Work

Empagliflozin alleviates doxorubicin-induced myocardial injury by inhibiting RIP3-dependent TLR4/MyD88/NF-κB signaling pathway

Year: 2025

Type: article

Abstract: Doxorubicin (DOX), a widely used chemotherapeutic agent, is associated with dose-dependent cardiotoxicity that limits its clinical application. Emerging evidence implicates that receptor-interacting protein kinase 3 (RIP3) and the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor kappa-B (NF-κB) signaling pathway play pivotal roles in DOX-induced cardiac inflammation and cell death. Empagliflozin, an sodium-glucose co-transporter 2 (SGLT2) inhibitor, has shown potential cardioprotective effects independent of its glucose-lowering actions. This study investigated the cardioprotective role of empagliflozin in DOX-induced myocardial injury, with a focus on the mechanistic involvement of RIP3-mediated signaling.Using a murine DOX-induced cardiotoxicity model and H9C2 cardiomyocytes, empagliflozin was found to significantly attenuate DOX-induced cardiac dysfunction, histopathological damage, and oxidative stress. DOX administration led to upregulation of RIP3 and activation of the TLR4/MyD88/NF-κB pathway, accompanied by increased markers of apoptosis and ferroptosis. Empagliflozin treatment reversed these molecular changes. In vitro overexpression of RIP3 exacerbated DOX-induced inflammatory signaling and cardiomyocyte injury, while empagliflozin effectively mitigated these effects.These findings suggest that empagliflozin protects against DOX-induced myocardial injury by suppressing RIP3-dependent activation of the TLR4/MyD88/NF-κB signaling pathway, thereby reducing both apoptotic and ferroptotic cell death. This study provides novel insight into the mechanism of empagliflozin-mediated cardioprotection and identifies RIP3 as a potential therapeutic target for DOX-induced cardiomyopathy.

Source: Biochemical Pharmacology

DOI: 10.1016/j.bcp.2025.117277

Authors: Yunfei Zou, Junyi Li, Changwen Xu, Bingju Yan

Institution: Jinzhou Medical University

Language: English

Topic: Chemotherapy-induced cardiotoxicity and mitigation

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,590