural compounds. In GC cell lines, curcumin reduces via- https://doi.org/10.3390/ijms27031347 https://BioRender.com/5qt1g8o https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 8 of 25 bility in a dose-dependent manner and induces significant apoptosis through coordinated mitochondrial disruption [91,92]. Curcumin shifts the Bax/Bcl-2 equilibrium toward a pro- apoptotic state, triggers mitochondrial membrane depolarization, and promotes cytochrome-c release, ultimately activating caspase-9 and caspase-3 [93,94]. This integrated mitochondrial and caspase activation has also been observed in vivo, where curcumin treatment suppresses xenograft tumor growth and increases intratumoral caspase-3 expression [95]. Curcumin’s abil- ity to simultaneously inhibit NF-κB and MDR1 further strengthens its therapeutic relevance by lowering inflammatory and chemoresistant thresholds [96]. 3.2. Resveratrol: Dual Engagement of p53 and Mitochondrial Pathways Resveratrol demonstrates a multi-targeted pro-apoptotic effect, acting on both the mito- chondrial pathway and upstream tumor suppressor mechanisms. In GC models, resveratrol increases Bax and decreases Bcl-2 expression, promotes mitochondrial permeabilization, and activates the caspase cascade [97]. Importantly, resveratrol enhances p53 activation, reinforcing transcriptional upregulation of pro-apoptotic genes and strengthening mito- chondrial commitment to apoptosis [98]. Suppression of PI3K/AKT and NF-κB signaling provides a complementary survival blockade, creating a convergent pro-death signal that lowers the apoptotic threshold [99]. Although in vivo GC-specific studies remain limited, the mechanistic rationale and cross-cancer validation support its translational potential. 3.3. Betulinic Acid and Ginsenosides: Direct Mitochondrial Initiators Betulinic acid (BA) exerts selective cytotoxicity against cancer cells by directly impair- ing mitochondrial stability. BA induces rapid loss of mitochondrial membrane potential, promotes cytochrome-c release, and triggers activation of caspase-9 and caspase-3 [100–102]. BA also shifts the Bax/Bcl-2 ratio toward apoptosis, a mechanism confirmed in GC cell models and xenografts [103]. Ginsenosides—including Rg3, Rh1, Rk1, and M1—activate mitochondrial apoptosis by promoting Bax translocation, reducing MMP, and triggering caspase-dependent cell death [85,86]. Ginsenosides also attenuate EMT and reverse chemoresistant phenotypes, giving them a dual apoptotic and anti-resistance profile validated across multiple in vivo GC models [104]. 3.4. Oridonin: Threshold-Dependent Cell Death Induction Oridonin displays a concentration-dependent dichotomy of biological responses. At lower doses, it induces cell cycle arrest and senescence, whereas higher concentrations activate the intrinsic apoptotic cascade through Bax upregulation, Bcl-2 suppression, cytochrome-c release, and caspase-9/3 activation [105,106]. These effects have been corroborated in several GC xenograft models [107]. Oridonin’s clear dose–response transition between cytostasis and apoptosis provides a rational basis for therapeutic dose optimization. 4. Countering the Inflammatory Tumor Microenvironment with Natural Compounds Chronic inflammation is a defining feature of gastric carcinogenesis and a major driver of tumor initiation, progression, and immune evasion [67]. Persistent activation of inflam- matory signaling pathways such as NF-κB and STAT3 establishes a self-reinforcing tumor microenvironment (TME) characterized by sustained cytokine production, macrophage reprogramming toward immunosuppressive phenotypes, and attenuation of cytotoxic im- mune surveillance [68]. Natural products exert potent anti-inflammatory and immunomod- ulatory effects that disrupt this tumor-promoting inflammatory loop by inhibiting key signaling hubs, reshaping cytokine networks, and actively reprogramming the immune composition of the gastric TME [108]. Through these coordinated mechanisms, natural https://doi.org/10.3390/ijms27031347 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 9 of 25 compounds suppress inflammation-driven malignant transformation while restoring an- titumor immune competence, thereby creating a biological context more permissive to immune-mediated tumor control [109] (Figure 2). A detailed summary of preclinical studies supporting the anti-inflammatory