Preclinical humanized bone models reveal metabolic reprogramming and simvastatin benefits in castration-resistant prostate cancer in bone

Although initially effective to treat prostate cancer (PCa), resistance to antiandrogen therapies is inevitable and leads to metastatic castration-resistant PCa. Bone marrow adipocytes (BMAs) may play a role in bone metastasis therapy resistance by promoting metabolic reprogramming, yet their value as a therapeutic target remains understudied due to a lack of relevant models. Here, we used multicellular, modular hydrogel models in advanced humanized settings to examine the value of BMA targeting in advanced PCa. Our in vitro and in vivo findings confirmed that BMAs induce lipid metabolism dysregulation and pro-inflammatory signaling, creating a tumor-supportive environment that fosters resistance to androgen deprivation. Combining enzalutamide with the anti-cholesterol drug simvastatin significantly reduced these effects, notably through ferroptosis and bone tumor microenvironment modulations, impairing cancer cell survival. This study suggests that targeting BMA-PCa interactions with simvastatin may enhance enzalutamide’s efficacy, emphasizing the synergistic value of human-specific multicellular preclinical models for assessing therapeutic strategies in bone metastasis.