Key Takeaways & Executive Findings
- •• • Morin at 100–400 μmol/L dose-dependently inhibited AGS cell proliferation (P<0.05, 0.01), with an IC50 of 214.28 μmol/L in HeLa cells, indicating moderate potency but favorable safety (no adverse effects at 300 mg/kg daily in animals). This positions morin as a low-toxicity alternative to synthetic PI3K inhibitors like LY294002, which suffer from poor solubility and off-target effects. • • Morin induced G0/G1 phase arrest and apoptosis, reducing G2/M phase cells, and downregulated PI3K/Akt pathway proteins (p85α, p110β, p-Akt) and cell cycle regulators (Bcl-2, CCND1, CDK4, CDK6) while upregulating Bax and p21 (P<0.05, 0.01). These molecular changes directly correlate with inhibition of malignant proliferation, offering a multi-target mechanism that may overcome resistance to single-target therapies. • • The PI3K agonist 740Y-P significantly reversed morin's anti-proliferative, pro-apoptotic, and cell cycle arrest effects (P<0.05, 0.01), confirming that morin's activity is mediated through PI3K/Akt pathway suppression. This validation provides a mechanistic basis for targeting PIK3R1, which is overexpressed in gastric cancer (GSE54129 dataset), as a therapeutic strategy. • • Molecular docking and dynamics simulations demonstrated high affinity and stable binding between morin and PIK3R1, with the complex maintaining structural integrity. This supports PIK3R1 as a direct target, distinguishing morin from other flavonoids and underscoring its potential for development as a PIK3R1-specific inhibitor with improved pharmacokinetics over wortmannin and LY294002.
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Abstract
This study integrates network pharmacology, molecular docking, and in vitro experiments to elucidate the anti-gastric cancer mechanism of morin, an active flavonoid from Mori Ramulus. Network analysis identified 178 potential targets of Mori Ramulus and 13,100 gastric cancer-related targets, with 159 intersecting targets. Enrichment analysis highlighted the PI3K/Akt pathway as a key mediator. Molecular docking and dynamics simulations confirmed stable binding between morin and PIK3R1, which is significantly overexpressed in gastric cancer tissues. In vitro, morin (100–400 μmol/L) dose-dependently inhibited AGS cell proliferation, induced G0/G1 phase arrest, and promoted apoptosis (P<0.05, 0.01). Western blotting revealed downregulation of PI3K/Akt pathway proteins (p85α, p110β, p-Akt) and cell cycle-related proteins (Bcl-2, CCND1, CDK4, CDK6), alongside upregulation of Bax and p21 (P<0.05, 0.01). Co-treatment with the PI3K agonist 740Y-P significantly reversed these effects (P<0.05, 0.01), confirming pathway dependence. These findings demonstrate that morin targets PIK3R1 to suppress PI3K/Akt signaling, thereby inhibiting proliferation and inducing apoptosis and cell cycle arrest in gastric cancer cells. The study underscores morin's potential as a natural, multi-target lead compound with low toxicity, though further validation in additional cell lines and gene-level manipulations is warranted.
1. Introduction
Gastric cancer remains a leading cause of cancer-related mortality worldwide, with advanced-stage patients facing poor prognosis due to limited treatment options and unclear molecular targets. Existing therapies, including synthetic PI3K inhibitors such as wortmannin and LY294002, have shown potent preclinical activity but failed in clinical translation due to poor solubility, unfavorable pharmacokinetics, and severe off-target toxicity. The PI3K/Akt pathway is frequently dysregulated in gastric cancer, driving proliferation, apoptosis resistance, and cell cycle progression, making it an attractive therapeutic target. However, the lack of safe and effective inhibitors that can modulate this pathway without systemic toxicity represents a critical bottleneck.
