Cell proliferation constitutes the fundamental basis for tumor initiation and progression (Li P. et al., 2024). The cell cycle, an orchestrated sequence of events governing cell growth and division, is composed of the G1, S, G2, and M phases, each regulated by stringent molecular checkpoints that govern phase transitions. Dysregulation of these regulatory mechanisms can culminate in uncontrolled cellular proliferation, a hallmark event in tumorigenesis (Gao et al., 2018). Consequently, inhibiting the aberrant proliferation of GC cells represents a critical therapeutic strategy in GC.

In a seminal study by Li F. and colleagues, AS-IV was shown to suppress GC cell proliferation and metastatic potential through downregulation of circular RNA dihydrolipoamide S-succinyltransferase (circDLST) (Li F. et al., 2022). Previous studies have established that circDLST promotes GC progression (Zhang et al., 2020). Mechanistically, circDLST acts as a “sponge” for microRNA-489-3p (miR-489-3p), sequestering the micro Ribonucleic Acid (microRNA) and relieving its inhibition of Eukaryotic Translation Initiation Factor 4A1, (EIF4A1,a direct target of miR-489-3p). AS-IV disrupts this axis by reducing circDLST expression, thereby releasing miR-489-3p from circDLST-mediated sequestration. Elevated miR-489-3p levels enhance the suppression of EIF4A1, ultimately inhibiting GC cell proliferation and metastasis.

Notably, this study represents the first to delineate the circDLST/miR-489-3p/EIF4A1 signaling axis as a key mediator of AS-IV’s antitumor activity in GC, providing a robust mechanistic framework for the development of AS-IV as a novel therapeutic agent in GC treatment. These findings underscore the potential of AS-IV to target non-coding RNA networks for cancer therapy, offering new insights into the molecular mechanisms underlying TCM-derived metabolite efficacy. However, it must be pointed out that current research on AS-IV inhibiting GC cell proliferation is extremely limited. This study lacks sufficient corroboration, and whether there are other underlying mechanisms still requires further investigation.

Inducing apoptosis represents a critical therapeutic mechanism for GC treatment. Apoptosis, a genetically regulated program of programmed cell death, is fundamental to maintaining normal physiological balance and internal environmental stability in the body (D'Arcy, 2019). During the development of tumor, apoptotic mechanisms are often suppressed, leading to abnormal proliferation and survival of cancer cells (Kashyap et al., 2021).

Xia D. et al. demonstrated that AS-IV induces apoptosis in GC cells via the mitochondrial pathway. Mechanistically, AS-IV exerts direct effects on AGS cells, leading to decline of mitochondrial membrane potential, increased mitochondrial membrane permeability, and subsequent release of cytochrome C from mitochondria into the cytosol. This initiates a cascade of events culminating in the activation of caspase family proteases (Caspase-3, Caspase-7, and Caspase-9) via proteolytic cleavage, ultimately driving apoptotic cell death (Xia et al., 2023). Notably, caspase-3 serves as a central executor of mitochondrial apoptosis in this context (Eskandari and Eaves, 2022).

AS-IV further modulates the mitochondrial pathway through regulation of B-cell lymphoma 2 (Bcl-2) family proteins, which comprise anti-apoptotic (e.g., Bcl-2, B-cell lymphoma-extra large [Bcl-xL])and pro-apoptotic (e.g., Bcl-2 associated X protein [Bax], Bcl-2 homologous antagonist/killer [Bak]) members that play pivotal roles in apoptotic regulation (Campbell and Tait, 2018). Experimental evidence demonstrates that AS-IV upregulates Bax expression while downregulating Bcl-2, resulting in an elevated Bax/Bcl-2 ratio. This shift in protein balance promotes mitochondrial outer membrane permeabilization (MOMP) and subsequent release of apoptotic factors, thereby amplifying the apoptotic response (Zhao et al., 2019) (Figure 2).

There is a close mechanistic connection between cell proliferation and apoptosis, and the two together constitute an important pathway for its anti-GC effect. For example, proliferation inhibition creates conditions for apoptosis induction, while apoptosis induction strengthens the effect of proliferation inhibition. This is specifically manifested in the formation of a synergistic network through mechanisms such as cell cycle regulation, cross-talk of signaling pathways, and mitochondrial dysfunction. This dual action mode of “inhibition-clearance” demonstrates unique advantages in anti-GC research, providing a theoretical basis for the development of anti-tumor strategies based on AS-IV.

