Targeting the PKR1 pathway and the ROS/NRF/PK2 axis for cardioprotection and biomarker discovery in anthracycline therapy

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ID: 323337
2026
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Ranked #150 of 282 articles by views in European heart journal supplements : journal of the European Society of Cardiology

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Abstract
Abstract Background and purpose Anthracycline-induced cardiotoxicity limits cancer treatment efficacy and long-term cardiac outcomes. Dexrazoxane, the only approved cardioprotective agent, has restricted use, underscoring the need for mechanism-based alternatives. Prokineticins (PK1, PK2) and their receptors (PKR1, PKR2) regulate cardiac stress responses. We investigated the cardioprotective potential of the selective PKR1 agonist IS20 and assessed PK2 as a mechanistic and biomarker candidate in doxorubicin (DOX)-induced cardiotoxicity. Methods and Results In hiPSC-derived cardiomyocytes, cardiac spheroids, and murine models, IS20 preserved cardiac function by activating Akt and MAPK pathways, reducing apoptosis and fibrosis, and improving survival without compromising DOX antitumor efficacy. Genetic or pharmacological PKR1 inhibition abolished these effects, confirming receptor specificity. Plasma analysis from 200 oncology patients receiving anthracyclines or tyrosine kinase inhibitors showed that troponin I predicted early cardiotoxicity. Notably, PK2 levels significantly increased post-treatment and inversely correlated with left ventricular ejection fraction, supporting its biomarker potential. Mechanistically, DOX-induced reactive oxygen species upregulated PK2 via a novel NRF-dependent transcriptional pathway, independent of HIF1α. In cancer spheroids, elevated ROS enhanced DOX efficacy and induced hypoxia-independent PK2 expression. Conclusion The ROS/NRF/PK2 axis emerges as a key mediator of anthracycline cardiotoxicity. Targeting PKR1 with IS20 and monitoring PK2 may improve cardioprotection and risk stratification in cancer therapy
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openalex_W7172319224 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors C G Nebigil
Journal European heart journal supplements : journal of the European Society of Cardiology
Year 2026
DOI
10.1093/eurheartjsupp/suag097.209
URL
https://doi.org/10.1093/eurheartjsupp/suag097.209
Keywords Keywords not found

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