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. 2025 Jun;182(11):2409-2425.
doi: 10.1111/bph.17468. Epub 2025 Feb 11.

Targeting FDX1 by trilobatin to inhibit cuproptosis in doxorubicin-induced cardiotoxicity

Jiajia Wei  1   2 , Guozhen Lan  1   2 , Wenfang Zhang  1   2 , Wang Ran  1   2 , Yu Wei  3 , Xin Liu  4 , Yuandong Zhang  1   2 , Qihai Gong  1   2 , Haibo Li  4 , Jianmei Gao  1   2
Affiliations

Targeting FDX1 by trilobatin to inhibit cuproptosis in doxorubicin-induced cardiotoxicity

Jiajia Wei et al. Br J Pharmacol. 2025 Jun.

Abstract

Background and purpose: Doxorubicin (DOX), an anthracycline chemotherapeutic agent, whose use is limited owing to its dose-dependent cardiotoxicity. Mitochondrial oxidative stress plays a crucial role in the pathogenesis of DOX-induced cardiotoxicity (DIC). Trilobatin (TLB), a naturally occurring food additive, exhibits strong antioxidant properties, but its cardioprotective effects in DIC is unclear. This study investigates the cardioprotective effect of TLB on DIC.

Experimental approach: DOX was used to generate an in vivo and in vitro model of cardiotoxicity. Echocardiography, enzyme-linked immunosorbent assay (ELISA) and haematoxylin and eosin (H&E) staining were used to evaluate the cardiac function in these models. To identify the targets of TLB, RNA-sequence analysis, molecular dynamics simulations, surface plasmon resonance binding assays and protein immunoblotting techniques were used. Transmission electron microscopy, along with dihydroethidium and Mito-SOX staining, was conducted to examine the impact of trilobatin on mitochondrial oxidative stress. SiRNA transfection was performed to confirm the role of ferredoxin 1 (FDX1) in DIC development.

Key results: In DIC mice, TLB improved cardiac function in a dose-dependent manner and inhibited myocardial fibrosis in DIC mice. TLB also attenuated DOX-induced mitochondrial dysfunction and reduced cardiac mitochondrial oxidative stress. TLB was found to directly bind to FDX1 and suppresses cuproptosis after DOX treatment, causing significant inhibition of cuproptosis-related proteins.

Conclusions and implications: This is the first study to show that TLB strongly inhibits DIC by reducing mitochondrial oxidative stress and controlling DOX-mediated cuproptosis by targeting FDX1. Therefore, TLB is as a potential phytochemical cardioprotective candidate for ameliorating DIC.

Keywords: cardiotoxicity; cuproptosis; doxorubicin; ferredoxin 1; oxidative stress; trilobatin.

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