Research ArticleOriginal Article
Open Access

FDX1 expression promotes DSF/Cu-induced cuproptosis in gastric cancer cells

Qirong Li, Yi Guo, Jiahuan Yuan, Qiang Feng, Hengzong Zhou, Ming Hao, Boqiang Tao, Liqun Sun, Chao Lin, Jianfeng Mu, Gongliang Guo and Dongxu Wang
Cancer Biology & Medicine July 2026, 20250323; DOI: https://doi.org/10.20892/j.issn.2095-3941.2025.0323

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Figures

  • Part 1 demonstrates that synthesized DSF/Cu functions to promote cuproptosis in gastric cancer (GC) cells. In Part 2, the differentially expressed gene, WDR43, was screened by protein sequencing. WDR43 expression was shown to be related to FDX1 expression and decreased WDR43 expression inhibited the development of GC. Part 3 demonstrates that FDX1 overexpression enhanced the sensitivity of GC cells to DSF/Cu treatment and promoted the death of GC cells by reducing WDR43 expression. In Part 4, Cu-EXO was synthesized and shown to have a good effect on promoting the death of GC cells. In Part 5, after constructing a mouse model of GC and applying Cu-EXO for treatment, Cu-EXO was shown to have good therapeutic effects and biological safety. DSF, disulfiram; Cu-EXO, exosomes loaded with DSF/Cu.
    StudyFlow

    Part 1 demonstrates that synthesized DSF/Cu functions to promote cuproptosis in gastric cancer (GC) cells. In Part 2, the differentially expressed gene, WDR43, was screened by protein sequencing. WDR43 expression was shown to be related to FDX1 expression and decreased WDR43 expression inhibited the development of GC. Part 3 demonstrates that FDX1 overexpression enhanced the sensitivity of GC cells to DSF/Cu treatment and promoted the death of GC cells by reducing WDR43 expression. In Part 4, Cu-EXO was synthesized and shown to have a good effect on promoting the death of GC cells. In Part 5, after constructing a mouse model of GC and applying Cu-EXO for treatment, Cu-EXO was shown to have good therapeutic effects and biological safety. DSF, disulfiram; Cu-EXO, exosomes loaded with DSF/Cu.

  • Expression patterns of genes associated with cuproptosis in GC cells. (A) Cell proliferation after DSF/Cu treatment was detected by CCK-8 (n = 3). (B) The clonogenesis ability of 1 μM DSF/Cu-treated cells for 24 h was detected by a plate cloning experiment (n = 3) and statistical analysis of plate cloning results (scale bar, 10 mm). (C) Immunofluorescence assay (n = 3) was used to detect oligomerization of DLAT in cells treated with 1 μM DSF/Cu for 24 h (scale bar, 50 μm). (D) Western blot detection of FDX1 and DLAT gene expression levels in GES1, AGS, and MKN45 cells (n = 3). (E) Statistical analysis of western blot. (F) qPCR was used to detect the levels of FDX1, DLAT, and LIAS gene expression in GES1, AGS, and MKN45 cells (n = 3). (G) The levels of LC3A, LC3B, PINK1, P62, BECLIN, and PARKIN gene expression in GC-and DSF/Cu-treated GC cells were detected by qPCR (n = 3). (H) The levels of GPX4, ACSL4, SLC7A11, NOX1, ALOX15, and FTH1 gene expression in GC-and DSF/Cu-treated GC cells were detected by qPCR (n = 3). (I) qPCR was used to detect the levels of P53, BAX, BCL2, and CASPASE3 gene expression in GC-and DSF/Cu-treated GC cells (n = 3). Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, indicating statistically significant differences.
    Expression patterns of genes associated with cuproptosis in GC cells. (A) Cell proliferation after DSF/Cu treatment was detected by CCK-8 (n = 3). (B) The clonogenesis ability of 1 μM DSF/Cu-treated cells for 24 h was detected by a plate cloning experiment (n = 3) and statistical analysis of plate cloning results (scale bar, 10 mm). (C) Immunofluorescence assay (n = 3) was used to detect oligomerization of DLAT in cells treated with 1 μM DSF/Cu for 24 h (scale bar, 50 μm). (D) Western blot detection of FDX1 and DLAT gene expression levels in GES1, AGS, and MKN45 cells (n = 3). (E) Statistical analysis of western blot. (F) qPCR was used to detect the levels of FDX1, DLAT, and LIAS gene expression in GES1, AGS, and MKN45 cells (n = 3). (G) The levels of LC3A, LC3B, PINK1, P62, BECLIN, and PARKIN gene expression in GC-and DSF/Cu-treated GC cells were detected by qPCR (n = 3). (H) The levels of GPX4, ACSL4, SLC7A11, NOX1, ALOX15, and FTH1 gene expression in GC-and DSF/Cu-treated GC cells were detected by qPCR (n = 3). (I) qPCR was used to detect the levels of P53, BAX, BCL2, and CASPASE3 gene expression in GC-and DSF/Cu-treated GC cells (n = 3). Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, indicating statistically significant differences.
    Figure 1

