PROJECT SUMMARY In tandem with recent improvements in anti-cancer treatment efficacy, cancer treatment-related cardiotoxicity has become a serious clinical problem. Doxorubicin-induced cardiotoxicity (DIC) is one of the most common chemotherapy-related cardiotoxicities. Here, combining human induced pluripotent stem cells (iPSCs) with large-scale CRISPR screening, nanotechnology, and engineered 3D cardiac microtissue technology, we will develop a pipeline which enables us to identify therapeutic targets and potential chemical compounds that protect cardiomyocytes from DIC. First, we will perform genome-wide perturbation screening in doxorubicin resistance using CRISPR technology. It will enable us to identify druggable genes that are causative for DIC or essential for resistance in DIC. Second, we will perform high-throughput screening of chemical compounds using nanoparticles. It will enable us to identify cardioprotective chemicals and compile a Cardioprotective Drug Repurposing Library. Third, we will develop a 3D cardiac microtissue platform that can detect cardioprotective effects of the candidate therapies. The 3D cardiac microtissue will consist of iPSC-derived cardiomyocytes, endothelial cells, and fibroblasts, reflective of complex cell-cell interaction and microenvironment. The goal of this proposal is identify cardioprotective therapy for DIC and to develop platforms that are expandable to other cancer treatment-related cardiotoxicities.