Zhong et al. demonstrate that SREBP-1 and SOAT1 are co-upregulated in GBM and NSCLC, coupling cholesterol acquisition and storage. They reveal that SREBP-1 transcriptionally activates SOAT1, enabling cancer cells to sustain cholesterol homeostasis, and that targeting SOAT1 disrupts this balance, leading to ROS accumulation, mitochondrial dysfunction, and tumor cell death.