Metabolic vulnerabilities in advanced prostate cancer: the interplay of ferroptosis, cuproptosis, and the inflammatory microenvironment

Abstract

Advanced prostate cancer, particularly metastatic castration-resistant disease (mCRPC), represents a major clinical challenge due to its evasion of classical apoptotic pathways. Exploiting alternative regulated cell death modalities, specifically ferroptosis and cuproptosis, has emerged as a critical therapeutic goal. This review evaluates the complex biochemical structure of these metal-dependent vulnerabilities, emphasizing their intersection with mitochondrial bioenergetics, lipid remodeling, and the inflammatory tumor microenvironment. We review the role of the NRF2/GPX4 antioxidant axis and the modulatory influence of pro-inflammatory signaling on metal ion homeostasis. By synthesizing current multi-omics data and pharmacological strategies, including nanotherapies and theranostic radiopharmaceuticals, this manuscript emphasizes the necessity for predictive biomarkers and combinatorial rationales. Bridging these mechanistic discoveries with precision oncology is essential for overcoming therapeutic resistance and improving clinical outcomes in advanced prostate cancer.