PhD Scientific Days 2026

Pharmaceutical Sciences and Health Technologies 3.

Febuxostat potentiates doxorubicin-induced cardiac remodelling in mice

Name of the presenter

Jezsoviczky, Sára

Institute/workplace of the presenter

Department of Pharmacology and Pharmacotherapy

Authors

Sára Jezsoviczky^1,2, Artúr Tóth^1,2, Márk E. Jakab^1,2,3, Szabolcs Farkas^1,2, Péter Ferdinandy^1,2,4,5, Zoltán V. Varga^1,2,3, Zsófia Onódi^1,2,3
1: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
2: Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary
3: MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, Budapest, Hungary
4: Pharmahungary Group, Szeged, Hungary
5: HUN-REN-SU System Pharmacology Research Group, Semmelweis University, Budapest, Hungary

Text of the abstract

Introduction: Clinical trials evaluating the cardiovascular risk of the anti-gout medication febuxostat (FEBU) show contradictory mortality results. As FEBU is often prescribed alongside cardiotoxic chemotherapeutics like doxorubicin (DOXO), assessing their combined cardiac risk is important.
Aims: This study investigated whether FEBU exacerbates DOXO-induced cardiotoxicity in a murine model of cardiomyopathy.
Methods: Ten-week-old female BALB/c mice were randomised into four groups: control (n=12), FEBU (n=12), DOXO (n=13), and DOXO+FEBU (n=13). To induce subacute cardiomyopathy, mice received DOXO (5 mg/kg) or saline intraperitoneally twice weekly to reach a cumulative dose of 20 mg/kg. Concurrent FEBU (20 mg/kg) or vehicle was administered via oral gavage. Body and organ weights were recorded, while cardiac structure and function was assessed via echocardiography, histology and qRT-PCR.
Results: Both DOXO and DOXO+FEBU groups exhibited weight loss compared to controls, however, the combination therapy caused significantly greater weight loss than DOXO alone. In both DOXO and DOXO+FEBU groups the ex vivo heart weights were reduced. Only the DOXO+FEBU group showed significantly elevated left ventricular end-diastolic and systolic volume indices, as well as significantly decreased left ventricular remodelling index. Furthermore, co-administration reduced structural parameters, like diastolic and systolic left ventricular posterior wall thickness, as well as the relative wall thickness of the heart. Picrosirius red staining confirmed increased myocardial fibrosis in both DOXO and DOXO+FEBU groups compared to controls. qRT-PCR measurements revealed significantly upregulated Nppa, Ctgf and Myh7 mRNA levels, while Myh6/Myh7 ratio was significantly reduced.
Conclusion: FEBU co-administration exacerbates adverse cardiac remodelling and functional impairment in DOXO-induced cardiomyopathy. These findings suggest a potential drug interaction that warrants further mechanistic investigation to ensure patient safety.
Funding: This project was funded by the European Union [Project no. RRF-2.3.1-21-2022-00003], by the Momentum Research Grant from the Hungarian Academy of Sciences (LP- 2021-38), by the NRDIO of Hungary [NKKP STARTING 152247] and by Semmelweis 250+ Excellence Fellowship.