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Purpose: Myocardial ischemic reperfusion injury (MIRI) is a crucial clinical problem globally. The molecular mechanisms of MIRI need to be fully explored to develop new therapeutic methods. Galangin (Gal), which is a natural flavonoid extracted from Alpinia Officinarum Hance and Propolis, possesses a wide range of pharmacological activities, but its effects on MIRI remain unclear. This study aimed to determine the pharmacological effects of Gal on MIRI., Methods: C57BL/6 mice underwent reperfusion for 3 h after 45 min of ischemia, and neonatal rat cardiomyocytes (NRCs) subjected to hypoxia and reoxygenation (HR) were cultured as in vivo and in vitro models. Echocardiography and TTC-Evans Blue staining were performed to evaluate the myocardial injury. Transmission electron microscope and JC-1 staining were used to validate the mitochondrial function. Additionally, Western blot detected ferroptosis markers, including Gpx4, FTH, and xCT., Results: Gal treatment alleviated cardiac myofibril damage, reduced infarction size, improved cardiac function, and prevented mitochondrial injury in mice with MIRI. Gal significantly alleviated HR-induced cell death and mitigated mitochondrial membrane potential reduction in NRCs. Furthermore, Gal significantly inhibited ferroptosis by preventing iron overload and lipid peroxidation, as well as regulating Gpx4, FTH, and xCT expression levels. Moreover, Gal up-regulated nuclear transcriptive factor Nrf2 in HR-treated NRCs. Nrf2 inhibition by Brusatol abolished the protective effect of Gal against ferroptosis., Conclusion: This study revealed that Gal alleviates myocardial ischemic reperfusion-induced ferroptosis by targeting Nrf2/Gpx4 signaling pathway., Competing Interests: The authors declare no conflict of interest., (© 2023 Yang et al.)

Background and Purpose Experimental Approach Key Results Conclusion and Implications Doxorubicin is widely used in the treatment of malignant tumours, but doxorubicin‐induced cardiotoxicity severely limits its clinical application. Spexin is a neuropeptide that acts as a novel biomarker in cardiovascular disease. However, the effects of spexin on doxorubicin‐induced cardiotoxicity is unclear.We established a model of doxorubicin‐induced cardiotoxicity both in vivo and in vitro. Levels of cardiac damage in mice was assessed through cardiac function assessment, determination of serum cardiac troponin T and CKMB levels and histological examination. CCK8 and PI staining were used to assess the doxorubicin‐induced toxicity in cultures of cardiomyocytes in vitro. Ferroptosis was assessed using FerroOrange staining, determination of MDA and 4‐HNE content and ferroptosis‐associated proteins SLC7A11 and GPX4. Mitochondrial membrane potential and lipid peroxidation levels were measured using TMRE and C11‐BODIPY 581/591 probes, respectively. Myocardial autophagy was assessed by expression of P62 and Beclin1.Spexin treatment improved heart function of mice with doxorubicin‐induced cardiotoxicity, and attenuated doxorubicin‐induced cardiotoxicity by decreasing iron accumulation, abnormal lipid metabolism and inhibiting ferroptosis. Interestingly, doxorubicin caused excessive autophagy in cardiomyocyte in culture, which could be alleviated by treatment with spexin. Knockdown of Beclin 1 eliminated the protective effects of spexin in mice with DIC.Spexin ameliorated doxorubicin‐induced cardiotoxicity by inhibiting excessive autophagy‐induced ferroptosis, suggesting that spexin could be a drug candidate against doxorubicin‐induced cardiotoxicity. Beclin 1 might be critical in mediating the protective effect of spexin against doxorubicin‐induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Ferroptosis, a newly identified type of programmed cell death type, has been proven to contribute to the progression of myocardial ischemia/reperfusion (I/R) injury. However, little is known about ferroptosis regulation in I/R injury. We identified activating transcription factor 3 (ATF3) as a vital regulator of I/R induced ferroptosis and investigated the effects and potential mechanism of ATF3 in cardiac ferroptosis. In this study, the dynamic RNA-sequencing (RNA-seq) analysis were performed on mouse hearts exposed to different I/R schedules to identify that ATF3 represents an important modulatory molecule in myocardial I/R injury. Then knockout, rescue and overexpression methods were used in mice and neonatal mouse cells (NMCs) to illustrate the effect of ATF3 on myocardial I/R injury. Loss/gain of function techniques were used both in vivo and in vitro to explore the effects of ATF3 on ferroptosis in I/R injury. Furthermore, chromatin immunoprecipitation sequence (ChIP-seq) analysis was performed in the AC16 human cardiomyocyte cell line to investigate potential genes regulated by ATF3. ATF3 expression reached highest level at early stage of reperfusion, knockout of ATF3 significantly aggravated I/R injury, which could be rescued by ATF3 re-expression. Knockout and the re-expression of ATF3 changed the transcription levels of multiple ferroptosis genes. In addition, results showed that overexpression of ATF3 inhibits cardiomyocyte ferroptosis triggered by erastin and RSL3. Lastly, ChIP-seq and dual luciferase activity analysis revealed ATF3 could bind to the transcription start site of Fanconi anaemia complementation group D2 (FANCD2) and increased the FANCD2 promoter activity. Furthermore, we first demonstrated that overexpression of FANCD2 exerts significant anti-ferroptosis and cardioprotective effect on AC16 cell H/R injury. ATF3 inhibits cardiomyocyte ferroptotic death in I/R injury, which might be related with regulating FANCD2. Our study provides new insight into the molecular target for the therapy of myocardial I/R injury. [Display omitted] • ATF3 is a vital regulator during I/R injury. • ATF3 inhibits cardiac ferroptosis in response to I/R injury. • Overexpression of ATF3 could reduce the ferroptotic death of cardiomyocytes induced by erastin and RSL3. • ATF3 could upregulate FANCD2 by directly activating the promoter of FANCD2 in AC16. • FANCD2 exerts significant anti-ferroptosis and protective effects in myocardial H/R injury. [ABSTRACT FROM AUTHOR]