Autophagy, a conserved programmed catabolic process, enables cells to degrade intracellular components—including damaged organelles, misfolded proteins, and intracellular pathogens—via lysosomal machinery, serving as a fundamental mechanism for maintaining cellular homeostasis and adapting to stress stimuli (Debnath et al., 2023). In the context of GC development, autophagy acts as a “double-edged sword,” with its effects depending on the tumor microenvironment (TME) and genetic background. Among these, Autophagy-related Protein 1 (Ambra1), an important marker of the autophagic process (Li X. et al., 2022). It promotes the formation of class III PI3KC3 complexes by interacting with Beclin1 and Vps34/PI3KC3, thereby mediating the initial steps of autophagosome formation. In subsequent phases, autophagy-related genes (ATGs) such as ATG5, ATG7, ATG10, ATG12, and ATG16 drive autophagosomal membrane expansion, promoting autophagosome maturation and contributing to GC progression (Wang et al., 2021).

Cai T. et al. reported that AS-IV modulates autophagy through regulation of the Ambra1/Beclin1 complex, reducing both protein expression of Ambra1 and Beclin1 in tumor-bearing rat models and thereby exerting protective effects on gastric mucosa. Mechanistic analyses revealed that AS-IV significantly suppresses mRNA expression of ATG5, ATG12, and other core autophagy genes, providing direct evidence that autophagic gene networks are critical regulators of autophagic flux and GC progression (Cai et al., 2018). Notably, however, a potential caveat exists: excessive AS-IV exposure may paradoxically induce cytoprotective autophagy in tumor cells, enabling their survival via stress adaptation mechanisms. This risk may not only lead to the survival of tumor cells but also induce their proliferation. We believe that the “contradictory nature” of autophagy essentially stems from the adaptive response of its dynamic regulatory network to different physiological and pathological signals. This risk may not only lead to the survival of tumor cells but also induce proliferation. We believe that the “paradoxical” nature of autophagy is the adaptive response of its dynamic regulatory network to different physiological and pathological signals. This characteristic poses challenges for research and treatment. In the future, it is necessary to deeply analyze the key regulatory nodes of autophagy in specific environments to achieve precise intervention in the paradox of autophagy and promote its application in disease treatment.

Pyroptosis is an inflammatory form of programmed cell death mediated by inflammasome activation, characterized by plasma membrane pore formation, cell swelling and rupture, and the release of pro-inflammatory cytokines (such as Interleukin-1 beta [IL-1β]and Interleukin-18 [IL-18]) (Rao et al., 2022). It plays a critical role in pathological processes including infections, inflammatory diseases, and tumors. Emerging research in recent years has highlighted the substantial potential of AS-IV in leveraging pyroptotic mechanisms for tumor therapy (You et al., 2025). The canonical pyroptotic pathway involves regulation of caspase family proteins, enhancement of Caspase-1 expression or activity, and direct promotion of Gasdermin D (GSDMD) cleavage and inflammatory factor release (Makoni and Nichols, 2021).

Multiple studies have confirmed that AS-IV exerts dual mechanisms to induce pyroptosis. On one hand, it significantly increases Caspase-1 expression and activation, leading to GSDMD cleavage and initiation of pyroptosis (Li C. et al., 2023). On the other hand, it upregulates ROS levels to trigger and activate the NLRP3 inflammasome, which recruits and activates Caspase-1. This cascade results in the release of large quantities of mature IL-1β and IL-18, inducing inflammatory responses that drive pyroptotic cell death (Zhang et al., 2022; Fu and Wu, 2023). Collectively, these studies unravel the pyroptosis-inducing mechanisms of AS-IV and provide mechanistic validation for its role in suppressing GC progression via pyroptosis.

The pyroptosis and apoptosis of GC cells induced by AS-IV are centered on “inflammatory rupture” and “non-inflammatory autophagy” in mechanisms, respectively. The former relies on the caspase-1/GSDMD pathway accompanied by strong immune activation, while the latter achieves precise cell clearance through the caspase cascade reaction. The synergistic effect of the two may provide new strategies for the treatment of GC, but further studies on the selective regulatory mechanisms in different subtypes of GC (such as microsatellite instability type and HER2-positive type) are required to optimize clinical applications.

