Background: The Nrf2/HO-1 signaling pathway is a critical antioxidative stress and cytoprotective pathway, and oxidative stress plays a significant role in myocardial ischemia-reperfusion injury (MIRI). Liquiritigenin, a flavonoid compound derived from licorice, is hypothesized to alleviate MIRI, though its specific mechanism remains unclear. Methods: Following a 15-min pretreatment with liquiritigenin, animals underwent myocardial ischemia-reperfusion injury induction comprising 30-min coronary occlusion and 2-h reperfusion. Continuous cardiac monitoring incorporated both electrocardiography (ECG) and ventricular pressure dynamics, specifically tracking systolic pressure (LVSP), end-diastolic pressure (LVEDP), and ventricular contractility indices (±dp/dtmax). Post-experimental biospecimen analysis included: Myocardial injury evaluation: Serum quantification of lactate dehydrogenase and CK-MB isoenzyme levels. Redox status assessment: Measurement of antioxidant enzyme activities (SOD, GSH) and lipid peroxidation biomarker MDA concentration Histopathological damage: Evaluated via hematoxylin-eosin (HE) staining. Apoptosis: Detected by TUNEL assay. Protein expression: Western blot analysis of Nrf2/HO-1 pathway components (Nrf2, Keap1, HO-1). Conclusion: Liquiritigenin exerts cardioprotective effects against MIRI by activating the Nrf2/HO-1 signaling pathway, thereby attenuating post-reperfusion oxidative stress. This study elucidates the central role of Nrf2/HO-1 pathway interactions in MIRI and identifies liquiritigenin as a potential therapeutic candidate for targeting this pathway.

1. Zeng C, Jiang W, Zheng R, et al. Cardioprotection of tilianin ameliorates myocardial ischemia-reperfusion injury: Role of the apoptotic signaling pathway. Fan GC, ed. PLOS ONE. 2018; 13(3): e0193845. doi: 10.1371/journal.pone.0193845

2. Zhang XJ, Liu X, Hu M, et al. Pharmacological inhibition of arachidonate 12-lipoxygenase ameliorates myocardial ischemia-reperfusion injury in multiple species. Cell Metabolism. 2021; 33(10): 2059-2075.e10. doi: 10.1016/j.cmet.2021.08.014

3. Yang Z, Xie Y, Li M, et al. Ramelteon alleviates myocardial ischemia/reperfusion injury (MIRI) through Sirt3-dependent regulation of cardiomyocyte apoptosis. Biomedicine & Pharmacotherapy. 2024; 172: 116229. doi: 10.1016/j.biopha.2024.116229

4. Valikeserlis I, Athanasiou AA, Stakos D. Cellular mechanisms and pathways in myocardial reperfusion injury. Coronary Artery Disease. 2021; 32(6): 567-577. doi: 10.1097/mca.0000000000000997

5. Yao D, Bao L, Wang S, et al. Isoliquiritigenin alleviates myocardial ischemia-reperfusion injury by regulating the Nrf2/HO-1/SLC7a11/GPX4 axis in mice. Free Radical Biology and Medicine. 2024; 221: 1-12. doi: 10.1016/j.freeradbiomed.2024.05.012

6. Li L, Fang H, Yu YH, et al. Liquiritigenin attenuates isoprenaline induced myocardial fibrosis in mice through the TGF β1/Smad2 and AKT/ERK signaling pathways. Molecular Medicine Reports. 2021; 24(4). doi: 10.3892/mmr.2021.12326

7. Tong HQ, Fan ML, Sun T, et al. Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury. Journal of Visualized Experiments. 2022; (181). doi: 10.3791/63510-v

8. Luo SY, Chen S, Qin YD, et al. Urotensin-ⅡReceptor Antagonist SB-710411 Protects Rat Heart against Ischemia-Reperfusion Injury via RhoA/ROCK Pathway. Gallyas F, ed. PLOS ONE. 2016; 11(1): e0146094. doi: 10.1371/journal.pone.0146094

9. Xu K, Yang Y, Lan M, et al. Apigenin alleviates oxidative stress-induced myocardial injury by regulating SIRT1 signaling pathway. European Journal of Pharmacology. 2023; 944: 175584. doi: 10.1016/j.ejphar.2023.175584

