Recent advances in potential of Fisetin in the management of myocardial ischemia-reperfusion injury–A systematic review

The primary therapeutic strategy in managing ischemic heart diseases is to restore the perfusion of the myocardial ischemic area by surgical methods that often result in an unavoidable injury called ischemia-reperfusion injury (IR). Fisetin is an effective flavonoid with antioxidant and anti-inflammatory properties, proven to be cardioprotective against IR injury in both in-vitro and invivo models, apart from its promising health benefits against cancer, diabetes, and neurodegenerative ailments. The potential of fisetin in attenuating myocardial IR is inconclusive as the effectiveness of fisetin needs more understanding in terms of its possible target sites and underlying different mechanisms. Considering the surge in recent scientific interests in fisetin as a pharmacological agent, this review not only updates the existing preclinical and clinical studies with fisetin and its underlying mechanisms but also summarizes its possible targets during IR protection. We performed a literature survey using search engines Pubmed, PMC, Science direct, Google, and research gate published across the years 2006-2021. The relevant studies were extracted from the databases with the combinations of the following keywords and summarized: myocardial ischemia-reperfusion injury, natural products, flavonoid, fisetin, PI3K, JAK-STAT, Nrf2, PKC, JNK, autophagy. Fisetin is reported to be effective in attenuating IR injury by delaying the clotting time, preserving the mitochondrial function, reducing oxidative stress, and inhibiting GSK 3β. But it failed to protect diseased cardiomyocytes challenged to IR. As discussed in the current review, fisetin not only acts as a conventional antioxidant and anti-inflammatory agent to exert its biological effect but may also exert modulatory action on the cellular metabolism and adaptation via direct action on various signalling pathways that comprise PI3K, JAK-STAT, Nrf2, PKC, JNK, and autophagy. Moreover, the dosage of fisetin and co-morbidities like diabetes and obesity are found to be detrimental factors for cardioprotection. For further evaluation and smooth clinical translation of the fisetin molecule in IR treatment, researchers should pay close attention to the potential of fisetin to possibly alter the key cardioprotective pathways and dosage, as the efficacy of fisetin is tissue and cell type-specific and varies with different doses.