Super-enhancers mediates SLC7A11 via FOXA1 to regulate disulfidptosis in prostate cancer.

Prostate cancer (PCa) remains a major therapeutic challenge due to aberrant androgen receptor signaling and a remodeled tumor microenvironment. Disulfidptosis, a recently identified form of cell death characterized by cytoskeletal collapse under conditions of glucose deprivation and elevated SLC7A11 expression, presents a potential novel avenue for intervention. In this study, we integrated TCGA and GEO data and employed machine learning techniques to identify disulfidptosis-related genes in prostate cancer. Functional analyses using SLC7A11-overexpressing and knockout cell lines demonstrated that SLC7A11 promotes cellular proliferation, migration, and invasion, while its overexpression under glucose-starved conditions triggers disulfidptosis, also inducible pharmacologically using the glucose uptake inhibitor BAY-876. Through CUT&Tag, ChIP-seq, and luciferase assays, we identified FOXA1 as a key transcriptional regulator of SLC7A11, driven by a super-enhancer located at chr14:37583488-37589585. CRISPR-Cas9 deletion of this super-enhancer reduced FOXA1 and SLC7A11 expression, thereby protecting cells from disulfidptosis. These findings highlight the critical role of the SE/FOXA1/SLC7A11 regulatory axis in driving both disulfidptosis and tumor progression, suggesting that targeting this pathway, particularly in glucose-deprived tumor environments, may offer promising therapeutic strategies for PCa.