Gastric adenocarcinoma is a highly aggressive malignancy characterized by a complex tumor microenvironment. Nano-curcumin liposomes hold great potential in inhibiting tumor growth and survival, as well as inducing cuproptosis and oxidative stress. Although the anticancer properties of curcumin have been demonstrated, the specific mechanisms by which curcumin inhibites gastric adenocarcinoma through cuproptosis remains unclear. This study investigated how nano-curcumin liposomes mediated the inhibition of gastric adenocarcinoma cell proliferation and survival via cuproptosis.This study utilized the gastric adenocarcinoma cell line AGS to establish 2D and 3D in vitro gastric adenocarcinoma models. Furthermore, we prepared nano-curcumin liposomes to investigate their effects and regulatory mechanisms on AGS gastric adenocarcinoma models. A series of in vitro assays, including flow cytometry, CCK-8, scratch assays and morphological assessments, were performed to evaluate the effects of nano-curcumin liposomes on cell apoptosis, proliferation and migration. Additionally, bioinformatics and machine learning methods were employed to identify key targets that inhibited gastric adenocarcinoma growth and survival associated with nano-curcumin liposomes, which were further validated through RT-qPCR and omics analysis. Computer simulations were also conducted to assess the stability of binding interactions between curcumin and key target proteins.Cellular experiments demonstrated that nano-curcumin liposomes significantly inhibited proliferation and invasive capacity of gastric adenocarcinoma cells while promoting cellular oxidative stress. Bioinformatics and machine learning analyses identified FDX1, GPX4, SERPINE1 and SLC27A5 as key targets. RT-qPCR results confirmed that nano-curcumin liposomes significantly downregulated the expression of these targets. Molecular dynamics simulations indicated that curcumin could form stable binding interactions with key protein targets.This study revealed that nano-curcumin liposomes inhibited growth and survival of gastric adenocarcinoma cells by interfering with the expression of FDX1, GPX4, SERPINE1 and SLC27A5, which were closely linked to copper-induced oxidative stress. Nano-curcumin liposomes downregulated the expression of FDX1 and GPX4, disrupted mitochondrial energy metabolism, and induced oxidative stress, thereby promoting tumor-associated programmed cell death linked to cuproptosis. Furthermore, by downregulating SERPINE1, nano-curcumin liposomes modulated cell adhesion and migration, inhibiting the invasive and metastatic potential of tumor cells. Finally, downregulation of SLC27A5 altered tumor metabolism and cellular homeostasis, induced oxidative stress, and disrupted intracellular environmental stability, thereby suppressing the growth of gastric adenocarcinoma.Copyright © 2025 Elsevier B.V. All rights reserved.