{"doi":"10.1096/fj.202201885rr","title":"Integrative transcriptomics and cell systems analyses reveal protective pathways controlled by Igfbp‐3 in anthracycline‐induced cardiotoxicity","abstract":"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.","journal":"The FASEB Journal","year":2023,"id":352614,"datarank":0.3453877639491069,"base_score":2.302585092994046,"endowment":2.302585092994046,"self_citation_contribution":0.3453877639491069,"citation_network_contribution":0.0,"self_endowment_contribution":0.3453877639491069,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9595,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":579353,"name":"Douglas J. Chapski","orcid":"0000-0002-6730-7627","position":1,"is_corresponding":false},{"id":906470,"name":"Jeremy Jong","orcid":null,"position":2,"is_corresponding":false},{"id":1098932,"name":"Jerome Awada","orcid":null,"position":3,"is_corresponding":false},{"id":291456,"name":"Yijie Wang","orcid":"0000-0002-2681-0138","position":4,"is_corresponding":false},{"id":33579,"name":"Dennis J. Slamon","orcid":"0000-0002-6330-498X","position":5,"is_corresponding":false},{"id":597356,"name":"Thomas M. Vondriska","orcid":"0009-0000-5238-1245","position":6,"is_corresponding":false},{"id":584469,"name":"René R. Sevag Packard","orcid":"0000-0002-8520-5843","position":7,"is_corresponding":false},{"id":892882,"name":"Junjie Chen","orcid":"0000-0002-8984-1986","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:12:54.209378Z","pmid":"37219486","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}