Targeting FANCD2 to overcome enzalutamide resistance in prostate cancer

Background Fanconi anemia complementation group D2 (FANCD2) is a key component of DNA damage repair and has emerged as a potential cancer therapy target. Its role in enzalutamide (ENZ) resistance in prostate cancer remains unclear. Methods FANCD2 expression was examined in prostate cancer cells. Gain- and loss-of-function experiments were performed to assess ferroptosis, mitochondrial morphology, and cell viability. Nrf2 and GPX4 expression were measured to elucidate antioxidant regulation. Combination therapy using the ferroptosis inducer RSL3 and ENZ was evaluated in vitro and in vivo for antitumor efficacy. Results FANCD2 was significantly upregulated in prostate cancer and promoted ENZ resistance by inhibiting ferrous iron accumulation and lipid peroxidation, thereby suppressing ferroptosis. Mechanistically, FANCD2 stabilized Nrf2, increasing GPX4 expression and maintaining redox homeostasis. FANCD2 downregulation reduced Nrf2 and GPX4 expression, induced mitochondrial damage, and triggered ferroptosis, enhancing sensitivity to ENZ. Furthermore, combined treatment with RSL3 and ENZ synergistically suppressed cell growth, migration, and tumor progression in vivo. Conclusion FANCD2 regulates ferroptosis through the Nrf2–GPX4 axis, contributing to ENZ resistance in prostate cancer. Targeting FANCD2 or combining enzalutamide with ferroptosis inducers offers a promising strategy to overcome drug resistance and improve therapeutic outcomes. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s40170-026-00419-4.