and immunomodulatory effects of these natural products in gastric cancer models is provided in Appendix B. Figure 2. Inflammatory pathways and anti-inflammatory mechanisms modulated by natural prod- ucts in gastric cancer. This schematic illustrates the central inflammatory signaling axes involved in gastric carcinogenesis, including NF-κB activation through TNF-α/IKK signaling, COX-2-derived prostaglandin pathways, and IL-6-mediated JAK/STAT3 oncogenic transcription. Key natural compounds—curcumin, berberine, quercetin, EGCG, resveratrol, and ginsenosides—exert inhibitory effects on these nodes by reducing IKK phosphorylation, blocking STAT3 activation, suppressing COX-2 expression, decreasing cytokine release (TNF-α, IL-6, IL-1β), and modulating immune cell polarization. Crosstalk among NF-κB, COX-2/PGE2, and STAT3 pathways is shown to highlight the interconnected inflammatory microenvironment characteristic of gastric cancer [31,32,110–113]. Sym- bols and color coding: Molecular icons represent receptors, signaling complexes, transcription factors, and nuclear translocation for illustrative purposes. Colored arrows indicate pathway activation or inhibition as depicted in the figure. Green upward and downward arrows (↑/↓) denote upregulation or downregulation of the indicated molecular targets, respectively. Created in BioRender. Reytor, C. (2026) https://BioRender.com/saenqa1. 4.1. Curcumin and Berberine: Targeting the NF-κB-Driven Inflammatory and Immunosuppressive Axis Curcumin and berberine act as archetypal inhibitors of the NF-κB pathway, a central orchestrator ofinflammation, survival signaling, immune evasion, and macrophage polar- ization in gastric cancer. Inhibition of this master regulator yields dual therapeutic benefits by simultaneously attenuating inflammatory signaling and lowering the apoptotic thresh- old of tumor cells, while also mitigating NF-κB-dependent immune suppression [114,115]. Curcumin exerts robust anti-inflammatory activity largely through suppression of NF- κB activation [116,117]. n preclinical Helicobacter pylori-induced gastritis models, curcumin significantly reduces mucosal inflammation and pro-tumorigenic cytokine production, interrupting early steps of the Correa cascade [116]. By diminishing NF-κB-regulated expression of COX-2, IL-6, and TNF-α, curcumin weakens the inflammatory milieu that https://doi.org/10.3390/ijms27031347 https://BioRender.com/saenqa1 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 10 of 25 supports gastric tumor initiation, progression, and immune escape [118,119]. Emerging evidence further suggests that curcumin-mediated NF-κB inhibition indirectly limits the expansion of immunosuppressive myeloid populations, thereby favoring a shift toward a more immune-permissive TME [120,121]. Berberine complements this mechanism through a highly specific mode of NF- κB inhibition. By covalently modifying Cys-179 of the IKKβ subunit, berberine pre- vents IκBα phosphorylation and degradation, maintaining NF-κB in its inactive cytoso- lic state [122]. The downstream impact includes suppression of COX-2, MMP-9, cy- clin D1, survivin, and Bcl-xL—genes that collectively sustain inflammatory signaling, proliferation, resistance to apoptosis, and immune evasion in gastric cancer [122,123]. Through this broad repression of NF-κB-dependent programs, berberine disrupts the inflammation–survival–immunosuppression axis that underlies GC progression and ther- apeutic resistance [124,125]. 4.2. Flavonoids (Quercetin, EGCG): Immunomodulatory Reprogramming of the Tumor Microenvironment Flavonoids such as quercetin and epigallocatechin-3-gallate (EGCG) extend their therapeutic effects beyond direct anti-inflammatory activity by actively reprogramming the immune landscape of the gastric TME. Rather than acting solely on tumor cells, these compounds modulate macrophage polarization, suppress immunosuppressive cytokines, and enhance cytotoxic immune cell function, thereby reshaping both innate and adaptive immune responses [126,127]. Quercetin inhibits NF-κB and MAPK signaling, leading to reduced expression of TNF- α, IL-6, and COX-2, while simultaneously promoting a shift from M2-like tumor-associated macrophages (TAMs) toward an antitumor M1 phenotype [128,129]. This macrophage re-education is accompanied by enhanced CD8+ T-cell activity and reduced regulatory