SLC3A1 Mitigates Ferroptosis and Promotes Enzalutamide Resistance in Prostate Cancer.

Prostate cancer (PCa) remains a leading cause of cancer-related mortality in aging male, with resistance to enzalutamide (Enza) representing a major therapeutic challenge. This study identifies SLC3A1 as a key driver of Enza resistance. Through integrative bioinformatics analysis of GEO datasets, we found SLC3A1 significantly upregulated in Enza-resistant PCa models. WGCNA and single-cell RNA sequencing confirmed its association with adverse prognosis and activation of key survival pathways. Functional experiments demonstrated that SLC3A1 knockdown reduced AKT phosphorylation, and inhibited colony formation in LNCaP cells. Conversely, SLC3A1 overexpression activated PI3K-AKT signaling, suppressed ferroptosis and conferred Enza resistance in vitro and in vivo. These results reveal SLC3A1 is a promising therapeutic target for advanced prostate cancer.