This study functionally validates genes associated with doxorubicin-induced cardiotoxicity (DIC) using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The researchers identified 80 genes linked to anthracycline-induced cardiotoxicity (AIC) through genome-wide association studies and candidate gene association studies. These genes were systematically knocked out in hiPSC-CMs to assess their impact on DIC. The study found that knocking out 26 genes increased the susceptibility of hiPSC-CMs to DIC, with notable genes including efflux transporters, well-established DIC-associated genes, and genome-wide association study-discovered genes. Conversely, knocking out other genes had no significant effect on DIC. The study also identified that knocking out uptake transporters protected against DIC. The findings establish a comprehensive platform for functional validation of DIC-associated genes, providing insights into potential mechanistic targets for developing cardioprotective drugs. The study highlights the role of genes in ROS production, DNA damage, iron uptake, doxorubicin uptake, calcium handling, and electric activity in DIC. The results confirm that more than 55% of the DIC genes identified in association studies are expressed in cardiac cells, reliably recapitulating alterations in DIC phenotype in the hiPSC-CM model. The study also identifies potential genetic variants that may be used to predict DIC risk and develop personalized treatment strategies. The study has limitations, including the need for further research on individual SNP corrections and patient-specific hiPSC-CMs. Overall, the study provides a valuable resource for understanding the genetic basis of DIC and developing targeted therapies to prevent doxorubicin-induced cardiotoxicity.This study functionally validates genes associated with doxorubicin-induced cardiotoxicity (DIC) using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The researchers identified 80 genes linked to anthracycline-induced cardiotoxicity (AIC) through genome-wide association studies and candidate gene association studies. These genes were systematically knocked out in hiPSC-CMs to assess their impact on DIC. The study found that knocking out 26 genes increased the susceptibility of hiPSC-CMs to DIC, with notable genes including efflux transporters, well-established DIC-associated genes, and genome-wide association study-discovered genes. Conversely, knocking out other genes had no significant effect on DIC. The study also identified that knocking out uptake transporters protected against DIC. The findings establish a comprehensive platform for functional validation of DIC-associated genes, providing insights into potential mechanistic targets for developing cardioprotective drugs. The study highlights the role of genes in ROS production, DNA damage, iron uptake, doxorubicin uptake, calcium handling, and electric activity in DIC. The results confirm that more than 55% of the DIC genes identified in association studies are expressed in cardiac cells, reliably recapitulating alterations in DIC phenotype in the hiPSC-CM model. The study also identifies potential genetic variants that may be used to predict DIC risk and develop personalized treatment strategies. The study has limitations, including the need for further research on individual SNP corrections and patient-specific hiPSC-CMs. Overall, the study provides a valuable resource for understanding the genetic basis of DIC and developing targeted therapies to prevent doxorubicin-induced cardiotoxicity.