Natural flavonoids like morin, derived from Mori Ramulus, exhibit anti-tumor activity with minimal cytotoxicity, but their precise mechanisms in gastric cancer remain undefined. This study addresses the translational gap by integrating network pharmacology, molecular docking, and in vitro validation to identify PIK3R1 as a direct target of morin. By demonstrating that morin stabilizes PIK3R1 binding and suppresses PI3K/Akt signaling, leading to G0/G1 arrest and apoptosis in AGS cells, the research provides a mechanistic foundation for developing morin as a low-toxicity, multi-target therapeutic. The findings also highlight the need for further validation in additional cell lines and gene-level studies to confirm direct targeting and overcome current limitations in gastric cancer treatment.
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CUI Yutong, HE Li, LI Junjie, HOU Yi, BO Sihan, YOU Yong, LIU Lei, GAO Yaxian, WANG Yongwei (2026). Mechanism of Morin in Inhibiting Gastric Cancer Cells via Regulation of the PI3K/Akt Pathway. Chinese Traditional and Herbal Drugs. https://doi.org/10.7501/j.issn.0253-2670.2026.15.20261511
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Frequently Asked Questions
What is the binding affinity and stability of the morin-PIK3R1 complex, and how does it compare to synthetic PI3K inhibitors?
Molecular docking and dynamics simulations confirmed high binding affinity and structural stability of the morin-PIK3R1 complex, with sustained interactions over the simulation period. In contrast, synthetic inhibitors like LY294002 exhibit poor pharmacokinetics and off-target effects, while wortmannin has administration limitations. Morin's stable binding to PIK3R1, coupled with its low toxicity (no adverse effects at 300 mg/kg daily in animals), suggests a superior safety profile and potential for chronic administration.
What is the IC50 of morin in gastric cancer cells, and how does it impact scalability for clinical development?
The IC50 of morin in HeLa cells is 214.28 μmol/L, and in AGS cells, significant effects were observed at 100–400 μmol/L. This relatively high IC50 reflects morin's natural origin and mild activity, which may necessitate higher doses or prolonged treatment. However, its low cytotoxicity and ability to inhibit P-glycoprotein, enhancing intracellular chemotherapy concentrations without damaging normal cells, support further optimization through formulation or prodrug strategies to improve potency and scalability.
How does morin's mechanism of action differ from synthetic PI3K inhibitors, and what are the implications for overcoming resistance?
Morin targets PIK3R1 and modulates multiple downstream effectors (p85α, p110β, p-Akt, Bcl-2, CCND1, CDK4, CDK6, Bax, p21), whereas synthetic inhibitors like LY294002 primarily compete for the ATP-binding site of PI3K. This multi-target action may reduce the likelihood of resistance development. Additionally, morin's natural flavonoid structure allows for interactions with core PI3K sites distinct from synthetic inhibitors, as shown by molecular simulations, providing a differentiated mechanism that could complement existing therapies.
What are the limitations of the current study, and what steps are required for clinical translation?
The study is limited to AGS cells and lacks gene-level validation (e.g., siRNA knockdown or overexpression) to confirm direct PIK3R1 targeting. The relatively high IC50 and moderate potency also pose challenges for clinical translation. Future work should include additional gastric cancer cell lines and normal gastric epithelial cells to assess selectivity, in vivo efficacy and toxicity studies, and formulation optimization to enhance bioavailability. These steps are essential to establish morin as a viable therapeutic candidate.
How does morin's safety profile compare to existing PI3K inhibitors, and what is its potential for combination therapy?
Morin exhibits extremely low cytotoxicity, with animal studies showing no adverse effects at 300 mg/kg daily over long-term administration. In contrast, wortmannin and LY294002 have shown dose-limiting toxicities and poor pharmacokinetics. Morin's ability to inhibit P-glycoprotein and increase intracellular concentrations of chemotherapeutic agents without damaging normal cells suggests potential for combination therapy to enhance efficacy and reduce side effects. This positions morin as a promising adjunct to conventional gastric cancer treatments.
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