Ferroptosis, an iron dependent form of regulated cell death driven by lipid peroxidation, has emerged as a pivotal process in prostate cancer biology and therapy. This review summarizes the multifaceted regulation of ferroptosis in prostate cancer from molecular, metabolic, and microenvironmental perspectives. Core regulators such as GPX4, SLC7A11, and ACSL4 coordinate redox balance, glutathione metabolism, and lipid peroxidation, together determining ferroptotic sensitivity. Transcriptional, epigenetic, and post translational mechanisms including STAT3, the JMJD6 ATF4 axis, and TRIM family proteins further refine ferroptosis regulation. Metabolic reprogramming involving APOC1, SLC25A10, and BCAT2, as well as mitochondrial dynamics governed by VSTM2L and RPS6KC1, establishes metabolic dependencies that influence resistance or susceptibility to ferroptosis. Within the tumor microenvironment, cancer-associated fibroblasts and extracellular matrix components modulate ferroptosis through lactate signaling, exosomal microRNAs, and detachment resistance. Clinically, ferroptosis-related gene signatures provide valuable prognostic tools and predict responses to radiotherapy, antiandrogen therapy, and immunotherapy, linking ferroptotic dysregulation with immune suppression and treatment resistance. Emerging therapeutic strategies that inhibit GPX4 or system Xc-, modulate iron metabolism, and employ PSMA-targeted nanoplatforms have shown potent antitumor efficacy, especially in castration resistant disease. Repurposed drugs such as flubendazole and the ezetimibe derivative L14-8, along with natural compounds including evodiamine and luteolin, demonstrate translational potential for ferroptosis induction. Collectively, ferroptosis represents a promising therapeutic vulnerability for precision treatment of advanced prostate cancer.
Wang et al. (2026) studied this question.