CDDO-Me alleviates doxorubicin/lapatinib-induced cardiotoxicity by activating the NRF2/GPX4 axis to inhibit oxidative stress and ferroptosis

Abstract

The combination of doxorubicin (DOX) and lapatinib (LAP) enhances the antitumor efficacy of breast cancer. However, previous studies indicated that this combination exacerbated cardiotoxicity through ferroptosis, characterized by mitochondrial dysfunction, lipid peroxidation, and glutathione depletion. Current cardiotoxicity treatments are inadequate, necessitating alternative solutions. Here, this study investigates whether bardoxolone methyl (CDDO-Me), a synthetic triterpenoid NRF2 activator, alleviates DOX/LAP-induced cardiac injury by modulating the NRF2/GPX4 pathway. Our data showed that CDDO-Me significantly reduced DOX/LAP-induced cardiotoxicity in mice, improving cardiac function, reducing myocardial fibrosis, and attenuating hypertrophy. Mechanistically, CDDO-Me directly bound and stabilized GPX4, inhibiting its ubiquitination and degradation through the ubiquitin-proteasome (UPS) pathway. This restored glutathione homeostasis, suppressed lipid peroxidation, and mitigated mitochondrial dysfunction and iron overload. Furthermore, CDDO-Me did not compromise the antitumor efficacy of DOX/LAP in breast cancer cells. CDDO-Me protects against DOX/LAP-induced cardiotoxicity by stabilizing GPX4 and inhibiting ferroptosis, offering a promising therapeutic strategy that preserves cardiac function without interfering with chemotherapy.

Keywords: CDDO-Me; Cardiotoxicity; Doxorubicin; Ferroptosis; Lapatinib; Mitochondria.