Isoliquiritigenin alleviates myocardial ischemia-reperfusion injury by regulating the Nrf2/HO-1/SLC7a11/GPX4 axis in mice

Deshan Yao; Liuxiang Bao; Sichuan Wang; Meng Tan; Yuanyuan Xu; Tianxu Wu; Zhengang Zhang; Kaizheng Gong

doi:10.1016/j.freeradbiomed.2024.05.012

Isoliquiritigenin alleviates myocardial ischemia-reperfusion injury by regulating the Nrf2/HO-1/SLC7a11/GPX4 axis in mice

Free Radic Biol Med. 2024 May 9:221:1-12. doi: 10.1016/j.freeradbiomed.2024.05.012. Online ahead of print.

Authors

Deshan Yao¹, Liuxiang Bao¹, Sichuan Wang¹, Meng Tan¹, Yuanyuan Xu², Tianxu Wu¹, Zhengang Zhang¹, Kaizheng Gong³

Affiliations

¹ Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, Yangzhou, Jiangsu, 225001, China.
² Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, Yangzhou, Jiangsu, 225001, China; Heze Medical College, Shandong, 274000, China.
³ Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, Yangzhou, Jiangsu, 225001, China. Electronic address: yungkzh@163.com.

PMID: 38734270
DOI: 10.1016/j.freeradbiomed.2024.05.012

Abstract

Ischemia-reperfusion (I/R) injury, a multifaceted pathological process, occurs when the prolongation of reperfusion duration triggers ferroptosis-mediated myocardial damage. Isoliquiritigenin (ISL), a single flavonoid from licorice, exhibits a wide range of pharmacological impacts, but its function in ferroptosis caused by myocardial I/R injury remains unclear. This study delved into the protective effect of ISL on myocardial I/R injury-induced ferroptosis and its mechanism. Neonatal mouse cardiomyocytes (NMCM) underwent hypoxia/reoxygenation (H/R) to simulate the pathological process of myocardial I/R. ISL significantly attenuated H/R-triggered production of reactive oxygen species in NMCM, reduced the expression of malondialdehyde and the activity of lactate dehydrogenase, enhanced superoxide dismutase and catalase activity, and increased the expression of nuclear factor E2-related factor 2 (Nrf2) and its downstream heme oxygenase 1 (HO-1), thereby mitigating oxidative stress damage. CCK8 experiment revealed that the ferroptosis inhibitor Ferrostatin-1 significantly improved myocardial cell viability after 24 h of reoxygenation, and ISL treatment showed a similar effect. ISL reduced intracellular free iron accumulation, up-regulated glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression, and inhibited lipid peroxidation accumulation, thereby alleviating ferroptosis. The Nrf2-specific inhibitor ML385 counteracted ISL's defensive role against H/R-triggered oxidative stress damage and ferroptosis. In vivo experiments further confirmed that by regulating the translocation of Nrf2 into the nucleus, ISL treatment increased the levels of HO-1, GPX4, and SLC7A11, inhibited the expression of ACSL4, Drp1 to exert the antioxidant role, alleviated mitochondrial damage, and ferroptosis, ultimately reducing myocardial infarction area and injury induced by I/R. ML385 nearly abolished ISL's protective impact on the I/R model by inhibiting Nrf2 function. In summary, ISL is capable of mitigating oxidative stress, mitochondrial damage, and cardiomyocyte ferroptosis caused by I/R, thereby reducing myocardial injury. A key mechanism includes triggering the Nrf2/HO-1/SLC7A11/GPX4 pathway to prevent oxidative stress damage and cardiomyocyte ferroptosis caused by I/R.

Keywords: Ferroptosis; HO-1; Ischemia reperfusion; Isoliquiritigenin; Nrf2.