    Expression patterns of genes associated with cuproptosis in GC cells. (A) Cell proliferation after DSF/Cu treatment was detected by CCK-8 (n = 3). (B) The clonogenesis ability of 1 μM DSF/Cu-treated cells for 24 h was detected by a plate cloning experiment (n = 3) and statistical analysis of plate cloning results (scale bar, 10 mm). (C) Immunofluorescence assay (n = 3) was used to detect oligomerization of DLAT in cells treated with 1 μM DSF/Cu for 24 h (scale bar, 50 μm). (D) Western blot detection of FDX1 and DLAT gene expression levels in GES1, AGS, and MKN45 cells (n = 3). (E) Statistical analysis of western blot. (F) qPCR was used to detect the levels of FDX1, DLAT, and LIAS gene expression in GES1, AGS, and MKN45 cells (n = 3). (G) The levels of LC3A, LC3B, PINK1, P62, BECLIN, and PARKIN gene expression in GC-and DSF/Cu-treated GC cells were detected by qPCR (n = 3). (H) The levels of GPX4, ACSL4, SLC7A11, NOX1, ALOX15, and FTH1 gene expression in GC-and DSF/Cu-treated GC cells were detected by qPCR (n = 3). (I) qPCR was used to detect the levels of P53, BAX, BCL2, and CASPASE3 gene expression in GC-and DSF/Cu-treated GC cells (n = 3). Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, indicating statistically significant differences.

  • Protein sequencing analysis of GC cells treated with DSF/Cu. (A) Volcano map analysis of differentially expressed proteins. (B) Protein domain enrichment analysis of biological process. (C) Protein domain enrichment analysis of cellular component. (D) GO annotation analysis. (E) COG/KOG functional classification analysis. (F) Prediction of the prognostic correlation between FDX1 and WDR43 in patients with GC. (G) Bioinformatics analysis predicts the expression of differentially expressed genes in GC tissues. (H) The level of WDR43 expression in GES1, AGS, and MKN45 cells was detected by qPCR (n = 3). (I) qPCR was used to detect the expression of WDR43 in GC cells and 1 μM DSF/Cu-treated GC cells (n = 3). (J) Western blot analysis of WDR43 expression in GES1, AGS, and MKN45 cells (n = 3). (K) Statistical analysis of western blot. Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 indicated statistically significant differences.
    Protein sequencing analysis of GC cells treated with DSF/Cu. (A) Volcano map analysis of differentially expressed proteins. (B) Protein domain enrichment analysis of biological process. (C) Protein domain enrichment analysis of cellular component. (D) GO annotation analysis. (E) COG/KOG functional classification analysis. (F) Prediction of the prognostic correlation between FDX1 and WDR43 in patients with GC. (G) Bioinformatics analysis predicts the expression of differentially expressed genes in GC tissues. (H) The level of WDR43 expression in GES1, AGS, and MKN45 cells was detected by qPCR (n = 3). (I) qPCR was used to detect the expression of WDR43 in GC cells and 1 μM DSF/Cu-treated GC cells (n = 3). (J) Western blot analysis of WDR43 expression in GES1, AGS, and MKN45 cells (n = 3). (K) Statistical analysis of western blot. Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 indicated statistically significant differences.
    Figure 2

    Protein sequencing analysis of GC cells treated with DSF/Cu. (A) Volcano map analysis of differentially expressed proteins. (B) Protein domain enrichment analysis of biological process. (C) Protein domain enrichment analysis of cellular component. (D) GO annotation analysis. (E) COG/KOG functional classification analysis. (F) Prediction of the prognostic correlation between FDX1 and WDR43 in patients with GC. (G) Bioinformatics analysis predicts the expression of differentially expressed genes in GC tissues. (H) The level of WDR43 expression in GES1, AGS, and MKN45 cells was detected by qPCR (n = 3). (I) qPCR was used to detect the expression of WDR43 in GC cells and 1 μM DSF/Cu-treated GC cells (n = 3). (J) Western blot analysis of WDR43 expression in GES1, AGS, and MKN45 cells (n = 3). (K) Statistical analysis of western blot. Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 indicated statistically significant differences.

