Unravelling the role of gene variants in Doxorubicin-Induced Cardiotoxicity

Doxorubicin (DOX), an effective anthracycline chemotherapeutic agent, is widely used for treating various cancers, but its use is limited by dose-dependent cardiotoxicity, which can lead to both acute and chronic cardiovascular complications. The susceptibility of cardiomyocytes to oxidative stress and mitochondrial damage are thought to be central to the development of doxorubicin-induced cardiotoxicity (DIC). Nevertheless, the molecular mechanisms underlying anthracycline-induced cardiotoxicity (AIC) are complex and involve a range of genetic and patient-specific factors, which complicate prediction and management of the disease. Emerging tools, such as genomic and proteomic technologies, hold promise for improving early detection and enabling individualized treatment of AIC. Fonoudi et al. address a critical gap in the functional validation of genetic variants linked to AIC by utilizing human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Their research categorizes genes into six mechanistic groups and employs CRISPR/Cas9 technology to generate knockout lines, identifying several genes that either increase susceptibility to or provide protection against DIC. This systematic approach offers valuable insights into the mechanistic pathways of DIC and highlights the potential of hiPSC-CMs for patient-specific studies. In parallel, the first article by Magdy et al. focus on specific genetic variants and their roles in DIC. They investigate the rs2229774 (S427L) variant in the RARG gene, demonstrating that it increases susceptibility to DIC by affecting topoisomerase 2β (TOP2B) and the extracellular signal-regulated kinase (ERK) pathway. Their findings suggest that RARG agonists, such as CD1530, could mitigate DIC, highlighting a promising cardioprotective strategy. Additionally, the second article by Magdy et al. identify rs11140490 in the SLC28A3 locus as a significant variant associated with cardioprotection. This variant regulates the long noncoding RNA SLC28A3-AS1, influencing DOX uptake and cardioprotection. The study also reveals desipramine (DESP), a tricyclic antidepressant, as a potential cardioprotective agent, although further testing is required. Overall, these findings advance our understanding of genetic factors influencing DIC and highlight the potential of integrating genetic testing into clinical practice to personalize chemotherapy regimens and improve the outcomes for patients at risk of cardiotoxicity