Tumor growth and metastatic dissemination are inherently dependent on neovascularization, a process by which nascent blood vessels supply tumor cells with essential nutrients, oxygen, and metastatic routes (Qian et al., 2016). Inhibiting tumor angiogenesis represents a key therapeutic mechanism of TCM in GC treatment, whereby TCM metabolites suppress tumor growth and metastasis by blocking angiogenesis-related factors, and depriving tumors of nutrient supply. AS-IV is a representative agent in this context.

Vascular endothelial growth factor (VEGF), a prototypical pro-angiogenic cytokine, exerts pleiotropic effects on vascular endothelial cells, including promotion of proliferation, migration, and survival, ultimately driving neovascularization (Khodabakhsh et al., 2021). Elevated VEGF expression in GC tissues correlates significantly with tumor progression, metastatic burden, and adverse clinical outcomes (Macedo et al., 2017). Experimental evidence demonstrates that AS-IV potently reduces intratumoral VEGF levels, concomitantly downregulating both protein and mRNA expression of matrix metalloproteinase-2 (MMP-2) and fibroblast growth factor 2 (FGF-2). These actions collectively impede tumor cell invasion, metastatic dissemination, and angiogenic sprouting (Zhang et al., 2017).

Notably, AS-IV has been shown to modulate both angiogenic and immune regulatory pathways. In a recent study, AS-IV enhanced antitumor immunity while suppressing angiogenesis by upregulating miR-195-5p and reducing programmed death-ligand 1 (PD-L1) expression in SGC7901 and MGC803 cell lines. This dual activity inhibits cell proliferation, epithelial-mesenchymal transition (EMT), and neovascularization (Liu et al., 2021). This study introduces a novel therapeutic strategy for GC: combination therapy with AS-IV and PD-1 inhibitors, offering promising insights for clinical translation.

The immune system orchestrates a multifaceted role in tumor initiation, progression, and clinical outcome (Humphrey, 1971). Under physiological homeostasis, immunosurveillance mechanisms effectively eliminate transformed cells. But, chronic immune suppression permits cancer cells to evade detection, fostering uncontrolled proliferation and metastatic dissemination in tumor contexts (Ma et al., 2017). This immune evasion is intrinsically linked to dysregulation of the TME, a complex ecosystem characterized by dynamic crosstalk between fibroblasts and immune cell subsets (Anderson and Simon, 2020). Emerging evidence highlights bidirectional regulatory networks between fibroblasts and immune cells, which collectively govern tumor immunosurveillance and clearance (Di et al., 2024).

A defining feature of the TME is the “education” of normal fibroblasts into cancer-associated fibroblasts (CAFs), which exhibit striking heterogeneity and functional plasticity. As dominant stromal effectors, CAFs drive tumor progression by promoting cell proliferation, orchestrating immune escape pathways, inducing EMT, and mediating therapeutic resistance (Minoura et al., 2025; Song et al., 2025; Cao et al., 2025). Wang ZF et al. demonstrated that AS-IV induces microRNA reprogramming in gastric CAFs (GCAFs), specifically upregulating miR-214 and downregulating miR-301a expression in BGC-823-derived GCAFs. This epigenetic modulation abrogates pathological GCAF functions and reconfigures TME architecture (Wang et al., 2017). Concurrently, independent studies reveal that AS-IV suppresses the HOXA6/ZBTB12 transcriptional axis in GCAFs, reducing HOXA6 and ZBTB12 expression to attenuate GC cell malignancy and normalize TME composition (Liu et al., 2023). Collectively, these findings validate the TME as a critical therapeutic target in GC (Xiao and Yu, 2021). And they highlight AS-IV-mediated TME modulation as a promising new direction for GC therapy.

Based on the above discussions, we hypothesize that AS-IV regulates the TME through a network interaction of “anti-angiogenesis-programmed cell death-immune/stromal remodeling”. Its anti-angiogenic effect enhances the sensitivity of tumor cells to apoptosis/pyroptosis by improving the hypoxic microenvironment and reducing nutrient supply; in turn, factors released by programmed cell death (such as inflammatory factors and apoptotic bodies) affect angiogenesis and immune cell recruitment. This multi-target synergistic effect provides new therapeutic ideas for remodeling the TME, but preclinical studies are needed to clarify its selective regulatory mechanisms for different TME subtypes to achieve precise treatment. Meanwhile, various in vivo and in vitro experiments should continue to be conducted to corroborate this approach.