  • Effects of FDX1 overexpression on GC cells. (A) qPCR was used to detect the level of FDX1 gene expression in overexpressed FDX1 GC cells (n = 3). (B) CCK-8 detected the proliferation of non-treated GC cells (CON), GC cells overexpressing FDX1 (+FDX1), GC cells treated with 1 μM DSF/Cu for 24 h, and GC cells overexpressing FDX1 and treated with DSF/Cu [Cu + FDX1] (n = 3). (C) Western blot analysis of the levels of FDX1, WDR43, and DLAT in FDX1 overexpressed GC cells (n = 3). (D) Scratch healing assay to detect cell migration (n = 3) (scale bar, 500 μm). (E) Statistical analysis of the results of scratch healing experiments (n = 3). (F) Invasion assay to detect the invasion ability of cells (n = 3) (scale bar, 100 μm). (G) Statistical analysis of the results of invasion experiments (n = 3). (H) Cell cycle was measured by flow cytometry (n = 3). (I) Statistical analysis of cell cycle test results (n = 3). Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, indicating statistically significant differences.
    Figure 3

    Effects of FDX1 overexpression on GC cells. (A) qPCR was used to detect the level of FDX1 gene expression in overexpressed FDX1 GC cells (n = 3). (B) CCK-8 detected the proliferation of non-treated GC cells (CON), GC cells overexpressing FDX1 (+FDX1), GC cells treated with 1 μM DSF/Cu for 24 h, and GC cells overexpressing FDX1 and treated with DSF/Cu [Cu + FDX1] (n = 3). (C) Western blot analysis of the levels of FDX1, WDR43, and DLAT in FDX1 overexpressed GC cells (n = 3). (D) Scratch healing assay to detect cell migration (n = 3) (scale bar, 500 μm). (E) Statistical analysis of the results of scratch healing experiments (n = 3). (F) Invasion assay to detect the invasion ability of cells (n = 3) (scale bar, 100 μm). (G) Statistical analysis of the results of invasion experiments (n = 3). (H) Cell cycle was measured by flow cytometry (n = 3). (I) Statistical analysis of cell cycle test results (n = 3). Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, indicating statistically significant differences.

  • Effect of FDX1 knockout on GC cells. (A) qPCR was used to detect the level of FDX1 gene in GC expression cells with FDX1 knockout (n = 3). (B) CCK-8 detected the proliferation of normal GC cells (CON), GC cells knocked out FDX1 (KOFDX1), GC cells treated with 1 μM DSF/Cu for 24 h, and GC cells knocked out FDX1, then treated with DSF/Cu [Cu + KOFDX1] (n = 3). (C) Western blot detection of the levels of WDR43 and DLAT in GC cells after FDX1 knockout (n = 3). (D) Scratch healing assay to detect cell migration (n = 3) (scale bar, 500 μm). (E) Statistical analysis of the results of scratch healing experiments (n = 3). (F) Invasion assay to detect the invasion ability of cells (n = 3) (scale bar, 100 μm). (G) Statistical analysis of the results of invasion experiments (n = 3). (H) Cell cycle was measured by flow cytometry (n = 3). (I) Statistical analysis of cell cycle test results (n = 3). Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001, indicating statistically significant differences.
    Figure 4

    Effect of FDX1 knockout on GC cells. (A) qPCR was used to detect the level of FDX1 gene in GC expression cells with FDX1 knockout (n = 3). (B) CCK-8 detected the proliferation of normal GC cells (CON), GC cells knocked out FDX1 (KOFDX1), GC cells treated with 1 μM DSF/Cu for 24 h, and GC cells knocked out FDX1, then treated with DSF/Cu [Cu + KOFDX1] (n = 3). (C) Western blot detection of the levels of WDR43 and DLAT in GC cells after FDX1 knockout (n = 3). (D) Scratch healing assay to detect cell migration (n = 3) (scale bar, 500 μm). (E) Statistical analysis of the results of scratch healing experiments (n = 3). (F) Invasion assay to detect the invasion ability of cells (n = 3) (scale bar, 100 μm). (G) Statistical analysis of the results of invasion experiments (n = 3). (H) Cell cycle was measured by flow cytometry (n = 3). (I) Statistical analysis of cell cycle test results (n = 3). Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001, indicating statistically significant differences.

