Recent observational research, published in Nature, provides a comprehensive overview of the “state of the art” in our understanding of ferroptosis, an iron-dependent form of programmed cell death, highlighting its potential as a promising therapeutic target for castration-resistant prostate cancer (CRPC).

Unlike apoptosis or autophagy, ferroptosis is characterized by the accumulation of lipid peroxides, leading to cell death. This unique mechanism offers new avenues for treatment, especially when combined with existing therapies.

Understanding Ferroptosis:

• Mechanism: Ferroptosis involves disrupted iron metabolism and lipid peroxidation. Iron (Fe²⁺) facilitates the peroxidation of polyunsaturated fatty acids (PUFAs), while enzymes like glutathione peroxidase 4 (GPX4) and the cystine/glutamate antiporter system Xc⁻ (comprising SLC7A11 and SLC3A2) play crucial roles in preventing this process.
• Characteristics: Cells undergoing ferroptosis exhibit mitochondrial shrinkage, increased membrane density, and elevated lipid peroxidation, along with reduced glutathione (GSH) levels.

Ferroptosis in CRPC:

• Negative Regulators: Pathways such as PI3K/AKT/mTOR, and proteins like SLC7A11, inhibit ferroptosis, contributing to CRPC progression. Notably, androgen receptor variants can upregulate SLC7A11, driving resistance to antiandrogen therapies.
• Positive Regulators: Factors like CHAC1 enhance ferroptosis, increasing the sensitivity of prostate cancer cells to treatments like docetaxel.

Ferroptosis Inducers (FINs) as Therapeutic Agents:

• Class I FINs: Agents such as erastin inhibit the system Xc⁻ antiporter, depleting GSH and leading to ferroptosis. Erastin has demonstrated anti-tumor activity and can enhance the efficacy of other anticancer drugs.
• Class II FINs: Compounds like RSL3 directly inhibit GPX4, promoting lipid peroxidation and cell death.
• Class III and IV FINs: Agents such as FIN56 and FINO2 deplete coenzyme Q10 and oxidize iron, respectively, inducing ferroptosis through distinct mechanisms.

Combination Therapy with Radiotherapy:

• Radiotherapy and Ferroptosis: Radiotherapy induces lipid peroxidation, a key feature of ferroptosis. Combining radiotherapy with ferroptosis inducers can enhance cancer cell sensitivity to treatment.
• Improving Radiosensitivity: Inhibitors of SLC7A11 and GPX4 may improve radiosensitivity, making cancer cells more susceptible to radiation-induced ferroptosis.

Ferroptosis-Related Genes and Prognosis:

• Biomarkers: Genes associated with ferroptosis can serve as indicators for predicting tumor prognosis. For instance, upregulation of AKR1C3 in tumors, including prostate cancer, is linked to aggressive cancer, poor prognosis, and treatment resistance.
• Risk Models: Several risk models utilizing ferroptosis-related genes have been developed, demonstrating promising predictive capabilities for patient outcomes.

Source.