T-cell abundance, indicating a broader restoration of antitumor immune surveillance. Importantly, quercetin also suppresses PD-L1 expression on tumor cells, a mechanism with direct relevance to immune checkpoint blockade and the potential to sensitize gastric tumors to PD-1/PD-L1-targeted therapies [130,131]. EGCG exhibits similarly extensive immunomodulatory effects. In gastric cancer mod- els, EGCG inhibits IL-6/STAT3 signaling, resulting in decreased expression of downstream angiogenic and immunosuppressive mediators such as VEGF [112,132]. EGCG further lim- its macrophage infiltration by downregulating CCL2 and CSF-1 and prevents M2 polariza- tion through miR-16-mediated suppression of NF-κB signaling within macrophages [126]. Through these coordinated actions, EGCG dismantles the immunosuppressive TME that promotes tumor survival and therapeutic resistance, aligning with the growing interest in flavonoids as immunological co-adjuvants capable of enhancing responses to immune checkpoint inhibitors [126]. 4.3. Celastrol: Disrupting Cytokine Networks and the Inflammatory–Immune Interface Celastrol, a triterpenoid derived from Tripterygium wilfordii, displays potent anti- inflammatory activity in gastric cancer through disruption of cytokine networks and inhibition of tumor-supportive inflammatory mediators [133]. In GC cell models, celastrol markedly suppresses TNF-α and IL-8 secretion while downregulating Biglycan (BGN), a proteoglycan that amplifies innate immune signaling and cytokine release [134]. Ex- perimental overexpression of BGN rescues cytokine production, confirming its role as a functional target [135]. Although necroptosis has been implicated as part of celastrol’s cytotoxic profile, its anti-inflammatory effect in GC is most consistently associated with downregulation of BGN and inhibition of inflammatory cytokine release more consistently linked to BGN/cytokines https://doi.org/10.3390/ijms27031347 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 11 of 25 in GC models [134]. By simultaneously inducing tumor cell death and attenuating cytokine- driven inflammation, celastrol disrupts a key interface between cellular and microenviron- mental processes that sustain gastric carcinogenesis [136,137]. Collectively, these findings position anti-inflammatory and immunomodulatory natu- ral products not as standalone immunotherapies, but as biologically rational co-adjuvants capable of reshaping the gastric tumor microenvironment to improve responsiveness to immune checkpoint inhibition. 5. Overcoming Chemoresistance: The Role of Natural Products as Chemo-Sensitizers Chemoresistance remains one of the principal barriers to successful treatment of ad- vanced gastric cancer, contributing directly to poor survival outcomes and high recurrence rates [18]. Natural products are emerging as promising chemo-sensitizers capable of over- coming resistance through multi-target actions that simultaneously intercept the cellular and microenvironmental mechanisms that sustain the resistant phenotype [138]. Their pleiotropic nature allows them to interfere with efflux pumps, restore apoptosis, suppress survival signaling, and target epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) traits—features that make resistance so difficult to reverse with single-target synthetic agents [139] (Figure 3). Preclinical studies demonstrating the ability of natural products to reverse chemoresistance and enhance the efficacy of conventional chemotherapy in gastric cancer models are summarized in Appendix C. Figure 3. Chemoresistance Mechanisms and Natural Product Reversal Strategies in Gastric Can- cer. This figure illustrates the major molecular pathways driving chemoresistance in gastric cancer—including drug efflux via ABC transporters (P-gp/ABCB1, MRP1/ABCC1, ABCG2), can- cer stem cell-associated persistence (CD44, CD133, ALDH1), EMT activation (Snail, Twist, Zeb1), enhanced DNA repair (RAD51, MLH1/MSH2), and pro-survival signaling through PI3K/AKT, NF-κB, TGF-β/Smad, and Wnt/β-catenin. Natural products counteract these mechanisms by inhibit- ing drug efflux (curcumin, resveratrol, berberine, quercetin), suppressing CSC and EMT programs (ginsenosides, EGCG), attenuating pro-survival pathways, and disrupting DNA repair networks. Synergistic combinations with cisplatin, 5-FU, doxorubicin, or oxaliplatin restore