  • Effect of WDR43 knockdown on GC cells. (A) Western blot detection of WDR43 protein expression in GC cells with WDR43 knockdown (n = 3). (B) Statistical analysis of western blot. (C) CCK-8 detected the proliferation of non-treated GC (CON) and GC cells (siWDR43) after knocking down WDR43 (n = 3). (D) Invasion assay to detect the invasion ability of cells (n = 3) (scale bar, 100 μm). (E) Statistical analysis of the results of the invasion experiment (n = 3). (F) Scratch healing assay to detect cell migration (n = 3) (scale bar, 500 μm). (G) Statistical analysis of the results of scratch healing experiments (n = 3). (H) Cell cycle was measured by flow cytometry (n = 3). (I) Statistical analysis of cell cycle test results (n = 3). (J) Western blot analysis was performed to detect the levels of CDK2, cyclinD-1, and DLAT gene expression in GC cells with FDX1 knockout (n = 3). (K) Statistical analysis of western blot. Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, indicating statistically significant differences.
    Figure 5

    Effect of WDR43 knockdown on GC cells. (A) Western blot detection of WDR43 protein expression in GC cells with WDR43 knockdown (n = 3). (B) Statistical analysis of western blot. (C) CCK-8 detected the proliferation of non-treated GC (CON) and GC cells (siWDR43) after knocking down WDR43 (n = 3). (D) Invasion assay to detect the invasion ability of cells (n = 3) (scale bar, 100 μm). (E) Statistical analysis of the results of the invasion experiment (n = 3). (F) Scratch healing assay to detect cell migration (n = 3) (scale bar, 500 μm). (G) Statistical analysis of the results of scratch healing experiments (n = 3). (H) Cell cycle was measured by flow cytometry (n = 3). (I) Statistical analysis of cell cycle test results (n = 3). (J) Western blot analysis was performed to detect the levels of CDK2, cyclinD-1, and DLAT gene expression in GC cells with FDX1 knockout (n = 3). (K) Statistical analysis of western blot. Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, indicating statistically significant differences.

  • DSF/Cu loaded into NK cell exosomes for the treatment of GC cells. (A) The morphology of NK cell exosomes was observed under transmission electron microscopy (scale bar, 200 nm). (B) Exosome particle size analysis of Cu-EXO. (C) Western blot detection of Cu-EXO exosome surface markers (TSG101 and CD9). (D) The proliferation of normal GC cells (CON), GC cells treated with 4 mg/mL of NK cell exosomes (EXO) for 24 h and GC cells treated with 4 mg/ml of DSF/Cu-loaded exosomes (Cu-EXO) for 24 h was detected by CCK-8 (n = 3). (E) qPCR was used to detect the levels of FDX1 and DLAT gene expression in Cu-EXO treated GC cells (n = 3). (F) Western blot analysis of FDX1, DLAT, and WDR43 gene expression in Cu-EXO treated GC cells (n = 3). (G) Scratch healing assay to detect cell migration (n = 3) (scale bar, 500 μm). (H) Statistical analysis of the results of scratch healing experiments (n = 3). (I) Invasion assay to detect the invasion ability of cells (n = 3) (scale bar, 100 μm). (J) Statistical analysis of the results of invasion experiments (n = 3). (K) Cell cycle was measured by flow cytometry (n = 3). (L) Statistical analysis of cell cycle test results (n = 3). Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, indicating statistically significant differences.
    DSF/Cu loaded into NK cell exosomes for the treatment of GC cells. (A) The morphology of NK cell exosomes was observed under transmission electron microscopy (scale bar, 200 nm). (B) Exosome particle size analysis of Cu-EXO. (C) Western blot detection of Cu-EXO exosome surface markers (TSG101 and CD9). (D) The proliferation of normal GC cells (CON), GC cells treated with 4 mg/mL of NK cell exosomes (EXO) for 24 h and GC cells treated with 4 mg/ml of DSF/Cu-loaded exosomes (Cu-EXO) for 24 h was detected by CCK-8 (n = 3). (E) qPCR was used to detect the levels of FDX1 and DLAT gene expression in Cu-EXO treated GC cells (n = 3). (F) Western blot analysis of FDX1, DLAT, and WDR43 gene expression in Cu-EXO treated GC cells (n = 3). (G) Scratch healing assay to detect cell migration (n = 3) (scale bar, 500 μm). (H) Statistical analysis of the results of scratch healing experiments (n = 3). (I) Invasion assay to detect the invasion ability of cells (n = 3) (scale bar, 100 μm). (J) Statistical analysis of the results of invasion experiments (n = 3). (K) Cell cycle was measured by flow cytometry (n = 3). (L) Statistical analysis of cell cycle test results (n = 3). Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, indicating statistically significant differences.
    Figure 6

