Infection-associated lipopolysaccharide aggravates doxorubicin-induced cardiotoxicity via modulation of the FOXO1-GPX4 ferroptosis pathway.
TL;DR
Findings indicate that DOX and LPS synergistically promote myocardial injury by activating the FOXO1/GPX4-mediated ferroptosis pathway, providing mechanistic insight into infection-associated cardiotoxicity during DOX chemotherapy.
Abstract
Doxorubicin (DOX) is an effective chemotherapeutic agent, but its clinical utility is limited by dose-dependent cardiotoxicity. However, the mechanisms by which infection exacerbates DOX-induced myocardial injury remain unclear. This study investigated the role of ferroptosis in lipopolysaccharide (LPS)-potentiated DOX-mediated myocardial damage. Clinical data were analyzed to evaluate the association between infection and myocardial injury in patients receiving DOX-based chemotherapy. In vitro and in vivo experiments were performed to assess ferroptosis and cardiac injury following DOX and/or LPS exposure. The results showed that infection was associated with aggravated myocardial injury in DOX-treated patients. Both DOX and LPS individually induced ferroptosis, and combined exposure further enhanced ferroptotic responses. Mechanistic analyses demonstrated that FOXO1 binds to the promoter region of GPX4 and suppresses its transcriptional activity. Collectively, these findings indicate that DOX and LPS synergistically promote myocardial injury by activating the FOXO1/GPX4-mediated ferroptosis pathway, providing mechanistic insight into infection-associated cardiotoxicity during DOX chemotherapy.