chemosensitivity and enhance therapeutic response. Solid arrows indicate activation, dotted arrows reduction or crosstalk, and T-bars denote inhibition [140–145]. Arrows within text boxes indicate reported in- creases or decreases in molecular activity or expression (↑/↓). Created in BioRender. Reytor, C. (2026) https://BioRender.com/5a62wlg. https://doi.org/10.3390/ijms27031347 https://BioRender.com/5a62wlg https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 12 of 25 5.1. Mechanisms of Action: Disrupting the Architecture of Chemoresistance The multifactorial design of natural products is a strategic advantage in combat- ting chemoresistance. Rather than inhibiting a single node, these compounds mount a multipronged attack that destabilizes the resistant phenotype at its foundations[54]. • Inhibition of ABC Transporters: Overexpression of ATP-binding cassette (ABC) ef- flux pumps—particularly P-glycoprotein (P-gp/MDR1) and MRP1—is a dominant mechanism of multidrug resistance. Flavonoids, alkaloids, and terpenoids have been shown to (i) Directly inhibit ATPase activity of P-gp/MDR1, (ii) block drug efflux, (iii) downregulate MDR1/MRP1 transcription, leading to increased intracellular drug accumulation and restoration of cytotoxicity [146]. • Restoration of Apoptotic Sensitivity: Chemoresistant cells typically display heightened thresholds for apoptosis due to elevated Bcl-2 expression or impaired mitochondrial signaling. Many natural products reverse this state by (i) Shifting the Bax/Bcl-2 ratio, (ii) promoting cytochrome-c release, (iii) activating caspase-3/8/9, thereby lowering the apoptotic threshold and enabling chemotherapeutic agents to trigger cell death more effectively [70]. • Targeting EMT and Cancer Stem Cells: EMT contributes to invasiveness, survival, and drug resistance, while CSCs act as reservoirs for tumor regrowth. Natural compounds have demonstrated the ability to: (i) Reverse EMT by upregulating E-cadherin and suppressing Snail/Twist/ZEB1, (ii) reduce CSC markers such as CD44, ALDH1, and CD133, (iii) impair sphere formation and self-renewal capacity [147]. Berberine, in particular, has shown capacity to reduce CSC-like populations in various cancer models [54]. • Suppression of Pro-survival Signaling: Hyperactivation of pathways such as PI3K/AKT/mTOR provides survival cues that blunt chemotherapy-induced dam- age. Natural products including berberine and resveratrol inhibit these pathways, dismantling the signaling support that sustains resistance [86]. This broad-spectrum mechanistic action makes natural products fundamentally ad- vantageous: while a tumor cell may compensate for inhibition of one pathway, it is far more difficult to counteract simultaneous suppression of drug efflux, survival signaling, EMT, and apoptotic evasion. 5.2. Synergistic Interactions: Enhancing Conventional Chemotherapy Compelling preclinical evidence supports the synergistic integration of natural prod- ucts with frontline chemotherapeutic agents such as cisplatin (DDP), 5-fluorouracil (5-FU), and oxaliplatin. • Curcumin reverses 5-FU resistance by inhibiting NF-κB, thereby restoring apopto- sis and significantly enhancing cytotoxicity. When combined with the FP regimen (5-FU + cisplatin), curcumin displays potent synergy in MGC-803 cells—most pro- nounced at lower chemotherapy doses—suggesting its utility in dose reduction strate- gies. This synergy is mediated through (i) Caspase-3/8 activation, (ii) downregulation of Bcl-2, (iii) mitochondrial depolarization [148]. • In AGS cells, resveratrol enhances doxorubicin sensitivity by downregulating MDR1 and MRP1 expression, effectively targeting the efflux-driven mechanism of resis- tance [149]. This is consistent with its broader capacity to modulate PI3K/AKT and NF-κB pathways. • Ginsenosides demonstrate consistent synergy with platinum agents: Ginsenoside Rk1 significantly enhances cisplatin and oxaliplatin efficacy in vivo by inhibiting tumor growth [150]. Ginsenoside Rg3, in combination with a STING agonist, reverses https://doi.org/10.3390/ijms27031347 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 13 of 25 cisplatin resistance by suppressing EMT and downregulating resistance-associated proteins [151]. These findings support the inclusion of ginsenosides in combination regimens aimed at reversing EMT-driven chemoresistance. • Berberine exhibits some of the strongest chemo-sensitizing effects among natu- ral compounds. In cisplatin-resistant GC cells, berberine restores sensitivity by (i) Downregulating MDR1/MRP1, (ii) inducing mitochondrial apoptosis, (iii) in- hibiting PI3K/AKT/mTOR signaling [86]. These effects have been validated both in vitro and in vivo, positioning berberine as one of the most clinically promising natural sensitizers. 