    DSF/Cu loaded into NK cell exosomes for the treatment of GC cells. (A) The morphology of NK cell exosomes was observed under transmission electron microscopy (scale bar, 200 nm). (B) Exosome particle size analysis of Cu-EXO. (C) Western blot detection of Cu-EXO exosome surface markers (TSG101 and CD9). (D) The proliferation of normal GC cells (CON), GC cells treated with 4 mg/mL of NK cell exosomes (EXO) for 24 h and GC cells treated with 4 mg/ml of DSF/Cu-loaded exosomes (Cu-EXO) for 24 h was detected by CCK-8 (n = 3). (E) qPCR was used to detect the levels of FDX1 and DLAT gene expression in Cu-EXO treated GC cells (n = 3). (F) Western blot analysis of FDX1, DLAT, and WDR43 gene expression in Cu-EXO treated GC cells (n = 3). (G) Scratch healing assay to detect cell migration (n = 3) (scale bar, 500 μm). (H) Statistical analysis of the results of scratch healing experiments (n = 3). (I) Invasion assay to detect the invasion ability of cells (n = 3) (scale bar, 100 μm). (J) Statistical analysis of the results of invasion experiments (n = 3). (K) Cell cycle was measured by flow cytometry (n = 3). (L) Statistical analysis of cell cycle test results (n = 3). Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, indicating statistically significant differences.

  • DSF/Cu and Cu-EXO inhibit tumor growth in vivo. (A) Schematic diagram of experimental procedures in mice. The naked mice were divided into 5 groups (n = 8), which were treated with PBS and DMSO after AGS tumor bearing (CON), 10 mg/kg of DSF/Cu after AGS tumor bearing (Cu), and 100 mg/kg of Cu-EXO after AGS tumor bearing (Cu-EXO). AGS cells overexpressing FDX1 were treated with 10 mg/kg of DSF/Cu (Cu+FDX1) and 100 mg/kg Cu-EXO (EXO+FDX1). (B) In situ injection of DiR-labeled exosomes in nude mice and in vivo imaging detection. (C) Tumor volume in tumor-bearing mice (n = 8). (D) Tumor volume analysis (n = 8). (E) Weight changes in tumor-bearing mice after initiation of treatment (n = 8). (F) The levels of FDX1 and WDR43 gene expression in mouse tumor tissues were detected by qPCR (n = 3). (G) Western blot analysis of FDX1, DLAT, and WDR43 protein expression in mouse tumor tissues (n = 3). (H) Statistical analysis of western blot. Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, indicating statistically significant differences.
    Figure 7

    DSF/Cu and Cu-EXO inhibit tumor growth in vivo. (A) Schematic diagram of experimental procedures in mice. The naked mice were divided into 5 groups (n = 8), which were treated with PBS and DMSO after AGS tumor bearing (CON), 10 mg/kg of DSF/Cu after AGS tumor bearing (Cu), and 100 mg/kg of Cu-EXO after AGS tumor bearing (Cu-EXO). AGS cells overexpressing FDX1 were treated with 10 mg/kg of DSF/Cu (Cu+FDX1) and 100 mg/kg Cu-EXO (EXO+FDX1). (B) In situ injection of DiR-labeled exosomes in nude mice and in vivo imaging detection. (C) Tumor volume in tumor-bearing mice (n = 8). (D) Tumor volume analysis (n = 8). (E) Weight changes in tumor-bearing mice after initiation of treatment (n = 8). (F) The levels of FDX1 and WDR43 gene expression in mouse tumor tissues were detected by qPCR (n = 3). (G) Western blot analysis of FDX1, DLAT, and WDR43 protein expression in mouse tumor tissues (n = 3). (H) Statistical analysis of western blot. Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, indicating statistically significant differences.

