Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

ROS-induced degradation of hERG potassium channels contributes to aripiprazole-induced prolongation of the QTc interval

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

As antipsychotic administration often persists for a lifetime, antipsychotic-induced cardiotoxicity (AIC) becomes a significant and potentially life-threatening side effect. Owing to the lack of an appropriate human cardiomyocyte experimental model, current research on AIC is primarily based on clinical case reports. In this study, we generated human iPSC-derived cardiomyocytes (iPSC-CMs) and characterized the cardiotoxicity of 6 antipsychotics (clozapine, haloperidol, quetiapine, olanzapine, risperidone, and aripiprazole) used in clinical practice. Multielectrode array analysis revealed that all 6 antipsychotics, when used within their respective clinical plasma concentration (CPC) ranges, were likely to cause a significantly prolonged field potential duration (FPD) in iPSC-CMs. Moreover, administration of the third-generation antipsychotic aripiprazole (10 mg/kg, i.g.) led to marked QT interval prolongation in beagle dogs. We demonstrated that aripiprazole administration resulted in mitochondrial damage and oxidative stress, which accelerated protein degradation of human ether-à-go-go-related gene (hERG) channels, generating a rapid delayed rectifying potassium current (IKr) through the proteasome pathway, ultimately leading to FPD prolongation. Scavenging reactive oxygen species or suppressing the ubiquitin‒proteasome pathway (UPP) significantly restored hERG channel function and rescued the prolonged FPD phenotype in aripiprazole-treated iPSC-CMs. Our results suggest that caution should be taken when aripiprazole is prescribed to high-risk patients with preexisting comorbidities. Manipulation of excessive oxidative stress or suppression of the UPP may offer novel therapeutic strategies for mitigating aripiprazole-induced proarrhythmic risk.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The MEA/iPSC-CMs platform reveals antipsychotic-induced FPD/FPDc prolongation within clinical plasma concentration ranges.
Fig. 2: Antipsychotics at their respective CPCs do not affect the sarcomeric structure in iPSC-CMs.
Fig. 3: Antipsychotics affect the mitochondrial structure in iPSC-CMs within their respective CPC ranges.
Fig. 4: Chronic treatment of aripiprazole at its CPC causes FPD/FPDc prolongation in iPSC-CMs.
Fig. 5: Aripiprazole causes QT/QTc prolongation in beagle dogs.
Fig. 6: ROS-mediated accelerated protein degradation of hERG potassium channels in aripiprazole-treated iPSC-CMs.
Fig. 7: Scavenging ROS or suppressing the ubiquitin-proteasome pathway effectively restores the hERG channel function and rescues the prolonged FPD phenotype in aripiprazole-treated iPSC-CMs.
Fig. 8: Proposed work model of aripiprazole-induced cardiotoxicity.

Similar content being viewed by others

References

  1. Krogmann A, Peters L, von Hardenberg L, Bödeker K, Nöles VB, Correill CU. Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities. CNS Spectr. 2019;24:41–68.

    Article  Google Scholar 

  2. Gnanavel S, Hussain S. Audit of physical health monitoring in children and adolescents receiving antipsychotics in neurodevelopmental clinics in Northumberland. World J Psychiatr. 2018;8:27–32.

    Article  PubMed  PubMed Central  Google Scholar 

  3. D’Errico S, La Russa R, Maiese A, Santurro A, Scopetti M, Romano S, et al. Atypical antipsychotics and oxidative cardiotoxicity: review of literature and future perspectives to prevent sudden cardiac death. J Geriatr Cardiol. 2021;18:663–85.

    PubMed  PubMed Central  Google Scholar 

  4. Salvo F, Pariente A, Shakir S, Robinson P, Arnaud M, Thomas SHL, et al. Sudden cardiac and sudden unexpected death related to antipsychotics: a meta-analysis of observational studies. Clin Pharmacol Ther. 2016;99:306–14.

