Disrupting SCD acitivty supresses prostate cancer progression in bone through modulating cellular stress, mTOR signaling and DNA damage

The mechanisms supporting progression of metastatic prostate cancer (PCa) in adipocyte-rich bone marrow remain unclear. We hypothesized that Stearoyl-Coenzyme A Desaturase (SCD) promotes PCa survival in bone by modulating stress responses and regulating lipid peroxidation. We show that SCD-high PCa cells are sensitive to SCD loss, showing smaller spheroids, reduced mTOR signaling, and elevated ER stress. SCD expression is further augmented by adipocytes, and SCD loss induces DNA damage and repair activation only with adipocyte exposure. In vivo, pharmacological SCD inhibition reduces tumor size and increases ER stress and DNA damage in SCD-overexpressing bone tumors. These findings suggest SCD plays a role in redox regulation and DNA repair sensitivity, with therapeutic potential for targeting DNA repair pathways in combination with SCD inhibition.