FGF12 restrains mitochondria‐dependent ferroptosis in doxorubicin‐induced cardiomyocytes through the activation of FGFR1/AMPK/NRF2 signaling

Abstract

AbstractFibroblast growth factor‐12 (FGF12) has been reported to play important role in regulating heart diseases. We aimed to explore the role of FGF12 in doxorubicin (DOX)‐induced myocardial injury. DOX‐induced mice and DOX‐induced HL‐1 cells were used as the myocardial injury in vivo and in vitro. Then, FGF12, Anp, Bnp, and Myh7 expression was detected. The pathological injury in myocardium tissue was observed by H&E staining. The levels of markers related to myocardial damage and oxidative stress were assessed. Then, immunohistochemistry and immunofluorescence staining were used to detect FGF12 and 4‐HNE expression. Ferroptosis were detected by Prussian blue staining and western blot. The FGFR1/AMPK/NRF2 signaling was measured by western blot. FGF12 expression was downregulated in DOX‐induced mice myocardium tissues. FGF12 overexpression alleviated DOX‐induced myocardial tissue pathological injury and reduced Anp, Bnp, and Myh7 expression. Additionally, the levels of CK‐MB, LDH and cTnT in serum were decreased after FGF12 upregulation in DOX‐induced mice. Moreover, FGF12 overexpression reduced the levels of ROS, MDA, and 4‐HNE but increased SOD and GSH‐Px activities. Meanwhile, FGF12 led to less deposition of iron ion, decreased ACSL4, PTGS2 and increased GPX4, FTH1 expression. Additionally, FGF12 activated the expressions of FGFR1, p‐AMPK, and NRF2. Moreover, FGFR1 silencing reversed the protective effects of FGF12 overexpression on cell viability, oxidative stress, ferroptosis, and FGFR1/AMPK/NRF2 pathway. To sum up, FGF12 inhibited mitochondria‐dependent ferroptosis in cardiomyocytes induced by DOX through activation of FGFR1/AMPK/NRF2 signaling. These findings clarify a new mechanism of DOX‐induced cardiac injury and provide a promising target to limit the disease development.