    Article  CAS  PubMed  Google Scholar 

  5. Li XQ, Tang XR, Li LL. Antipsychotics cardiotoxicity: What’s known and what’s next. World J Psychiatr. 2021;11:736–53.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Savoji H, Mohammadi MH, Rafatian N, Toroghi MK, Wang EY, Zhao YM, et al. Cardiovascular disease models: a game changing paradigm in drug discovery and screening. Biomaterials. 2019;198:3–26.

    Article  CAS  PubMed  Google Scholar 

  7. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.

    Article  CAS  PubMed  Google Scholar 

  8. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–20.

    Article  CAS  PubMed  Google Scholar 

  9. Liang P, Lan F, Lee AS, Gong T, Sanchez-Freire V, Wang Y, et al. Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation. 2013;127:1677–91.

    Article  CAS  PubMed  Google Scholar 

  10. Navarrete EG, Liang P, Lan F, Sanchez-Freire V, Simmons C, Gong T, et al. Screening drug-induced arrhythmia [corrected] using human induced pluripotent stem cell-derived cardiomyocytes and low-impedance microelectrode arrays. Circulation. 2013;128:S3–13.

    Article  CAS  PubMed  Google Scholar 

  11. Shen J, Wang X, Zhou D, Li T, Tang L, Gong T, et al. Modelling cadmium-induced cardiotoxicity using human pluripotent stem cell-derived cardiomyocytes. J Cell Mol Med. 2018;22:4221–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang X, Pan Z, Wang J, Wang H, Fan H, Gong T, et al. Characterization of the molecular mechanisms underlying azithromycin-induced cardiotoxicity using human-induced pluripotent stem cell-derived cardiomyocytes. Clin Transl Med. 2021;11:e549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhou J, Cui B, Wang X, Wang H, Zheng J, Guo F, et al. Overexpression of KCNJ2 enhances maturation of human-induced pluripotent stem cell-derived cardiomyocytes. Stem Cell Res Ther. 2023;14:92–10.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lian X, Hsiao C, Wilson G, Zhu K, Hazeltine LB, Azarin SM, et al. Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc Natl Acad Sci USA. 2012;109:E1848–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wu H, Lee J, Vincent LG, Wang Q, Gu M, Lan F, et al. Epigenetic regulation of phosphodiesterases 2A and 3A underlies compromised β-adrenergic signaling in an iPSC model of dilated cardiomyopathy. Cell Stem Cell. 2015;17:89–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Streckfuss-Bömeke K, Tiburcy M, Fomin A, Luo X, Li W, Fischer C, et al. Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specific induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol. 2017;113:9–21.

    Article  PubMed  Google Scholar 

  17. Valente AJ, Maddalena LA, Robb EL, Moradi F, Stuart JA. A simple ImageJ macro tool for analyzing mitochondrial network morphology in mammalian cell culture. Acta Histochem. 2017;119:315–26.

    Article  CAS  PubMed  Google Scholar 

  18. Patteet L, Morrens M, Maudens KE, Niemegeers P, Sabbe B, Neels H. Therapeutic drug monitoring of common antipsychotics. Ther Drug Monit. 2012;34:629–51.

    Article  CAS  PubMed  Google Scholar 

  19. Cole LA, Dennis JH, Chase PB. Commentary: epigenetic regulation of phosphodiesterases 2A and 3A underlies compromised β-adrenergic signaling in an iPSC model of dilated cardiomyopatyh. Front Physiol. 2016;7:418–21.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Twig G, Elorza A, Molina AJA, Mohamed H, Wikstrom JD, Walzer G, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27:433–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fermini B, Fossa AA. The impact of drug-induced QT interval prolongation on drug discovery and development. Nat Rev Drug Discov. 2003;2:439–47.

    Article  CAS  PubMed  Google Scholar 

  22. U.S. Food and Drug Administration.Industry guidance: S7A safety pharmacology studies for human pharmaceuticals. FDA. 2000.

  23. Government of Canada, Health Canada. Guidance for industry: The non-clinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals: ICH topic S7B. Health Products and Food Branch. 2005.