6. Translational Barriers and Future Directions Despite compelling mechanistic evidence supporting the antitumor activity of natu- ral products in gastric cancer, their translation into clinically validated therapies remains limited. The gap between robust in vitro efficacy and modest in vivo or clinical outcomes reflects a constellation of scientific, pharmacological, regulatory, and economic barriers that continue to constrain progress. Addressing these limitations is essential to contex- tualize the mechanistic findings discussed throughout this review and to guide future development strategies. 6.1. Persistent Barriers to Clinical Translation One of the most significant challenges is the lack of chemical standardization and batch-to-batch consistency in natural product preparations. Variability arising from differ- ences in plant species or subspecies, geographic origin, cultivation conditions, harvesting, storage, and extraction protocols results in substantial heterogeneity in bioactive compound content [152]. Without rigorously standardized formulations manufactured under Good Manufacturing Practice (GMP) conditions, it remains difficult to attribute biological or clinical effects to a defined intervention, contributing to inconsistent and non-reproducible clinical findings [153]. Pharmacokinetic limitations represent an additional and critical obstacle. Many phyto- chemicals exhibit poor aqueous solubility, rapid metabolism, and limited tissue penetration, leading to a pronounced disconnect between potent in vitro IC50 values and insufficient in vivo exposure at tumor sites. As a consequence, promising compounds may fail to engage their molecular targets at therapeutically relevant concentrations in clinical settings, despite strong mechanistic rationale [153]. Safety considerations further complicate clinical translation. The widespread percep- tion that “natural” equates to “safe” is misleading. At pharmacologically active doses, several natural compounds have been associated with hepatotoxicity, nephrotoxicity, mi- tochondrial dysfunction, and hematologic alterations [154]. Of particular concern are drug–herb interactions mediated by cytochrome P450 enzymes, especially CYP3A4 and CYP2C9, which metabolize many chemotherapeutic agents. Inhibition or induction of these enzymes by natural products can result in clinically significant alterations in drug exposure, increasing the risk of toxicity or therapeutic failure [155]. Finally, limited financial incentives and challenges related to intellectual property pro- tection have curtailed pharmaceutical investment in natural product development. The lack of patentability of core chemical structures translates into fewer high-quality randomized clinical trials, insufficient pharmacokinetic and pharmacodynamic studies, and delayed adoption of advanced formulation strategies, despite strong biological plausibility [153]. https://doi.org/10.3390/ijms27031347 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 14 of 25 6.2. Delivery-Related Challenges: A Brief Perspective In addition to the barriers outlined above, delivery-related limitations play a con- tributory role in the restricted clinical performance of many natural compounds. Several agents highlighted in this review—including curcumin, resveratrol, ginsenosides, and epigallocatechin gallate (EGCG)—exhibit particularly low oral bioavailability due to poor solubility, physicochemical instability, and extensive first-pass metabolism [156–158]. Cur- cumin, for example, often remains undetectable in plasma following oral administration despite potent cytotoxic effects in gastric cancer cell lines, reflecting rapid glucuronidation, sulfation, and limited systemic exposure [159,160]. Nanotechnology-based delivery systems have been explored as enabling tools to partially address these pharmacokinetic constraints by improving compound stability, solubility, and circulation time [161]. Importantly, such