  • Mechanism underlying NK cell exosome-mediated DSF/Cu delivery and induction of cuproptosis in gastric cancer (GC). Upper panel: Fabrication and in vivo application of the Cu-EXO nanocarrier. Disulfiram (DSF), a small-molecule aldehyde dehydrogenase inhibitor, and Cu2+ were chelated at a 1:1 molar ratio and encapsulated into exosomes derived from natural killer (NK) cells. The resulting biomimetic Cu-EXO system exhibited enhanced biocompatibility and tumor-targeting capabilities, effectively suppressing tumor progression in GC murine models. Lower panel: Intracellular mechanisms underlying Cu-EXO-mediated cytotoxicity. Following cellular internalization (1), Cu-EXO releases the DSF/Cu complex, inducing intracellular copper accumulation (2) and activating ferredoxin 1 (FDX1), a mitochondrial iron-sulfur reductase. Acting as a central electron donor, FDX1 catalyzes the reduction of Cu2+ to the highly cytotoxic Cu+ (3) and facilitates the lipoylation of dihydrolipoamide S-acetyltransferase (DLAT), the E2 subunit of the pyruvate dehydrogenase complex, thus providing Cu+-binding sites. Subsequent Cu+ binding drives DLAT oligomerization, triggering profound proteotoxic stress and cuproptosis (4). Concurrently, FDX1 directly interacts with WD Repeat Domain 43 (WDR43), a scaffolding protein essential for ribosome biogenesis and cell proliferation via key structural residues (e.g., FDX1 N97–WDR43 P332) (5), which may facilitate the proteasomal degradation of WDR43 through uncharacterized, hypothetically ubiquitin-associated pathways, thereby inhibiting WDR43-driven oncogenic signaling that drives cell cycle progression and cell proliferation. Collectively, Cu-EXO drives robust GC cell death by converging the induction of DLAT-mediated cuproptosis and the targeted inhibition of WDR43. (Created with Biorender.com).
    Figure 8

    Mechanism underlying NK cell exosome-mediated DSF/Cu delivery and induction of cuproptosis in gastric cancer (GC). Upper panel: Fabrication and in vivo application of the Cu-EXO nanocarrier. Disulfiram (DSF), a small-molecule aldehyde dehydrogenase inhibitor, and Cu2+ were chelated at a 1:1 molar ratio and encapsulated into exosomes derived from natural killer (NK) cells. The resulting biomimetic Cu-EXO system exhibited enhanced biocompatibility and tumor-targeting capabilities, effectively suppressing tumor progression in GC murine models. Lower panel: Intracellular mechanisms underlying Cu-EXO-mediated cytotoxicity. Following cellular internalization (1), Cu-EXO releases the DSF/Cu complex, inducing intracellular copper accumulation (2) and activating ferredoxin 1 (FDX1), a mitochondrial iron-sulfur reductase. Acting as a central electron donor, FDX1 catalyzes the reduction of Cu2+ to the highly cytotoxic Cu+ (3) and facilitates the lipoylation of dihydrolipoamide S-acetyltransferase (DLAT), the E2 subunit of the pyruvate dehydrogenase complex, thus providing Cu+-binding sites. Subsequent Cu+ binding drives DLAT oligomerization, triggering profound proteotoxic stress and cuproptosis (4). Concurrently, FDX1 directly interacts with WD Repeat Domain 43 (WDR43), a scaffolding protein essential for ribosome biogenesis and cell proliferation via key structural residues (e.g., FDX1 N97–WDR43 P332) (5), which may facilitate the proteasomal degradation of WDR43 through uncharacterized, hypothetically ubiquitin-associated pathways, thereby inhibiting WDR43-driven oncogenic signaling that drives cell cycle progression and cell proliferation. Collectively, Cu-EXO drives robust GC cell death by converging the induction of DLAT-mediated cuproptosis and the targeted inhibition of WDR43. (Created with Biorender.com).

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