  24. Wang N, Kang HS, Ahmmed G, Khan SA, Makarenko VV, Prabhakar NR, et al. Calpain activation by ROS mediates human ether-a-go-go-related gene protein degradation by intermittent hypoxia. Am J Physiol Cell Physiol. 2016;310:C329–36.

    Article  CAS  PubMed  Google Scholar 

  25. Taglialatela M, Castaldo P, Iossa S, Pannaccione A, Fresi A, Ficker E, et al. Regulation of the human ether-a-gogo related gene (HERG) K+ channels by reactive oxygen species. Proc Natl Acad Sci USA. 1997;94:11698–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nanduri J, Bergson P, Wang N, Ficker E, Prabhakar NR. Hypoxia inhibits maturation and trafficking of hERG K+ channel protein: role of Hsp90 and ROS. Biochem Biophys Res Commun. 2009;388:212–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Creanza TM, Delre P, Ancona N, Lentini G, Saviano M, Mangiatordi GF. Structure-based prediction of hERG-related cardiotoxicity: a benchmark study. J Chem Inf Model. 2021;61:4758–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Vandenberg JI, Perry MD, Perrin MJ, Mann SA, Ke Y, Hill AP. hERG K+ channels: structure, function, and clinical significance. Physiol Rev. 2012;92:1393–478.

    Article  CAS  PubMed  Google Scholar 

  29. Cabassa LJ, Manrique Y, Meyreles Q, Capitelli L, Younge R, Dragatsi D, et al. Treated me … like I was family”: qualitative evaluation of a culturally-adapted health care manager intervention for Latinos with serious mental illness and at risk for cardiovascular disease. Transcult Psychiatry. 2019;56:1218–36.

    Article  PubMed  Google Scholar 

  30. Friis K, Aaby A, Lasgaard M, Pedersen MH, Osborne RH, Maindal HT. Low health literacy and mortality in individuals with cardiovascular disease, chronic obstructive pulmonary disease, diabetes, and mental illness: a 6-year population-based follow-up study. Int J Environ Res Public Health. 2020;17:9399.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Polcwiartek C, Kragholm K, Hansen SM, Atwater BD, Friedman DJ, Barcella CA, et al. Electrocardiogram characteristics and their association with psychotropic drugs among patients with schizophrenia. Schizophr Bull. 2020;46:354–62.

    PubMed  Google Scholar 

  32. Antoniou CK, Dilaveris P, Manolakou P, Galanakos S, Magkas N, Gatzoulis K, et al. QT prolongation and malignant arrhythmia: How serious a problem? Eur Cardiol. 2017;12:112–20.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Adetiloye AO, Abdelmottaleb W, Ahmed MF, Victoria AM, Ozbay MB, Valencia Manrique JC, et al. Clozapine-induced myocarditis in a young man with refractory schizophrenia: case report of a rare adverse event and review of the literature. Am J Case Rep. 2022;23:e936306.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Tisdale JE. Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management. Can Pharmacol J. 2016;149:139–52.

    Article  Google Scholar 

  35. Meyer-Massetti C, Cheng CM, Sharpe BA, Meier CR, Guglielmo BJ. The FDA extended warning for intravenous haloperidol and torsades de pointes: how should institutions respond? J Hosp Med. 2010;5:E8–16.

    Article  PubMed  Google Scholar 

  36. Aronow WS, Shamliyan TA. Effects of atypical antipsychotic drugs on QT interval in patients with mental disorders. Ann Transl Med. 2018;6:147.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Beach SR, Celano CM, Sugrue AM, Adams C, Ackerman MJ, Noseworthy PA, et al. QT prolongation, torsades de pointes, and psychotropic medications: a 5-year update. Psychosomatics. 2018;59:105–22.

    Article  PubMed  Google Scholar 

  38. Arzuk E, Karakus F, Orhan H. Bioactivation of clozapine by mitochondria of the murine heart: possible cause of cardiotoxicity. Toxicology. 2021;447:152628.