approachesdo not modify the intrinsic molecular mechanisms of action discussed in earlier sections but rather seek to enhance delivery efficiency and tumor accessibility [162]. Nanoformulations can protect labile phytochemicals from premature degradation and promote preferential tumor accu- mulation through enhanced permeability and retention effects, particularly for particles below 200 nm [163]. Advanced carrier designs may further allow controlled or stimuli- responsive release in response to tumor-associated cues such as acidic pH, redox imbalance, or elevated reactive oxygen species [164]. Preclinical studies have demonstrated improved antitumor efficacy of nano-encapsulated natural products in gastric cancer models, including liposomal curcumin, resveratrol- loaded solid lipid nanoparticles, ginsenoside-containing polymeric micelles, and EGCG- loaded chitosan-based nanoparticles [165,166]. Moreover, the clinical use of nanofor- mulated chemotherapeutics in gastric cancer, such as liposomal irinotecan (Onivyde®, Boulogne-Billancourt, France) and liposomal paclitaxel (Lipusu®, Nanjing, China), pro- vides proof-of-concept that nanocarrier-based delivery is feasible within this disease con- text [167,168]. Nevertheless, these strategies should be viewed as supportive measures to address delivery-related limitations rather than as central therapeutic drivers. 6.3. Integrating Natural Products into Precision Oncology Frameworks The therapeutic landscape of gastric cancer is increasingly shaped by precision oncol- ogy, with treatment decisions guided by molecular features such as HER2 amplification, microsatellite instability, PD-L1 expression, Epstein–Barr virus positivity, and alterations in key oncogenic pathways. Within this context, the traditionally perceived lack of specificity of natural products may represent a relative advantage, given their capacity to modulate multiple interconnected signaling networks involved in apoptosis dysregulation, chronic inflammation, and chemoresistance [169–171]. Future development efforts should prioritize biomarker-driven strategies to identify patient subsets most likely to benefit from specific natural compounds [172]. Predictive signa- tures related to inflammatory signaling, survival pathway activation, epithelial–mesenchymal transition, or cancer stem cell traits may guide rational selection and avoid non-specific application [173,174]. In parallel, natural products are more plausibly positioned as compo- nents of combination strategies rather than as monotherapies for advanced disease—acting as chemo-sensitizers, immunomodulatory co-adjuvants, or metabolic modulators that complement established cytotoxic, targeted, or immunotherapeutic agents [70]. 6.4. From Preclinical Promise to Clinical Validation Despite encouraging preclinical data, the clinical evidence base supporting natural products in gastric cancer remains fragmented and methodologically limited. Progress toward clinical credibility will require development pipelines that adhere to the same https://doi.org/10.3390/ijms27031347 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 15 of 25 scientific and regulatory standards applied to synthetic small molecules [153,175]. This in- cludes rigorous chemical standardization, GMP-compliant manufacturing, comprehensive pharmacokinetic and pharmacodynamic characterization, and well-designed randomized clinical trials incorporating biomarker-guided patient stratification and objective measures of target engagement. The principal limitation facing the field is therefore not a shortage of biologically active compounds, but an absence of pharmaceutical-grade rigor. Natural products possess gen- uine potential as multi-target modulators capable of addressing key molecular hallmarks of gastric cancer; however, their successful integration into evidence-based oncology will depend on disciplined translational strategies and high-quality clinical validation [153,176]. 