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Repurposing the hERG activator NS-1643 as a ferroptosis-targeting therapeutic against doxorubicin cardiotoxicity
Xie-Huang Sheng1, Lin-Song Teng2, Xin-Hui Wang1
1College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan, 250014, China.
Abstract:
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.
Insights
The drug NS-1643, initially an antiarrhythmic, shows potent ferroptosis inhibition, independent of its hERG channel activity. This repurposed drug protects against doxorubicin-induced cardiotoxicity by trapping radicals.
Area of Science:
- Biochemistry
- Cardiology
- Pharmacology
Background:
- Cardiovascular diseases involve complex cell-death and stress-response pathways, necessitating multi-target therapeutic strategies.
- Drug repurposing offers a viable approach to identify novel therapeutic applications for existing cardiovascular agents.
Purpose of the Study:
- To screen clinically explored cardiovascular compounds for unrecognized cytoprotective activities.
- To identify and characterize the ferroptosis inhibitory mechanism of NS-1643.
- To evaluate the cardioprotective efficacy of NS-1643 in a murine model of doxorubicin-induced cardiotoxicity.
Main Methods:
- Screening of clinically explored compounds for cytoprotective activity against ferroptosis.
- Assessing NS-1643's efficacy in suppressing GPX4 inhibitor-induced ferroptosis across various cell types.
- Investigating the mechanism of action through radical-scavenging assays and density functional theory calculations.
- Evaluating NS-1643's cardioprotective effects in a murine model of doxorubicin (DOX) cardiotoxicity.
Main Results:
- NS-1643 was identified as a potent ferroptosis inhibitor, effective across diverse cell types.
- Its ferroptosis inhibitory mechanism is independent of hERG/Kv11.1 ion channel modulation.
- NS-1643 functions as a direct lipid-peroxyl radical trapper via its ortho-amino-phenolic motif.
- In vivo, NS-1643 significantly improved survival and reduced cardiac injury in a murine model of DOX cardiotoxicity.
Conclusions:
- NS-1643 is repositioned as a dual-mechanism cardioprotective agent targeting ferroptosis.
- Drug repurposing of cardiovascular agents can uncover multi-target therapeutic potential.
- NS-1643 presents a promising strategy for mitigating anthracycline-induced cardiac injury.
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