10. Zhong Z, Luo XY, Xiang P, et al. MRTF-A alleviates myocardial ischemia reperfusion injury by inhibiting the inflammatory response and inducing autophagy. Molecular and Cellular Biochemistry. 2022; 478(2): 343-359. doi: 10.1007/s11010-022-04510-4

11. Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends in Biochemical Sciences. 2014; 39(4): 199-218. doi: 10.1016/j.tibs.2014.02.002

12. Kobayashi M, Yamamoto M. Nrf2–Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Advances in Enzyme Regulation. 2006; 46(1): 113-140. doi: 10.1016/j.advenzreg.2006.01.007

13. Dodson M, de la Vega MR, Cholanians AB, et al. Modulating NRF2 in Disease: Timing Is Everything. Annual Review of Pharmacology and Toxicology. 2019; 59(1): 555-575. doi: 10.1146/annurev-pharmtox-010818-021856

14. Egbujor MC, Buttari B, Profumo E, et al. An Overview of NRF2-Activating Compounds Bearing α,β-Unsaturated Moiety and Their Antioxidant Effects. International Journal of Molecular Sciences. 2022; 23(15): 8466. doi: 10.3390/ijms23158466

15. Zhang W, Feng C, Jiang H. Novel target for treating Alzheimer’s Diseases: Crosstalk between the Nrf2 pathway and autophagy. Ageing Research Reviews. 2021; 65: 101207. doi: 10.1016/j.arr.2020.101207

16. Wang R, Wu Y, Jiang S. FOXC2 Alleviates Myocardial Ischemia-Reperfusion Injury in Rats through Regulating Nrf2/HO-1 Signaling Pathway. Pichini S, ed. Disease Markers. 2021; 2021: 1-9. doi: 10.1155/2021/9628521

17. Lu P, Qi Y, Li X, et al. PEDF and 34‐mer peptide inhibit cardiac microvascular endothelial cell ferroptosis via Nrf2/HO‐1 signalling in myocardial ischemia‐reperfusion injury. Journal of Cellular and Molecular Medicine. 2024; 28(14). doi: 10.1111/jcmm.18558

18. Choi AM, Alam J. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. American Journal of Respiratory Cell and Molecular Biology. 1996; 15(1): 9-19. doi: 10.1165/ajrcmb.15.1.8679227

19. Qiu Y, Wu Y, Meng M, et al. GYY4137 protects against myocardial ischemia/reperfusion injury via activation of the PHLPP-1/Akt/Nrf2 signaling pathway in diabetic mice. Journal of Surgical Research. 2018; 225: 29-39. doi: 10.1016/j.jss.2017.12.030

20. Luo W, Li J, Li Z, et al. HO-1 nuclear accumulation and interaction with NPM1 protect against stress-induced endothelial senescence independent of its enzymatic activity. Cell Death & Disease. 2021; 12(8). doi: 10.1038/s41419-021-04035-6

21. Sohn E, Kim YJ, Kim JH, et al. Ficus erecta Thunb Leaves Alleviate Memory Loss Induced by Scopolamine in Mice via Regulation of Oxidative Stress and Cholinergic System. Molecular Neurobiology. 2021; 58(8): 3665-3676. doi: 10.1007/s12035-021-02358-1

22. Bellezza I, Giambanco I, Minelli A, et al. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2018; 1865(5): 721-733. doi: 10.1016/j.bbamcr.2018.02.010

23. Zhang B, Xu D. Wogonoside preserves against ischemia/reperfusion-induced myocardial injury by suppression of apoptosis, inflammation, and fibrosis via modulating Nrf2/HO-1 pathway. Immunopharmacology and Immunotoxicology. 2022; 44(6): 877-885. doi: 10.1080/08923973.2022.2090955

24. Wang J, Lu L, Chen S, et al. Up-regulation of PERK/Nrf2/HO-1 axis protects myocardial tissues of mice from damage triggered by ischemia-reperfusion through ameliorating endoplasmic reticulum stress. Cardiovascular Diagnosis and Therapy. 2020; 10(3): 500-511. doi: 10.21037/cdt-20-126