Androgen Receptor‐Induced Lactoferrin Accelerates Prostate Tumorigenesis Through Modulating Ferroptosis

TRAMP genetic mouse models, proteomics, TCGA-PARD data, and single-cell RNA-seq, we demonstrate that AR directly binds the LF promoter, driving LF expression, which in turn upregulates ferritin (FTH1/FTL) expression and suppresses p53-ALOX12-mediated ferroptosis in prostate cancer. Crucially, Lf deficiency delayed tumor progression and intensified ferroptotic stress in the TRAMP mice, while iron supplementation accelerated carcinogenesis-effects rescued by Lf knockout. Mechanistically, lactoferrin shields prostate cancer cells from iron-induced ferroptosis by maintaining iron-redox homeostasis. Preclinical targeting of this axis suggested a potential therapeutic strategy, as suppressed tumor growth in prostate cancer xenograft was observed following LF knockdown coupled with ferroptosis induction (via IKE) and androgen receptor inhibition (via enzalutamide). This work defines lactoferrin as: (i) an AR-regulated ferroptosis suppressor, (ii) a regulator of prostate cancer's "iron addiction," and (iii) a candidate target for therapeutic exploitation of iron-metabolic vulnerability.