Natural Products Targeting Key Molecular Hallmarks in Gastric Cancer: Focus on Apoptosis, Inflammation, and Chemoresistance

Abstract

Natural products have emerged as promising multi-target agents for addressing the complex biology of gastric cancer, a malignancy characterized by marked molecular heterogeneity, 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 apoptotic 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 behavior. 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 advances 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: ABC transporters; apoptosis; chemoresistance; gastric cancer; inflammation; natural products; phytochemicals; tumor microenvironment.

Figure 1

Integrated apoptotic pathways modulated by natural products in gastric cancer. The diagram 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 pathway involving Bax/Bak activation, mitochondrial outer membrane permeabilization, cytochrome c release, apoptosome assembly, and caspase-9 activation. Effector caspases (caspase-3, -6, and -7) execute 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 [88,89,90]. Color coding: 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.

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.

Figure 2

Inflammatory pathways and anti-inflammatory mechanisms modulated by natural products 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 [31,32,110,111,112,113]. Symbols 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.

Figure 3

Chemoresistance Mechanisms and Natural Product Reversal Strategies in Gastric Cancer. This figure illustrates the major molecular pathways driving chemoresistance in gastric cancer—including drug efflux via ABC transporters (P-gp/ABCB1, MRP1/ABCC1, ABCG2), cancer 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 inhibiting 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 [140,141,142,143,144,145]. Arrows within text boxes indicate reported increases or decreases in molecular activity or expression (↑/↓). Created in BioRender. Reytor, C. (2026) https://BioRender.com/5a62wlg.