FOS deficiency activates NRF2 signaling and CAF-mediated metabolic symbiosis to induce ferroptosis resistance in lung cancer initiation and brain metastasis

ABSTRACT: Lung cancer brain metastasis (LCBM) is a leading cause of mortality in lung cancer patients, with a median survival of merely 4-6 months post-metastasis. Ferroptosis, an iron-dependent form of programmed cell death, has emerged as a key regulator of cancer metastasis, yet its role and underlying mechanisms in LCBM remain elusive. This study investigates the involvement of ferroptosis resistance and the transcription factor FOS in LCBM progression. Through single-cell RNA sequencing (scRNA-seq) and clinical sample validation, we identified prominent ferroptosis resistance in LCBM tissues, characterized by elevated expression of resistance markers (e.g., GPX4, SLC7A11) and reduced pro-ferroptotic factors (e.g., ACSL4, TFRC). Functional assays demonstrated that ferroptosis activation inhibits epithelial-mesenchymal transition (EMT) and LCBM both in vitro and in vivo. Notably, FOS expression was progressively downregulated from normal lung tissues to primary lung cancer and LCBM tissues, and FOS overexpression significantly suppressed ferroptosis resistance and brain metastasis. Mechanistically, FOS transcriptionally inhibits the NRF2-SLC3A2-GPX4 axis while promoting the SLC39A8-ACSF2 axis, thereby regulating iron and lipid metabolism to induce ferroptosis. Additionally, FOS overexpression disrupts aberrant crosstalk between lung cancer epithelial cells and cancer-associated fibroblasts (CAFs), blocking CAF-mediated extracellular matrix (ECM) remodeling and cancer cell PD-L1-driven immunosuppression. Notably, FOS overexpression also enhances cisplatin sensitivity in chemo-resistant lung cancer cells, reinforcing its therapeutic potential. Our findings reveal FOS as a critical regulator of ferroptosis and CAF function in LCBM, highlighting targeting FOS and ferroptosis as a novel therapeutic strategy to improve outcomes for lung cancer patients with brain metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213590 | GEO | 2023/09/20

REPOSITORIES: GEO