    Article  CAS  PubMed  Google Scholar 

  39. McGill MR, Jaeschke H. Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharmacol Res. 2013;30:2174–87.

    Article  CAS  Google Scholar 

  40. Elmorsy E, Al-Ghafari A, Aggour AM, Mosad SM, Khan R, Amer S. Effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells. Toxicol Lett. 2017;272:94–100.

    Article  CAS  PubMed  Google Scholar 

  41. Balijepalli S, Kenchappa RS, Boyd MR, Ravindranath V. Protein thiol oxidation by haloperidol results in inhibition of mitochondrial complex I in brain regions: comparison with atypical antipsychotics. Neurochem Int. 2001;38:425–35.

    Article  CAS  PubMed  Google Scholar 

  42. Beauchemin M, Geguchadze R, Guntur AR, Nevola K, Le PT, Barlow D, et al. Exploring mechanisms of increased cardiovascular disease risk with antipsychotic medications: risperidone alters the cardiac proteomic signature in mice. Pharmacol Res. 2020;152:104589.

    Article  CAS  PubMed  Google Scholar 

  43. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995;81:299–307.

    Article  CAS  PubMed  Google Scholar 

  44. Arcangeli A, Bianchi L, Becchetti A, Faravelli L, Coronnello M, Mini E, et al. A novel inward-rectifying K+ current with a cell-cycle dependence governs the resting potential of mammalian neuroblastoma cells. J Physiol. 1995;489:455–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995;80:795–803.

    Article  CAS  PubMed  Google Scholar 

  46. Preda A, Shapiro BB. A safety evaluation of aripiprazole in the treatment of schizophrenia. Expert Opin Drug Saf. 2020;19:1529–38.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Xiao-li Hong and Chao Bi from the Core Facilities of Zhejiang University School of Medicine for their technical support. This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0521500, 2024ZD0521502) (PL); the “LingYan” Research and Development Project (2024C03155) (PL); and the National Natural Science Foundation of China (82370354) (PL), (82204348) (YHC), and (82400372) (XCW). PL would like to thank Tiffany Gong, Natalie Liang, and Michael Liang for their encouragement and consistent support.

Author information

Author notes

  1. These authors contributed equally: Yu-hong Cao, Xiao-chen Wang

Authors and Affiliations

  1. Key Laboratory of Combined Multiorgan Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Yu-hong Cao, Xiao-chen Wang, Hong-kun Wang, Zong-kuai Yang, Dan-dan Liu & Ping Liang

  2. Institute of Translational Medicine, Zhejiang University, Hangzhou, 310029, China

    Yu-hong Cao, Xiao-chen Wang, Hong-kun Wang, Zong-kuai Yang, Dan-dan Liu & Ping Liang

  3. NMPA Key Laboratory for Animal Alternative Testing Technology of Cosmetics, Zhejiang Institute for Food and Drug Control, Hangzhou, 310052, China

    Yu-hong Cao, Yang Yang & Rong Kuang

  4. School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua, 418000, China

    Yu-hong Cao

Authors
  1. Yu-hong Cao
    View author publications

    Search author on:PubMed Google Scholar

  2. Xiao-chen Wang
    View author publications

    Search author on:PubMed Google Scholar

  3. Hong-kun Wang
    View author publications

    Search author on:PubMed Google Scholar

  4. Zong-kuai Yang
    View author publications

    Search author on:PubMed Google Scholar

  5. Dan-dan Liu
    View author publications

    Search author on:PubMed Google Scholar

  6. Yang Yang
    View author publications

    Search author on:PubMed Google Scholar

  7. Rong Kuang
    View author publications

    Search author on:PubMed Google Scholar

  8. Ping Liang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

RK and PL designed and supervised the study. YHC, XCW, HKW, ZKY, and DDL performed the experiments and analyzed the data. YHC and PL wrote the manuscript.

Corresponding authors

Correspondence to Rong Kuang or Ping Liang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cao, Yh., Wang, Xc., Wang, Hk. et al. ROS-induced degradation of hERG potassium channels contributes to aripiprazole-induced prolongation of the QTc interval. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01648-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41401-025-01648-x

Keywords

Search

Advanced search

Quick links