Integrative transcriptomics and cell systems analyses reveal protective pathways controlled by Igfbp‐3 in anthracycline‐induced cardiotoxicity

Anthracyclines such as doxorubicin (Dox) are effective chemotherapeutic agents; however, their use is hampered by subsequent cardiotoxicity risk. Our understanding of cardiomyocyte protective pathways activated following anthracycline‐induced cardiotoxicity (AIC) remains incomplete. Insulin‐like growth factor binding protein (IGFBP) 3 (Igfbp‐3), the most abundant IGFBP family member in the circulation, is associated with effects on the metabolism, proliferation, and survival of various cells. Whereas Igfbp‐3 is induced by Dox in the heart, its role in AIC is ill‐defined. We investigated molecular mechanisms as well as systems‐level transcriptomic consequences of manipulating Igfbp‐3 in AIC using neonatal rat ventricular myocytes and human‐induced pluripotent stem cell‐derived cardiomyocytes. Our findings reveal that Dox induces the nuclear enrichment of Igfbp‐3 in cardiomyocytes. Furthermore, Igfbp‐3 reduces DNA damage, impedes topoisomerase IIβ expression (Top2β) which forms Top2β‐Dox‐DNA cleavage complex leading to DNA double‐strand breaks (DSB), alleviates detyrosinated microtubule accumulation—a hallmark of increased cardiomyocyte stiffness and heart failure—and favorably affects contractility following Dox treatment. These results indicate that Igfbp‐3 is induced by cardiomyocytes in an effort to mitigate AIC. Doxorubicin induces Igfbp‐3 upregulation and nuclear translocation in cardiomyocytes. Igfpb‐3 overexpression impedes Top2β expression and decreases Dox‐induced dsDNA break. In parallel, the heart failure markers Nppa and Nppb are significantly downregulated, while Cpt1b, Idh3g, and Ndufv1, which positively regulate cellular metabolic activity are significantly upregulated by Igfbp‐3 overexpression. Functionally, Igfbp‐3 knockdown leads to contractile dysfunction in iPSC‐CM after Dox treatment, associated with upregulation of tubulin family genes and accumulation of detyrosinated tubulin.