A recent review explores the rapidly expanding field of ferroptosis-based therapy for prostate cancer, presenting ferroptosis as a promising strategy to overcome resistance in advanced and castration-resistant prostate cancer (CRPC). The authors synthesize current knowledge of ferroptosis mechanisms, biomarkers, therapeutic agents, combination strategies, and translational challenges, proposing a framework that links ferroptosis regulatory networks with precision medicine approaches.
Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation. Unlike apoptosis, ferroptosis results from excessive accumulation of reactive oxygen species (ROS) and oxidative damage to polyunsaturated fatty acid-containing membrane lipids. The process is initiated by iron overload and propagated through lipid peroxidation, ultimately causing membrane disruption and cell death. Prostate cancer cells, particularly those with metastatic potential, appear especially vulnerable to ferroptotic injury, making this pathway an attractive therapeutic target.
The review identifies three central components governing ferroptosis: iron metabolism, lipid metabolism, and antioxidant defense systems. Iron enters cells through transferrin receptor 1 (TFR1), where intracellular Fe²⁺ catalyzes Fenton reactions that generate highly reactive hydroxyl radicals. These radicals initiate oxidation of membrane polyunsaturated fatty acids, creating a cascade of lipid damage. Counterbalancing this process are several antioxidant systems, including the glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, ferroptosis suppressor protein 1 (FSP1), dihydroorotate dehydrogenase (DHODH), and tetrahydrobiopterin (BH4)-dependent pathways. The schematic pathway diagram on pages 3–4 illustrates how ferroptosis results from the balance between oxidative damage and these protective mechanisms.
A major focus of the review is the role of lipid metabolism in determining ferroptosis sensitivity. Acyl-CoA synthetase long-chain family member 4 (ACSL4) promotes incorporation of polyunsaturated fatty acids into membrane phospholipids, increasing susceptibility to oxidation and ferroptosis. In contrast, stearoyl-CoA desaturase 1 (SCD1) generates monounsaturated fatty acids that stabilize membranes and protect against ferroptosis. Other lipid-related regulators include phospholipase A2G4A (PLA2G4A), prostaglandin E2 (PGE2), and the BH4-CoQ10 antioxidant system.
Several oncogenic signaling pathways also influence ferroptosis in prostate cancer. Loss of the tumor suppressor PTEN activates the PI3K–AKT–mTOR pathway, which promotes lipogenesis through SREBP1 and SCD1, creating resistance to ferroptosis. The Hippo/YAP pathway exhibits more complex behavior, acting as either a promoter or inhibitor of ferroptosis depending on context. Additionally, p53 can both promote and suppress ferroptosis through distinct mechanisms, underscoring the intricate regulation of cell death responses in prostate tumors.
The tumor immune microenvironment is increasingly recognized as a critical regulator of ferroptosis. Activated CD8⁺ T cells secrete interferon-γ, suppressing SLC7A11 expression and promoting ferroptosis in tumor cells. Immune checkpoint blockade, particularly PD-1 inhibition, may amplify this effect. Conversely, M2-polarized tumor-associated macrophages inhibit ferroptosis through the LXRα/SCD1 pathway. The review highlights the concept of an "immune–ferroptosis cycle," in which ferroptotic tumor cells release danger signals that enhance anti-tumor immunity while immune cells further sensitize tumors to ferroptosis.
The authors identify several promising biomarkers of ferroptosis susceptibility, including TFR1, ACSL4, SCD1, Nrf2, SLC7A11, GPX4, DECR1, and PI3K/AKT/mTOR pathway activation. Tables summarizing genomic, transcriptomic, proteomic, and metabolomic markers suggest that ferroptosis-related signatures may eventually guide patient selection and treatment stratification. High expression of SLC7A11 or GPX4, for example, is associated with treatment resistance and may identify tumors most likely to benefit from ferroptosis-targeted therapies.
Among therapeutic approaches, GPX4 inhibition represents one of the most direct methods of inducing ferroptosis. Compounds such as RSL3, ML162, ML210, and FIN56 disrupt GPX4 activity, leading to uncontrolled lipid peroxide accumulation. In preclinical prostate cancer models, RSL3 significantly reduced tumor growth, especially when combined with iron supplementation. Alternative strategies focus on depleting glutathione through agents such as Erastin, sulfasalazine, sorafenib, and buthionine sulfoximine, which indirectly disable GPX4 by limiting cellular antioxidant capacity.
Another therapeutic avenue involves increasing intracellular iron levels. Agents such as dihydroartemisinin, artemisinin, and PX-12 enhance oxidative stress through iron-dependent mechanisms, amplifying Fenton chemistry and lipid peroxidation. Additional compounds—including BAY 11-7085, sanguinarine chloride, and various natural products—promote ferroptosis through effects on ROS generation, lipid metabolism, or antioxidant signaling pathways. The review provides a detailed catalog of ferroptosis-inducing compounds and their molecular targets.
Combination therapy emerges as a particularly promising strategy. Ferroptosis inducers synergize with anti-androgen therapies such as enzalutamide and darolutamide by weakening antioxidant defenses. They also enhance responses to chemotherapy agents such as cisplatin and docetaxel, helping overcome drug resistance. Additional combinations involving mTOR inhibitors, PHGDH inhibitors, immunotherapies, and iron supplementation have shown encouraging preclinical results. The authors argue that ferroptosis-based combinations may be especially valuable in CRPC, where conventional therapies frequently fail.
Nanotechnology offers further opportunities for targeted delivery. The review highlights several innovative platforms, including PSMA-targeted nanoparticles carrying iron and RSL3, magnetic lipid nanoparticles delivering DECR1 siRNA, and manganese sulfide-based systems that generate ROS directly within tumors. These technologies improve tumor selectivity, reduce systemic toxicity, and may help overcome some limitations of conventional ferroptosis inducers. Early animal studies demonstrate substantial tumor suppression with minimal off-target effects.
Despite its promise, ferroptosis-based therapy faces significant challenges. Tumors can develop resistance through overexpression of GPX4, SLC7A11, FSP1, and Nrf2, activation of alternative antioxidant pathways, metabolic rewiring, and adaptation to hypoxic microenvironments. The substantial heterogeneity of prostate cancer further complicates biomarker development and patient selection. Moreover, most current evidence derives from cell culture and animal models, and no ferroptosis-specific therapy has yet advanced into routine clinical practice.
To facilitate clinical translation, the authors propose a precision oncology framework built around mechanism-driven biomarkers, rational combination therapies, and advanced delivery technologies. Potential future tools include ACSL4 immunohistochemical scoring, YAP localization indices, lipidomics-based profiling, ferroptosis imaging probes, and machine learning-guided biomarker discovery. Together, these innovations may enable more accurate patient stratification and maximize the therapeutic potential of ferroptosis-targeted interventions.
