Androgen receptor-regulated ZNF419 modulates ferroptosis sensitivity via the ZDHHC20-GPX4 pathway in prostate cancer.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently been recognized as a crucial determinant of therapeutic response in prostate cancer (PCa). However, how androgen receptor (AR) signaling regulates ferroptotic susceptibility remains poorly understood. Here, we identify ZNF419, a previously uncharacterized zinc finger protein, as an AR-regulated factor associated with reduced ferroptosis susceptibility in PCa cells. Transcriptomic profiling and functional validation revealed that ZNF419 expression is markedly elevated in PCa and correlates with poor clinical outcome. Promoter-proximal AR occupancy was detected at predicted ARE-containing regions of the ZNF419 locus and contributed to ZNF419 promoter activation in reporter assays, whereas enzalutamide treatment or AR knockdown reduced ZNF419 expression and increased ferroptosis-associated vulnerability. Mechanistically, ZNF419 promotes ZDHHC20 expression and is associated with activation of a candidate downstream enhancer region. ZDHHC20, a palmitoyltransferase, contributes to GPX4 palmitoylation-associated stabilization and limits ubiquitin-mediated proteasomal degradation of GPX4. Pharmacological interference with palmitoylation attenuates ZNF419-associated GPX4 stabilization, whereas ZDHHC20 restoration partially reverses the increased ferroptosis-associated vulnerability of ZNF419-deficient cells. Collectively, our findings support a previously unrecognized AR-associated ZNF419-ZDHHC20-GPX4 regulatory axis that links AR activity to ferroptosis-associated vulnerability. These findings provide a rationale for further investigating whether modulation of this pathway may influence responses to AR-targeted therapy in advanced PCa.