Inhibition, But Not Depletion, of Erk Signaling Ameliorates Anthracycline-Induced Cardiotoxicity in Zebrafish.

BACKGROUND: Anthracycline-induced cardiotoxicity (AIC) is a unique type of cardiomyopathy that limits the clinical use of anthracyclines in cancer therapy. Although several cardiomyopathy-related pathways have been identified, including extracellular signal-regulated kinase (ERK) signaling, pathway-specific interventions for AIC remain unclear. OBJECTIVES: The aim of this study was to investigate the role of Erk signaling in AIC using zebrafish genetics. METHODS: A zebrafish model of AIC was used to screen genes in known cardiomyopathy pathways, including Erk signaling. Heterozygous and homozygous mutants were evaluated for their modifying effects on AIC. In parallel, pharmacologic studies with ERK inhibitors were conducted to assess dose-dependent therapeutic effects of Erk inhibition. RESULTS: mek1+/- and erk1+/- mutants conferred protective effects in adult zebrafish with AIC. Consistent with this, Erk phosphorylation was aberrantly elevated in AIC hearts. Although heterozygous mutants mitigated AIC phenotypes, homozygous erk1-/- mutants caused cardiac dysfunction and worsened AIC. Similarly, pharmacologic inhibition of Erk with temuterkib was therapeutic at low doses but induced dose-dependent cardiotoxicity. Mechanistically, the AIC model exhibited accelerated cardiac senescence, which can be attenuated by Erk inhibition. CONCLUSIONS: Aberrant Erk activation contributes to AIC, and controlled Erk inhibition may offer therapeutic benefit, potentially via antiaging mechanisms. However, optimization is essential, as excessive inhibition can be cardiotoxic.