Oncogenic KRAS is a major driver in lung adenocarcinoma (LUAD) that has yet to be therapeutically conquered. Here we report that the SLC7A11/glutathione axis displays metabolic synthetic lethality with oncogenic KRAS. Through metabolomics approaches, we found that mutationally activated KRAS strikingly increased intracellular cystine levels and glutathione biosynthesis. SLC7A11, a cystine/glutamate antiporter conferring specificity for cystine uptake, was overexpressed in patients with KRAS-mutant LUAD and showed positive association with tumor progression. Furthermore, SLC7A11 inhibition by either genetic depletion or pharmacological inhibition with sulfasalazine resulted in selective killing across a panel of KRAS-mutant cancer cells in vitro and tumor growth inhibition in vivo, suggesting the functionality and specificity of SLC7A11 as a therapeutic target. Importantly, we further identified a potent SLC7A11 inhibitor, HG106, that markedly decreased cystine uptake and intracellular glutathione biosynthesis. Furthermore, HG106 exhibited selective cytotoxicity toward KRAS-mutant cells by increasing oxidative stress– and ER stress–mediated cell apoptosis. Of note, treatment of KRAS-mutant LUAD with HG106 in several preclinical lung cancer mouse models led to marked tumor suppression and prolonged survival. Overall, our findings reveal that KRAS-mutant LUAD cells are vulnerable to SLC7A11 inhibition, offering potential therapeutic approaches for this currently incurable disease.

Salinomycin exerts anti-angiogenic and anti-tumorigenic activities by inhibiting vascular endothelial growth factor receptor 2-mediated angiogenesis Salinomycin exerts anti-angiogenic and anti-tumorigenic activities by inhibiting vascular endothelial growth factor receptor 2-mediated angiogenesis

Background: Sorting nexin 9 (SNX9) is involved in intracellular vesicle transport and signal transduction, and its abnormal expression is related to the occurrence and development of a variety of cancers. In lung adenocarcinoma (LUAD), the role and molecular mechanism of SNX9 remain unclear. This study combined bioinformatics analysis and in vitro validation to explore its expression characteristics in LUAD, its specific effects on tumor development, and its potential molecular mechanism and prognostic value. Methods: In this study, the expression data and clinical information of SNX9 in LUAD were obtained from Tumor Immune Estimation Resource (TIMER) 2.0, The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) databases, and the relationship between SNX9 expression and prognosis was analyzed using TCGA database patient information and Kaplan-Meier plotter, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to reveal the mechanism of SNX9. Gene set enrichment analysis (GSEA) enrichment analysis highlighted the pathways and biological processes rich in gene sets in SNX9 high-expression samples, thereby providing insights into associated enrichment pathways. The effects of SNX9 on the proliferation, migration and invasion of LUAD cells were detected by Western blot and in vitro experiments. Results: The results of this study showed that the expression level of SNX9 in LUAD tissues was significantly higher than that in normal lung epithelial cells, and its high expression was closely related to the increase in tumor grade and poor prognosis of patients. Functional enrichment analysis showed that SNX9-related genes were concentrated in epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) and cell adhesion processes in LUAD, suggesting that the increased expression of SNX9 is positively correlated with the enhanced invasion ability of LUAD cells. In vitro experiments also showed that knockdown of endogenous SNX9 significantly inhibited the proliferation, migration and invasion of A549 and H1299 cells. Conclusions: This study shows that SNX9 is overexpressed in LUAD and is associated with poor prognosis. We speculate that SNX9 is expected to be a prognostic marker and a potential therapeutic target for LUAD, providing a new direction and theoretical basis for related research and clinical application.

This study aims to comprehensively apply network toxicology and molecular dynamics simulation techniques to investigate the molecular mechanisms of DNBaP-induced lung cancer. We first predicted the toxicological characteristics of DNBaP related to carcinogenicity. Subsequently, by integrating multiple databases, 71 potential cross-targets of DNBaP-induced lung cancer were screened. GO analysis and KEGG pathway enrichment analysis of these targets verified their functions in biological processes and signaling pathways, further confirming their association with lung cancer. Using these potential cross-targets, a STRING interaction network was constructed, and five core genes were identified through Cytoscape software. Molecular docking was performed to predict the binding affinity between DNBaP and these core genes. Finally, molecular dynamics simulations were conducted to further validate the stability of the complexes and infer how the biological functions of the protein structures are affected after complex formation. This study systematically reveals the molecular mechanism of DNBaP-induced lung cancer: it disrupts intracellular homeostasis by interfering with core genes (CDKN2A, EGFR, ESR1, TNF, TP53) and activating key signaling pathways such as PI3K-Akt and MAPK. The research demonstrates the effectiveness and feasibility of integrating network toxicology, molecular docking, and molecular dynamics simulation techniques in assessing the toxic mechanisms of environmental pollutants. It provides an important theoretical basis and scientific methodology for understanding the health risks of DNBaP, screening new targets for lung cancer intervention, and developing preventive strategies.