Diminished expression of decorin drives enzalutamide resistance in CRPC by suppressing ACSL4-dependent lipid...

Enzalutamide is a potent androgen receptor (AR) inhibitor widely used for the treatment of castration-resistant prostate cancer (CRPC). However, the development of drug resistance severely limits its therapeutic efficacy, and the underlying mechanisms remain poorly understood. We have demonstrated that decorin (DCN), a suppressor of prostate cancer (PCa) progression, is significantly down-regulated in enzalutamide-resistant PCa cells. Therefore, we hypothesized that diminished expression of DCN contributes to enzalutamide resistance in PCa. In this study, we found that DCN was decreased in enzalutamide-resistant LNCaP cells (LNCaP-ER), which exhibited resistance to ferroptosis. Consistently, DCN was significantly reduced in high-grade PCa and CRPC tissues, as well as in those with poor clinical survival outcomes through integrative analysis. Moreover, DCN overexpression re-sensitized LNCaP-ER cells to enzalutamide by activating ferroptosis. What's more, DCN overexpression significantly inhibited tumor growth and metastasis of LNCaP-ER cells in vivo under enzalutamide-treated conditions, in a ferroptosis-dependent manner. Mechanistically, DCN activated calcium-dependent Protein Kinase C Beta II (PKCβII), thereby enhancing phosphorylation of long-chain acyl-CoA synthetase 4 (ACSL4) to regulate lipid remodeling and promote ferroptosis. In addition, enzalutamide-mediated AR nuclear translocation negatively regulates DCN transcription. In conclusion, promoting DCN-mediated ferroptosis might be a potential strategy for enhancing the sensitivity of enzalutamide in PCa cells. This study delineates a novel mechanism by which DCN downregulation suppresses ferroptosis and drives enzalutamide resistance in CRPC.