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In recent years, polysaccharides with potential anticancer activity have attracted widespread attention. In this study, a homogeneous polysaccharide fraction, PEP-3 (102.35 kDa), was extracted and purified from the fruit of Phyllanthus emblica L. Structural analysis revealed that its backbone consists of methylated and unmethylated α-1,4-GalpA residues at the C-6 position. O-2 at α-2,4-Rhap-1→ participates in backbone extension, while O-4 serves as a branch point for the Galp and Araf side chains. Through machine learning-based target screening, HSP90 was identified as the core therapeutic target of PEP-3 for stomach adenocarcinoma (STAD) treatment and an important biomarker for diagnosis and prognosis. Mechanistic studies showed that PEP-3 inhibits HSP90 activity, leading to AKT degradation and activation of the Caspase cascade. In vitro experiments showed that the combination of PEP-3 and 5-fluorouracil (5-Fu) (PEP-3 concentration 400 μg/mL, 5-Fu concentration 3.13 μg/mL) exhibited a considerable synergistic effect, markedly enhancing apoptosis, inducing cell cycle arrest, promoting ROS and Ca²⁺ overload, and aggravating mitochondrial damage. These results indicate that PEP-3 enhances the chemosensitivity of 5-Fu by targeting HSP90 and inducing apoptosis through multiple pathways, while simultaneously reducing the toxic side effects of 5-Fu. This highlights its potential as a natural sensitizer for the treatment of STAD.