Ferroptosis is an oxidative cell death triggered by the excessive accumulation of iron-dependent lipid peroxides in the cell membrane, characterized by mitochondrial shrinkage, increased membrane density, and the absence of typical inflammatory responses. It is closely associated with glutathione (GSH) depletion and inhibition of glutathione peroxidase 4 (GPX4) activity, playing a critical role in pathological processes such as neurodegenerative diseases, cancer, and ischemia-reperfusion injury (Jiang et al., 2021).

Hepatic injury represents a common complication of cisplatin, a first-line chemotherapeutic agent for GC (Rha et al., 2023). Increasing evidence implicates ferroptosis—a non-apoptotic, iron-dependent form of lipid peroxidation-driven cell death—as a central executor of cisplatin-induced liver injury. Ferroptosis has therefore emerged as a promising strategy to mitigate chemotherapy-associated hepatotoxicity.

Guo J. et al. demonstrated that AS-IV potently alleviates cisplatin-induced hepatic injury, systemic inflammation, and oxidative stress. Mechanistically, AS-IV restores expression of glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1), two critical regulators of anti-ferroptotic defense, while significantly inhibiting iron-dependent lipid peroxidation and ferroptotic cell death (Guo et al., 2024). Correlative analyses revealed a strong positive correlation between ferroptotic activity and hepatic injury severity, such that enhanced lipid peroxidation correlates with exacerbated liver damage. These findings collectively establish AS-IV as an effective protector against cisplatin hepatotoxicity through ferroptosis inhibition. Meanwhile, they highlight its translational potential in managing ferroptosis-mediated complications of GC treatment. Some scholars believe that AS-IV’s inhibition of ferroptosis has certain interactive relationships with other forms of programmed cell death, such as synergism with apoptosis and antagonism with pyroptosis. However, the limitation is that these hypotheses all require further experimental verification.

Inflammation is intricately woven into the entire spectrum of GC initiation and progression, forming a complex bidirectional relationship characterized by mutual promotion (Jaroenlapnopparat et al., 2022). On one hand, chronic inflammation serves as a key initiator of gastric carcinogenesis. Through activation of canonical signaling pathways such as NF-κB and JAK-STAT, chronic inflammation induces gastric mucosal injury, aberrant cell proliferation, and premalignant lesions, ultimately culminating in GC. On the other hand, inflammatory responses within the TME act as accomplices in cancer progression. Pro-tumorigenic inflammatory cells release cytokines such as IL-6 and TNF-α, which promote tumor cell proliferation, invasion, and immune evasion while exacerbating chemoresistance and immunotherapy resistance.

More and more studies have demonstrated significant anti-inflammatory properties of AS-IV (Liang et al., 2023). The NF-κB pathway, a classical regulator of inflammation, represents a central target of AS-IV’s anti-inflammatory effects. A meta-analysis has shown that AS-IV potently suppresses the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) mediated by the NF-κB signaling axis, thereby alleviating tissue structural and functional damage (Li L. et al., 2023). These findings underscore the therapeutic potential of targeting inflammatory pathways with AS-IV for both gastritis management and primary prevention of GC, bridging the gap between anti-inflammatory pharmacology and oncology prevention.

As previously mentioned, Helicobacter pylori is a major cause of GC. Eradication of H. pylori can effectively reduce the incidence of GC and GC-related mortality, particularly in East Asian countries (Ford et al., 2020). The potential advantage of AS-IV lies in its multi-target inhibition of H. pylori infection and reduction of GC risk. It can regulate the host immune-inflammatory response, reduce the release of pro-inflammatory cytokines, and alleviate inflammatory damage to the gastric mucosa. By indirectly inhibiting the survival microenvironment of H. pylori, it effectively blocks the pathological process of “infection-inflammation-carcinogenesis”. Chronic atrophic gastritis (CAG) is a chronic inflammatory condition triggered by H. pylori infection. Its persistent progression can evolve into GC through pathological processes such as intestinal metaplasia and dysplasia, serving as a critical intermediate link between H. pylori infection and GC (Tran et al., 2024).

