SLC7A11 upregulation via AR and NEDD4L ubiquitination contributes to ferroptosis inhibition and enzalutamide resistance in castration-resistant prostate cancer

Advanced prostate cancer (PCa) is associated with a poor prognosis, particularly in patients who progress to castration-resistant prostate cancer (CRPC). The emergence of enzalutamide (Enz), a second-generation androgen receptor inhibitor, has effectively extended the median survival of these patients. However, drug resistance frequently develops during clinical use. Multiple studies have suggested that ferroptosis inducers can reverse cancer resistance to Enz, though the exact mechanisms remain unclear. In this study, we found that CRPC cells exhibit a concentration-dependent decrease in ferroptosis in response to Enz. This change is attributed to the upregulation of the protein level of SLC7A11. Protein stability assays and database analyses showed that SLC7A11 undergoes post-translational modification, likely connected to Enz-mediated downregulation of the SLC7A11-specific E3 ubiquitin ligase NEDD4L. This phenomenon was significantly reversed by the addition of erastin, a targeted inhibitor of the cystine/glutamate transport system Xc-. The data from both in vitro and in vivo experiments indicate that combining Enz with erastin significantly inhibits the proliferation of drug-resistant CRPC cells, thereby enhancing tumor suppression. These findings offer novel insights into targeting SLC7A11 with erastin as a potential strategy to overcome Enz resistance.