Respiratory research · 2026
Multi-cell death gene signature predicts lung adenocarcinoma prognosis and reveals FURIN regulates ferroptosis via NRF2-xCT-GPX4 axis.
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Ning Jiaoyang, Xiao Gang, Wen Su, Chen Liu, Wang Ce, Zhang Keqin, Wen Hao, Tanzhu Guilong, Yang Jie, Zhou Rongrong
Аннотация
BACKGROUND: FURIN, a proprotein convertase, has been implicated in tumor progression. Nevertheless, how it contributes to lung adenocarcinoma (LUAD) and ferroptosis is still not well understood.
METHODS: We investigated FURIN expression and its prognostic value using the TCGA-LUAD cohort, CPTAC, and GEO datasets. In vitro functional assays, including CCK-8, colony formation, EdU, wound healing, invasion, and tube formation, were conducted in HCC827, PC9 and H460 cells following FURIN knockdown, with or without the ferroptosis inhibitor Ferrostatin-1 (Fer-1). RNA-seq, ferroptosis signature scoring, and GSEA were used to explore mechanisms. Ferroptosis was assessed by ROS and Fe accumulation, MDA and GSH/GSSG ratio, T-AOC, and ferroptosis-related protein expression. Preliminary exploration of the mechanism by which FURIN regulates NRF2 was performed using confocal microscopy. A multiple cell death-related gene signature was developed for prognostic prediction and immune/mutational landscape analysis.
RESULTS: In LUAD, FURIN was highly expressed and linked to poor prognosis. Knockdown of FURIN suppressed proliferation, migration, invasion, and angiogenesis, accompanied by increased ROS, Fe2+, elevated MDA, and decreased GSH/GSSG ratio and T-AOC. RNA sequencing showed downregulation of SLC7A11, GPX4, FTH1, and GSS, accompanied by upregulation of ACSL4, PTGS2, NCOA4, and DPP4. Furthermore, Fer-1 treatment reversed these changes, supporting a ferroptosis-dependent mechanism. Western blot confirmed FURIN knockdown may inhibit the NRF2-xCT-GPX4 axis, which lead to ferroptosis. Mechanistically, we preliminarily demonstrated that FURIN promotes NRF2 nuclear translocation and upregulates xCT and GPX4. The FURIN inhibitor Decanoyl-RVKR-CMK effectively inhibits the growth of LUAD in vitro. The cell death-related gene signature showed robust predictive performance (AUC 0.73-0.78) and served as an independent prognostic factor. Risk stratification revealed distinct immune infiltration, with high-risk patients enriched in immunosuppressive macrophages and low-risk patients in CD8⁺ T and NK cells. High-risk patients also exhibited increased tumor mutational burden and driver mutations.
CONCLUSIONS: FURIN promotes LUAD progression by suppressing ferroptosis through the NRF2-xCT-GPX4 axis. Targeting the FURIN-ferroptosis axis and using ferroptosis-based risk stratification may offer novel strategies for prognosis and individualized therapy.
METHODS: We investigated FURIN expression and its prognostic value using the TCGA-LUAD cohort, CPTAC, and GEO datasets. In vitro functional assays, including CCK-8, colony formation, EdU, wound healing, invasion, and tube formation, were conducted in HCC827, PC9 and H460 cells following FURIN knockdown, with or without the ferroptosis inhibitor Ferrostatin-1 (Fer-1). RNA-seq, ferroptosis signature scoring, and GSEA were used to explore mechanisms. Ferroptosis was assessed by ROS and Fe accumulation, MDA and GSH/GSSG ratio, T-AOC, and ferroptosis-related protein expression. Preliminary exploration of the mechanism by which FURIN regulates NRF2 was performed using confocal microscopy. A multiple cell death-related gene signature was developed for prognostic prediction and immune/mutational landscape analysis.
RESULTS: In LUAD, FURIN was highly expressed and linked to poor prognosis. Knockdown of FURIN suppressed proliferation, migration, invasion, and angiogenesis, accompanied by increased ROS, Fe2+, elevated MDA, and decreased GSH/GSSG ratio and T-AOC. RNA sequencing showed downregulation of SLC7A11, GPX4, FTH1, and GSS, accompanied by upregulation of ACSL4, PTGS2, NCOA4, and DPP4. Furthermore, Fer-1 treatment reversed these changes, supporting a ferroptosis-dependent mechanism. Western blot confirmed FURIN knockdown may inhibit the NRF2-xCT-GPX4 axis, which lead to ferroptosis. Mechanistically, we preliminarily demonstrated that FURIN promotes NRF2 nuclear translocation and upregulates xCT and GPX4. The FURIN inhibitor Decanoyl-RVKR-CMK effectively inhibits the growth of LUAD in vitro. The cell death-related gene signature showed robust predictive performance (AUC 0.73-0.78) and served as an independent prognostic factor. Risk stratification revealed distinct immune infiltration, with high-risk patients enriched in immunosuppressive macrophages and low-risk patients in CD8⁺ T and NK cells. High-risk patients also exhibited increased tumor mutational burden and driver mutations.
CONCLUSIONS: FURIN promotes LUAD progression by suppressing ferroptosis through the NRF2-xCT-GPX4 axis. Targeting the FURIN-ferroptosis axis and using ferroptosis-based risk stratification may offer novel strategies for prognosis and individualized therapy.