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bioRxiv · 10.64898/2026.01.05.697595

Empagliflozin alleviates doxorubicin-induced cardiotoxicity by suppressing oxidative stress via modulation of the JNK/Nrf2 signaling pathway

Peng, G.·Ni, L.·Guo, Z.·Huang, L.·Ma, W.·Zheng, F.·Zhang, Y.·Gao, F.·Wang, Z.·Cai, W.
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Abstract

Doxorubicin (DOX) treatment increases the risk of myocardial dysfunction and heart failure, in which oxidative stress plays a central role. Empagliflozin (EMPA) has been shown to benefit heart failure patients, yet its underlying mechanism remains unclear. In this study, we showed that EMPA treatment improved cardiac function, ameliorated structural remodeling, and increased survival in DOX-treated mice. Furthermore, EMPA reduced DOX-induced reactive oxygen species (ROS) overproduction and myocardial injury. Through functional analysis overlapping DIC- and EMPA-regulated genes, we identified the involvement of JNK signaling in addition to redox pathways. Subsequent investigations demonstrated that EMPA restored redox homeostasis by inhibiting JNK activation, reactivating NRF2 and its downstream antioxidant proteins HO-1, NQO1, GPX4, and SOD2 both in vivo and in vitro. These protective effects were abolished by the Nrf2 inhibitor ML385 or the JNK activator anisomycin. Collectively, our findings indicate that EMPA protects against DOX-induced cardiotoxicity by modulating the JNK/Nrf2 signaling and attenuating oxidative stress. This study provides a rationale for further investigation of EMPA as a potential therapeutic strategy for chemotherapy-associated cardiac injury. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/697595v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@16743d4org.highwire.dtl.DTLVardef@96495borg.highwire.dtl.DTLVardef@aa343dorg.highwire.dtl.DTLVardef@4ba18c_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Peng, G., Ni, L., Guo, Z., Huang, L., Ma, W., Zheng, F., Zhang, Y., Gao, F., Wang, Z., Cai, W.. 2026-01-05. Empagliflozin alleviates doxorubicin-induced cardiotoxicity by suppressing oxidative stress via modulation of the JNK/Nrf2 signaling pathway. https://doi.org/10.64898/2026.01.05.697595

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