FOXA2 promotes the occurrence and development of osteosarcoma cells by regulating ferroptosis through the Rheb/mTOR axis

Osteosarcoma (OS) is a prevalent and aggressive primary carcinoma of the bone that predominantly influences children and adolescents. Inadequate therapeutic strategies have hindered improvements in patient survival. The forkhead box transcription factor FOXA2 plays a role in metabolic homeostasis and tumor progression. However, its association with OS remains underexplored. Firstly, we investigated the expression of FOXA2 in OS cells and in OS tissue samples from patients at different clinical stages using western blot and immunohistochemistry (IHC). Analysis of the R2 database revealed the association between FOXA2 and the prognosis of OS patients. Subsequently, a series of functional experiments confirmed the biological behaviors of OS caused by FOXA2. Furthermore, through western blot, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assays, and other experiments, we identified a key underlying molecular mechanisms. The present study determined that FOXA2 is overexpressed in OS cells and tissues, affecting OS patient prognosis. FOXA2 knockdownin functional experiments on OS cells attenuated their proliferation and migration while promoting ferroptosis, thereby offering an alternative intervention for OS as a form of programmed cell death. Upregulated Rheb restored the proliferation and migration in FOXA2 knockdown OS cells by facilitating ferroptosis induced by the mTOR pathway. The study results corroborated that FOXA2 suppresses ferroptosis via the Rheb/mTOR axis, stimulating OS cell proliferation and migration. Targeting the FOXA2/Rheb/mTOR axis and clarifying the fundamental mechanisms are thus crucial for the clinical OS treatment.