Duan B et al. demonstrated through in vivo and in vitro experiments that AS-IV exerts protective effects on the gastric mucosa in CAG rats by activating the thrombin/Protease-Activated Receptor 1 (PAR-1) signaling pathway, inhibiting NF-κB p65 phosphorylation, and reducing the expression of cyclooxygenase-2 (COX-2) and inflammatory cytokines (TNF-α, IL-6, etc.), thereby alleviating gastric mucosal injury (Duan et al., 2025). This study provides a theoretical basis for the application of AS-IV in the treatment of CAG, yet the specific action targets and long-term efficacy still require further investigation. Additionally, another study has shown that TCM formulas containing AS-IV can effectively increase the proliferation rate of GES-1 cells, inhibit apoptosis, and exhibit significant anti- H. pylori activity (Hu et al., 2022). However, current related research is mostly limited to in vitro cell experiments or animal models, lacking support from large-sample clinical data. The specific action targets, effective dosage, and long-term intervention effects in humans remain unclear, urgently requiring more high-quality studies to reveal its complete mechanism.

Despite significant progress, the majority of AS-IV studies in GC remain preclinical, with limited clinical translation (Chen et al., 2021). Many investigations rely heavily on in vitro models, which fail to recapitulate the complexity of the TME or predict human pharmacodynamics. To address this, interdisciplinary approaches integrating in vitro/in vivo models and clinical trials are urgently needed to provide robust mechanistic validation and therapeutic efficacy data.

Although various studies have reported the therapeutic doses of AS-IV, there is relatively little attention paid to its toxicity. Existing studies have shown that AS-IV has no obvious toxicity or adverse reactions. For example, Xuying W et al. intravenously injected AS-IV into SD rats at doses of 0.25, 0.5, and 1.0 mg/kg per day before mating for 4 consecutive weeks, continuing until the 6th day of pregnancy in females, to evaluate the fertility and early embryonic developmental toxicity of the rats. In addition, the perinatal toxicity of the rats was evaluated from gestational day (GD) 15–21 and lactation day (LD) 1–21. The results showed that AS-IV did not detect toxicity in the maternal body of rats in the range of 0.25–1.0 mg/kg. Further results showed that compared with the control group, maternal exposure to a dose of 1.0 mg/kg per day would have a certain inhibitory effect on the fur development of the pups, but it would not affect the memory and learning of the pups (Xuying et al., 2010). This study systematically evaluated the acute toxicity, maternal toxicity, embryotoxicity, and fetotoxicity of AS-IV, proving its safety. However, it must be pointed out that there are few clinical studies on AS-IV, and there is a lack of long-term toxicity data, long-term clinical outcome tracking, and follow-up. Especially now that the combination of AS-IV with chemotherapy and immunotherapy for GC has become a popular trend. But whether this model will produce toxic and side effects still requires more experiments to prove its safety.

Oral administration of AS-IV is hindered by its low absolute bioavailability (7.4%), attributed to poor intestinal permeability, high molecular weight, and low lipophilicity (Zhang et al., 2007). Innovative strategies are required to enhance systemic exposure: First, Nanotechnology-based Drug Delivery. Development of novel formulations, such as nanoparticles or hydrogels, can improve bioavailability and enable targeted delivery. The unique physicochemical properties of AS-IV provide a theoretical basis for the development of nano-formulations for GC biological barriers. The amphiphilic structure of AS-IV endows it with a balance of water solubility and lipid solubility, which helps to achieve solubilization and targeted delivery through nanocarriers. Its stable glycosidic bond structure exhibits good chemical stability in physiological environments, ensuring the integrity of nano-formulations during in vivo circulation. Based on the surface activity and intermolecular forces of AS-IV, technologies such as nanoprecipitation and emulsion solvent evaporation can be used to precisely regulate the particle size, surface charge, and morphology of nanoparticles, enabling them to effectively penetrate the physiological barriers of GC tissues. Meanwhile, leveraging its potential bioadhesion and specific interactions with the TME, a nano-delivery system with both active targeting and barrier regulation functions can be constructed to achieve efficient enrichment and sustained release of drugs at the site of GC. For example, Li X. et al. designed a pH-responsive hydrogel incorporating AS-IV-loaded nanoparticles to sustain drug release and induce ferroptosis in tumor cells (Li X. et al., 2025). Second, Gut Microbiome Modulation. Leveraging gut lactobacilli to enhance AS-IV metabolism represents a promising avenue, as intestinal microbiota play a critical role in its absorption and activation.

Finally, with ongoing mechanistic elucidation and technological innovation, AS-IV holds substantial promise for GC therapy. Addressing current limitations through multidisciplinary collaboration—including pharmacokinetics, nanomedicine, and clinical oncology—will accelerate its translation into evidence-based clinical applications, offering new hope for patients with this devastating disease.