Histol Histopathol. 2026 Mar 4:25054. doi: 10.14670/HH-25-054. Online ahead of print.
ABSTRACT
BACKGROUND: Doxorubicin (DOX), as a broad-spectrum antitumor drug, achieved great success in the clinic. Nevertheless, severe adverse effects, in particular cardiac toxicity, significantly restrict its clinical utilization. Urolithin A (UA), a metabolite produced by the metabolic activity of intestinal microorganisms on pomegranates, exerts novel protective potential against cardiovascular disease. However, the inhibitory effect of UA against DOX-mediated cardiotoxicity has not been fully explored. Herein, the protective effect and mechanism of UA against DOX-induced cardiotoxicity in vitro and in vivo were investigated.
METHODS: The effects of UA and DOX on cell activity and cell apoptosis were assessed by cell counting Kit-8 (CCK-8), flow cytometry, and Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) staining. Reactive oxygen species (ROS) were examined by fluorescent probes. Protein expression was detected by western blotting. A cardiotoxicity rat model was established via injection of DOX to evaluate the in vivo protective mechanism.
RESULTS: DOX induced obvious ROS-mediated oxidative damage and ultimately led to H9c2 cell apoptosis in vitro and myocardial dysfunction in vivo. However, UA-cotreatment effectively mitigated DOX-induced oxidative damage and apoptosis by regulating the Nrf2 pathway and Bcl-2 family expression, inhibiting ROS, superoxide anions, and MDA generation, enhancing GSH content, and downregulating the ATR-p53 pathway in vitro. Furthermore, UA administration also promoted eNOS activity, inhibited myocardial abnormal proliferation and fibrosis, and improved myocardial function in vivo.
CONCLUSION: Our findings validated the rational design that UA has the potential to mitigate DOX-induced myocardial injury in vitro and in vivo by inhibiting ROS-driven apoptosis, which yields significant insights for combating DOX-mediated myocardial injury.
PMID:41778360 | DOI:10.14670/HH-25-054