Prostate cancer is entering a new phase in the search for treatments that can overcome resistance. A recent review in Genes & Diseases examines ferroptosis, an iron-dependent form of regulated cell death, as a potential strategy against advanced disease, including castration-resistant prostate cancer (CRPC). Unlike apoptosis, the form of cell death targeted by many conventional therapies, ferroptosis is driven by the uncontrolled oxidation of lipids in cell membranes. The review brings together emerging evidence on how this process works, how it might be triggered therapeutically, and how molecular biomarkers could help identify patients most likely to respond.
Ferroptosis begins when the balance between oxidative damage and cellular antioxidant protection collapses. Iron imported into tumor cells through transferrin receptor 1 can be converted into reactive forms of Fe²⁺, which participate in Fenton reactions and generate highly damaging hydroxyl radicals. These radicals attack polyunsaturated fatty acids incorporated into phospholipids, initiating lipid peroxidation. As oxidized lipids accumulate, membrane integrity deteriorates until the cell can no longer survive. Prostate cancer cells, particularly aggressive and metastatic populations, may be unusually vulnerable to this process because their growth depends on extensive metabolic activity and altered iron and lipid handling.
Three interconnected systems determine whether a prostate cancer cell resists or undergoes ferroptosis: iron metabolism, lipid metabolism, and antioxidant defense. The glutathione–glutathione peroxidase 4, or GSH–GPX4, system is one of the most important protective mechanisms. GPX4 converts toxic lipid hydroperoxides into less harmful molecules, but it requires glutathione to function. Other protective systems include ferroptosis suppressor protein 1, known as FSP1, which supports membrane protection through coenzyme Q10, and dihydroorotate dehydrogenase, or DHODH, which helps defend mitochondrial membranes. A separate tetrahydrobiopterin-dependent pathway can also limit lipid oxidation. Ferroptosis therefore reflects a biochemical contest between the production of oxidative damage and the tumor cell’s ability to neutralize it.
Lipid composition is a particularly important determinant of sensitivity. The enzyme ACSL4 promotes the incorporation of polyunsaturated fatty acids into membrane phospholipids, creating substrates that are readily oxidized and increasing ferroptotic vulnerability. By contrast, stearoyl-CoA desaturase 1, or SCD1, produces monounsaturated fatty acids that are less prone to oxidation and can stabilize cellular membranes. Other regulators, including phospholipase A2G4A, prostaglandin E2, and the BH4–coenzyme Q10 antioxidant network, further shape this response. These relationships suggest that the metabolic profile of an individual tumor may be as important as its genetic profile when determining whether ferroptosis-based treatment will work.
The review also describes how major prostate cancer signaling pathways influence this metabolic balance. Loss of the tumor suppressor PTEN can activate the PI3K–AKT–mTOR pathway, stimulating lipid production through SREBP1 and SCD1 and thereby helping cancer cells avoid ferroptosis. The Hippo pathway and its transcriptional regulator YAP can either promote or suppress ferroptosis depending on the cellular context. The tumor suppressor p53 likewise has a dual role, capable of enhancing ferroptosis in some settings while supporting resistance in others. Such complexity may explain why a single ferroptosis-inducing drug is unlikely to be effective in every prostate tumor.
The immune system adds another layer of control. Activated CD8-positive T cells release interferon-gamma, which can reduce expression of SLC7A11, a transporter required for importing cystine and maintaining glutathione production. By weakening this antioxidant supply line, T cells may make tumor cells more susceptible to lipid peroxidation. Immune checkpoint inhibitors such as PD-1 blockers could intensify this interaction. At the same time, M2-polarized tumor-associated macrophages may protect cancer cells through the LXR-alpha/SCD1 pathway. The authors describe a potential “immune–ferroptosis cycle” in which ferroptotic tumor cells release danger signals that stimulate anti-tumor immunity, while immune activity further increases the tumor’s sensitivity to ferroptosis.
These mechanisms point toward a range of possible biomarkers. Levels of TFR1, ACSL4, SCD1, Nrf2, SLC7A11, GPX4, and DECR1, together with activation of the PI3K–AKT–mTOR pathway, could provide clues about ferroptosis susceptibility. High levels of GPX4 or SLC7A11 may indicate that a tumor has built strong antioxidant defenses and is likely to resist treatment. Conversely, elevated ACSL4 or increased intracellular iron could signal a more vulnerable metabolic state. The review proposes combining genomic, transcriptomic, proteomic, and metabolomic measurements rather than relying on a single marker. Such integrated profiles could eventually guide treatment selection in CRPC, where existing therapies often lose effectiveness.
Several experimental drugs directly or indirectly attack the antioxidant machinery. GPX4 inhibitors such as RSL3, ML162, ML210, and FIN56 can permit lipid peroxides to accumulate, while compounds including erastin, sulfasalazine, sorafenib, and buthionine sulfoximine reduce glutathione availability and indirectly disable GPX4. Other agents, including dihydroartemisinin, artemisinin, and PX-12, increase oxidative stress through iron-dependent reactions or effects on redox signaling. In laboratory and animal models, these approaches have shown stronger effects when combined with iron supplementation or with treatments that increase lipid oxidation. Ferroptosis inducers have also displayed preclinical synergy with anti-androgen drugs such as enzalutamide and darolutamide, as well as with cisplatin, docetaxel, mTOR inhibitors, PHGDH inhibitors, and immunotherapies.
Drug-delivery technology may help turn these experimental findings into more selective treatments. The review highlights nanoparticles engineered to recognize prostate-specific membrane antigen and deliver iron together with RSL3 directly to tumor cells. Other platforms use magnetic lipid nanoparticles to transport DECR1-targeting RNA molecules, or manganese sulfide systems that generate reactive oxygen species inside tumors. By concentrating ferroptosis-inducing activity at the cancer site, these platforms could reduce damage to healthy tissues and address the systemic toxicity that has limited many oxidative therapies. However, the field remains largely preclinical. Prostate tumors can adapt by increasing GPX4, SLC7A11, FSP1, or Nrf2, rewiring metabolism, and exploiting hypoxic regions that suppress oxidative reactions. The review therefore calls for mechanism-based biomarkers, lipidomics, ferroptosis imaging, improved delivery systems, and carefully designed clinical trials. Ferroptosis is not yet an established treatment, but its ability to exploit the metabolic weaknesses of resistant prostate cancer makes it one of the most closely watched emerging strategies in precision oncology.
Subject of Research: Ferroptosis-based therapy and precision medicine strategies for advanced and castration-resistant prostate cancer.
Article Title: Ferroptosis and prostate cancer: A translational path from molecular mechanisms to precision therapy
Web References: https://doi.org/10.1016/j.gendis.2025.101967
References: Yixiang Huang, Yuanxin Ma, Jiachen He, Tanjing Song, “Ferroptosis and prostate cancer: A translational path from molecular mechanisms to precision therapy,” Genes & Diseases, Volume 13, Issue 5, 2026, Article 101967.
Image Credits: Genes & Diseases
Keywords: Ferroptosis, prostate cancer, castration-resistant prostate cancer, lipid peroxidation, GPX4, ACSL4, SLC7A11, iron metabolism, immunotherapy, precision medicine
