Multi-cell death gene signature predicts lung adenocarcinoma prognosis and reveals FURIN regulates ferroptosis via NRF2-xCT-GPX4 axis

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. 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. In LUAD, FURIN was highly expressed and linked to poor prognosis. Knockdown of FURIN suppressed proliferation, migration, invasion, and angiogenesis, accompanied by increased ROS, Fe 2+ , 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. 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.