7. Conclusions Gastric cancer remains a major global health challenge due to its pronounced molecular heterogeneity, aggressive clinical behavior, and the frequent development of resistance to standard therapies. The convergence of three interrelated molecular hallmarks—evasion of apoptosis, chronic inflammation, and multidimensional chemoresistance—creates a highly adaptive tumor ecosystem that limits the effectiveness of single-target therapeutic strategies. These features underscore the need for interventions capable of modulating interconnected signaling networks that collectively sustain tumor survival, progression, and treatment failure. The evidence synthesized in this review indicates that natural products represent a mechanistically diverse class of multi-target modulators capable of engaging these hall- marks at multiple levels. Compounds such as curcumin, resveratrol, berberine, ginseno- sides, quercetin, and EGCG have been shown in preclinical models to restore apoptotic signaling, suppress pro-tumorigenic inflammatory pathways, and attenuate key mecha- nisms of chemoresistance, including efflux pump activity, epithelial–mesenchymal tran- sition, and cancer stem cell-associated traits. However, the clinical integration of these agents remains limited, not by a lack of biologically active compounds, but by insufficient pharmaceutical-grade rigor, including challenges related to bioavailability, standardization, pharmacokinetics, and clinical validation. Future progress will depend on disciplined trans- lational strategies, biomarker-guided patient selection, and well-designed clinical trials that position natural products as rational adjuncts—rather than replacements—to established cytotoxic, targeted, or immunotherapeutic regimens. Within such frameworks, natural products may contribute meaningfully to more biologically informed and evidence-based approaches for managing gastric cancer. Author Contributions: Conceptualization, J.C.-O., D.S.-R. and C.R.-G.; methodology, J.C.-O., C.R.-G., J.A.-I. and D.S.-R.; literature search, J.C.-O., C.R.-G. and J.M.P.-V.; data curation, J.C.-O. and J.M.P.-V.; investigation, J.C.-O., C.R.-G., J.A.-I. and J.M.P.-V.; validation, C.R.-G., J.A.-I. and D.S.-R.; writing—original draft preparation, J.C.-O.; writing—review and editing, C.R.-G., J.A.-I., J.M.P.-V. and D.S.-R.; visualization, J.C.-O.; supervision, D.S.-R.; project administration, J.C.-O. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Data Availability Statement: No new data were created or analyzed in this study. Conflicts of Interest: The authors declare no conflicts of interest. Appendix A. Chemical Structures of Representative Natural Products This appendix presents the chemical structures of representative natural products discussed in the main text. These structures are provided for reference and do not imply structure–activity relationships beyond those addressed in the mechanistic sections. https://doi.org/10.3390/ijms27031347 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 16 of 25 Figure A1. Chemical structures of representative natural products discussed in this review. (A) Curcumin; (B) Resveratrol; (C) Berberine; (D) Quercetin; (E) Epigallocatechin-3-gallate (EGCG); (F) Ginsenoside Rg3. Created in BioRender. Reytor, C. (2026) https://BioRender.com/ojozp53. Appendix B. Preclinical Evidence Supporting the Anticancer Activity of Natural Products in Gastric Cancer This appendix provides a structured overview of representative preclinical studies supporting the mechanistic effects of natural products discussed in the main text. These data complement the mechanistic sections by summarizing experimental models, dos- ing conditions, primary biological effects, and molecular pathways involved, without interrupting the narrative flow of the manuscript. Table A1. Preclinical evidence supporting anticancer activity of natural products in gastriccancer. Natural Product Experimental Model (Cell Line/Animal) Dose/Concentration Main Effects Molecular Pathways Reference Curcumin Gastric cancer cell lines (in vitro); preclinical animal models Micromolar concentrations in vitro; various dosing in vivo (see source) Inhibits proliferation, invasion, migration; induces apoptosis; modulates lncRNA and signaling pathways PI3K/Akt/mTOR; NF-κB; modulation of lncRNAs Wang B et al. (2024) [92] Resveratrol Gastric cancer cell models (in vitro) Micromolar range (dose–response reported) Suppresses proliferation; induces apoptosis; modulates pro-survival pathways Inhibition of PI3K/AKT and associated pathways Rojo D et al. (2022) [177] Betulinic acid Gastric cancer cells (in vitro); xenograft mouse model (in vivo) Dose–response concentrations in vitro; in vivo administration schemes reported Decreases