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This study investigated the anti-malignant effects and molecular mechanisms of glabridin (GLA), a licorice-derived flavonoid, in esophageal cancer. The effects of glabridin on the esophageal cancer cell lines KYSE150 and TE1 were evaluated using CCK-8 assays, colony formation assays, wound-healing assays, and flow cytometry. A systematic analysis was further conducted by integrating RNA sequencing, multi-platform pharmacological prediction, protein-protein interaction (PPI) network analysis, Western blot (WB) validation, molecular docking, cellular thermal shift assay (CETSA) and database mining. Glabridin concentration dependently suppressed cell viability, with 48-hour IC50 values of 37.85 and 20.00 μmol·L-1 in KYSE150 and TE1 cells, respectively. Notably, 5 μmol·L-1 inhibited colony formation, while 20 μmol·L-1 induced G0/G1 arrest (59.99% and 56.68% of cells) and reduced 24-hour migration rates to 30% and 25% (P < 0.000 1). Transcriptomics identified 2 104 differentially expressed genes enriched in ferroptosis, autophagy, and cell cycle pathways. Integrated analysis filtered 66 core targets. PPI network topology revealed cyclin A2 (CCNA2), heat shock protein 90 alpha family class A member 1 (HSP90AA1), cyclin-dependent kinase 2 (CDK2), and mechanistic target of rapamycin kinase (MTOR) as hub genes, with CCNA2 and HSP90AA1 synergizing with obesity to affect prognosis in TCGA esophageal cancer cohorts. WB confirmed downregulation of CCNA2, CDK2, cyclin-dependent kinase 1 (CDK1), snail family transcriptional repressor 2 (SNAI2), and phosphorylated protein kinase B (p-AKT), whereas HSP90AA1 protein levels remained unchanged. Molecular docking demonstrated stable binding of glabridin to the CCNA2 active pocket via hydrogen bonding, π-alkyl, and π-anion interactions. CETSA demonstrated that glabridin enhanced CCNA2 thermal stability, and the proteasome inhibitor MG132 blocked glabridin-induced CCNA2 degradation. DepMap and LinkedOmics Database analyses revealed that CCNA2 promotes esophageal cancer cell proliferation and is associated with cell cycle progression. Collectively, glabridin suppresses esophageal cancer cell proliferation and migration, potentially through modulation of the cell cycle and epithelial-mesenchymal transition (EMT) processes, and CCNA2 may represent a promising therapeutic target for esophageal cancer.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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