Repurposing the hERG activator NS-1643 as a ferroptosis-targeting therapeutic against doxorubicin cardiotoxicity

Cardiovascular diseases arise from intertwined cell-death and stress-response pathways, underscoring the need for therapeutics that extend beyond single-target mechanisms. Seeking drug-repurposing opportunities within existing cardiovascular agents, we screened clinically explored compounds for unrecognized cytoprotective activity and identified the hERG/Kv11.1 activator NS-1643-originally developed as an antiarrhythmic candidate-as a potent Ferroptosis inhibitor. NS-1643 broadly suppressed GPX4 inhibitor-induced ferroptotic death across diverse cell types, whereas Other hERG modulators were inactive, and neither pharmacologic blockade nor genetic silencing of hERG altered its efficacy, demonstrating that its protective mechanism is independent of ion-channel modulation. Mechanistic profiling showed that NS-1643 does not restore canonical ferroptosis-defense systems, but instead operates as a direct lipid-peroxyl radical trapper, supported by radical-scavenging assays and density functional theory revealing an energetically favorable hydrogen-atom transfer mediated by its ortho-amino-phenolic motif. In a murine model of doxorubicin (DOX) cardiotoxicity, NS-1643 markedly improved survival, preserved systolic performance, and reduced myocardial injury, fibrosis, and 4-HNE accumulation, whereas the comparator hERG agonist NS-3623 conferred no benefit. These findings reposition NS-1643 as a dual-mechanism, ferroptosis-targeting cardioprotective agent and illustrate how drug repurposing can reveal multi-target therapeutic potential within existing cardiovascular chemical space, offering a promising strategy to mitigate anthracycline-induced cardiac injury.