Curdione inhibits ferroptosis in isoprenaline‐induced myocardial infarction via regulating Keap1/Trx1/GPX4 signaling pathway

Abstract

Myocardial infarction (MI) is a common disease with high morbidity and mortality. Curdione is a sesquiterpenoid from Radix Curcumae. The current study is aimed to investigate the protective effect and mechanism of curdione on ferroptosis in MI. Isoproterenol (ISO) was used to induce MI injury in mice and H9c2 cells. Curdione was orally given to mice once daily for 7 days. Echocardiography, biochemical kits, and western blotting were performed on the markers of cardiac ferroptosis. Curdione at 50 and 100 mg/kg significantly alleviated ISO‐induced myocardial injury. Curdione and ferrostatin‐1 significantly attenuated ISO‐induced H9c2 cell injury. Curdione effectively suppressed cardiac ferroptosis, evidenced by decreasing malondialdehyde and iron contents, and increasing glutathione (GSH) level, GSH peroxidase 4 (GPX4), and ferritin heavy chain 1 expression. Importantly, drug affinity responsive target stability, molecular docking, and surface plasmon resonance technologies elucidated the direct target Keap1 of curdione. Curdione disrupted the interaction between Keap1 and thioredoxin1 (Trx1) but enhanced the Trx1/GPX4 complex. In addition, curdione‐derived protection against ISO‐induced myocardial ferroptosis was blocked after overexpression of Keap1, while enhanced after Keap1 silence in H9c2 cells. These findings demonstrate that curdione inhibited ferroptosis in ISO‐induced MI via regulating Keap1/Trx1/GPX4 signaling pathway.

TCM targets ferroptosis: potential treatments for cancer

“…Erianin has the capacity to induce ferroptosis in renal cancer stem cells by promoting the N6methyladenosine modification of ALOX12/P53 mRNA (Shen et al, 2023). Curdione can activate ferroptosis by enhancing the methylation of SLC7A11 mRNA and HOXA13 mRNA (Wang et al, 2023b). Erianin triggered ferroptosis in lung cancer cells by activating Ca2+/CaM signaling (Chen et al, 2020c).…”

“…Consequently, the expression of HOXA13 is reduced, resulting in a decrease in SLC3A2 expression. This intricate molecular modulation activates ferroptosis in colorectal cancer (Wang et al, 2023b). System Xc-, cystine/glutamic acid inverse transporter, can take cystine, excrete glutamic acid, both for intracellular glutathione synthesis to provide raw materials.…”