Luteolin ameliorated doxorubicin-induced cardiotoxicity in mice by targeting PFKFB3 to inhibit endothelial-mesenchymal transition, without compromising doxorubicin's antitumor efficacy.
BACKGROUND Despite the widespread use in chemotherapy, doxorubicin (DOX) has a limited clinical use due to the associated risk of DOX-induced cardiotoxicity (DIC). Endothelial-mesenchymal transition (EndMT) has been implicated as a potential mechanism in DIC. PURPOSE This study aimed to investigate the effects of luteolin on DIC and to explore its underlying mechanisms. METHODS The cardiac function and myocardial injury biomarkers were assessed in a DIC mouse model. Histological analysis was performed to evaluate myocardial structure and perivascular fibrosis. Single-nucleus RNA sequencing (snRNA-seq) of mouse heart tissue was utilized. The binding between luteolin and PFKFB3 was assessed using molecular docking and dynamics simulations. Endothelial dysfunction was assessed in human umbilical vein endothelial cells (HUVECs) by examining morphological changes, tube formation ability, migration, and collagen deposition. PFKFB3 was overexpressed in vitro to further verify the mechanism. Additionally, the anticancer activity of DOX in combination with luteolin was assessed in MCF-7 and SKBR3 cells. RESULTS In DIC mice, luteolin treatment noticeably improved cardiac function and reduced biomarkers related to myocardial injury. Histological analysis revealed that luteolin alleviated myocardial structural disruption and perivascular fibrosis. SnRNA-seq of mouse heart tissue identified glycolysis-related gene Pfkfb3 as a potential driver of EndMT. Molecular docking and dynamics simulations identified the formation of a stable complex between luteolin and PFKFB3. In vitro, luteolin mitigated DOX-induced endothelial dysfunction by suppressing PFKFB3-mediated EndMT pathway. Notably, PFKFB3 overexpression reversed luteolin's protection against DOX-induced injury in HUVECs. Furthermore, luteolin did not compromise the antitumor power of DOX in MCF-7 and SKBR3 cells. CONCLUSION These findings indicated that luteolin ameliorated DIC by targeting PFKFB3 to inhibit EndMT. Luteolin may be a promising adjuvant therapy for mitigating DIC.
Zhong et al. (Tue,) conducted a other in Doxorubicin-induced cardiotoxicity. Luteolin vs. Vehicle / DOX alone was evaluated on Cardiac function and myocardial injury biomarkers. Luteolin ameliorated doxorubicin-induced cardiotoxicity in mice by targeting PFKFB3 to inhibit endothelial-mesenchymal transition, without compromising doxorubicin's antitumor efficacy.