proliferation; induces apoptosis; reduces EMT and metastatic potential Mitochondrial apoptosis; EMT-associated signaling Che Y et al. [82] https://doi.org/10.3390/ijms27031347 https://BioRender.com/ojozp53 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 17 of 25 Table A1. Cont. Natural Product Experimental Model (Cell Line/Animal) Dose/Concentration Main Effects Molecular Pathways Reference Ginsenoside Rg3 Cisplatin- resistant gastric cancer cells (SGC- 7901/DDP) in vitro + in vivo assays Dosing varied (e.g., c-di-AMP + RG3 in combination; see study) Synergistic inhibition of proliferation, migration, invasion, and EMT; reversal of chemoresistance EMT suppression; stemness reduction; immune pathway modulation Lu Z et al. [178] Oridonin GC cell lines (in vitro) Micromolar concentrations (effective range reported) Induces apoptosis; reduces proliferation; alters expression of apoptosis-associated genes Caspase- dependent apoptosis, transcriptomic effects Ren D et al. [179] Berberine BGC-823 gastric cancer cells (in vitro) 5–40 µM in typical cellular assays Suppresses proliferation and invasion; impacts survival and inflammatory signaling NF-κB inhibition; apoptosis modulation Tian Y et al. [180] Quercetin AGS and HGC-27 gastric cancer cell lines (in vitro) 50–200 µM (AGS); 100–300 µM (HGC-27) Reduces migration and invasion; inhibits EMT; suppresses proliferative signaling MAPK/ERK; EMT regulation Deng H et al. [90] EGCG Gastric cancer cells (in vitro); mouse tumor models (in vivo) 5–40 µM (in vitro); 1.5 mg/day/mouse (in vivo) in some studies Inhibits proliferation; increases apoptosis; reduces tumor growth in vivo Apoptosis regulation; proliferative signaling pathways Jang J et al. [181] Celastrol HGC-27, AGS gastric cancer cell models (in vitro) 0.5 µM for 24 h (effective in cited study) Suppresses cytokine release (TNF-α/IL-8); anti-inflammatory and cytotoxic effects Biglycan (BGN) axis; inflammation– cell death interface Guo D et al. [134] Appendix C. Preclinical Evidence Supporting the Anticancer Activity of Natural Products in Gastric Cancer This appendix summarizes currently registered clinical trials that have evaluated or are evaluating selected natural products in gastric cancer or related precursor conditions, including chronic atrophic gastritis and gastric intestinal metaplasia. These trials provide limited but important clinical context to the preclinical and mechanistic evidence discussed in the main text. The information is presented to acknowledge ongoing translational efforts while recognizing that robust clinical validation remains limited. https://doi.org/10.3390/ijms27031347 https://doi.org/10.3390/ijms27031347 Int. J. Mol. Sci. 2026, 27, 1347 18 of 25 Table A2. Registered clinical trials involving natural products relevant to gastric cancer. Natural Product Trial ID Phase Population Intervention Outcomes (Primary/Key) Status Curcumin NCT02782949 Phase IIb Adults with chronic atrophic gastritis and/or gastric intestinal metaplasia (GC prevention setting) Curcumin vs. placebo (with biomarker/lab assessments; QoL components reported in registry descriptions) Prevention-oriented endpoints and biomarker/lesion- related assessments (registry-described) Active, not recruiting Berberine NCT07129460 Phase IV Patients with gastric intestinal metaplasia (risk/precancer context) Berberine hydrochloride vs. placebo Efficacy and safety outcomes for gastric intestinal metaplasia (registry-described) Not yet recruiting Ginsenoside Rg3 NCT01757366 Phase II Advanced gastric cancer (treatment setting) Ginsenoside Rg3 + first-line chemotherapy vs. chemotherapy (as described in registry sum- maries/aggregators) Safety and efficacy endpoints (registry-described); no results posted page identified Unknown/no results posted Curcumin (supportive care/cachexia context including GC) NCT05856500 (Not clearly displayed in public snippets; described as prospective controlled study in available documents) Patients with advanced upper GI tumors including gastric cancer (III–IV) with early cachexia Creatine + curcumin (oral) on top of basic nutritional support Inflammation/metabolic and nutrition-related outcomes; QoL/prognosis- related endpoints (per protocol/ICF text) Not yet recruiting (reported in curated summaries of GC-related curcumin trials) References 1. 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