Fisetin Attenuates Doxorubicin-Induced Cardiomyopathy In Vivo and In Vitro by Inhibiting Ferroptosis Through SIRT1/Nrf2 Signaling Pathway Activation

Abstract

Doxorubicin (DOX) is an anthracycline antibiotic that is used extensively for the management of carcinoma; however, its clinical application is limited due to its serious cardiotoxic side effects. Ferroptosis represents iron-dependent and reactive oxygen species (ROS)-related cell death and has been proven to contribute to the progression of DOX-induced cardiomyopathy. Fisetin is a natural flavonoid that is abundantly present in fruits and vegetables. It has been reported to exert cardioprotective effects against DOX-induced cardiotoxicity in experimental rats. However, the underlying mechanisms remain unknown. The present study investigated the cardioprotective role of fisetin and the underlying molecular mechanism through experiments in the DOX-induced cardiomyopathy rat and H9c2 cell models. The results revealed that fisetin treatment could markedly abate DOX-induced cardiotoxicity by alleviating cardiac dysfunction, ameliorating myocardial fibrosis, mitigating cardiac hypertrophy in rats, and attenuating ferroptosis of cardiomyocytes by reversing the decline in the GPX4 level. Mechanistically, fisetin exerted its antioxidant effect by reducing the MDA and lipid ROS levels and increasing the glutathione (GSH) level. Moreover, fisetin exerted its protective effect by increasing the SIRT1 expression and the Nrf2 mRNA and protein levels and its nuclear translocation, which resulted in the activation of its downstream genes such as HO-1 and FTH1. Selective inhibition of SIRT1 attenuated the protective effects of fisetin in the H9c2 cells, which in turn decreased the GSH and GPX4 levels, as well as Nrf2, HO-1, and FTH1 expressions. In conclusion, fisetin exerts its therapeutic effects against DOX-induced cardiomyopathy by inhibiting ferroptosis via SIRT1/Nrf2 signaling pathway activation.

Fisetin Attenuated Oxidative Stress-Induced Cellular Damage in ARPE-19 Human Retinal Pigment Epithelial Cells Through Nrf2-Mediated Activation of Heme Oxygenase-1

“…Our results showed that fisetin remarkably enhanced the expression and phosphorylation of Nrf2 as well as its expression in the nucleus in H 2 O 2 -treated ARPE-19 cells. Fisetin also improved the expression and enzymatic activity of HO-1, suggesting that fisetin was able to activate the Nrf2/AREs pathway, which was in good agreement with previous findings ( Hanneken et al, 2006 ; Sim et al, 2020 ; Jiang et al, 2021 ; Li et al, 2022 ). However, the ROS scavenging activity and viability-enhancing ability of fisetin were significantly abolished by blocking HO-1 activity via a HO-1 antagonist ZnPP.…”

“…Certain intracellular signaling pathways are involved in defense strategies against oxidative stress, and there is growing evidence that the Nrf2/AREs pathway is involved in the antioxidant activity of fisetin in multiple cell lines ( Sim et al, 2020 ; Jiang et al, 2021 ; Li et al, 2022 ). There is growing evidence that Nrf2 is an effective target in the regulation of oxidative stress-related retinal degeneration.…”

“…More interestingly, although excessive accumulation of ROS may be a major factor in fisetin-induced apoptosis of cancer cells ( Su et al, 2017 ; Tsai et al, 2019 ; Imran et al, 2021 ), the protective effects of fisetin against cell damage to various stimuli are associated with potent antioxidant activity by acting as a potent ROS scavenger ( Zhao et al, 2019 ; Rodius et al, 2020 ; Molagoda et al, 2021 ; Ding et al, 2022 ). Moreover, several previous studies have demonstrated that this compound can modulate the Nrf2/antioxidant response elements (AREs) pathway to exert antioxidant activity ( Sim et al, 2020 ; Jiang et al, 2021 ; Li et al, 2022 ). Although Hanneken et al ( Hanneken et al, 2006 ) have suggested that the antioxidant activity of fisetin in RPE cells could be related to an increased expression of Nrf2 and HO-1, one of the representative downstream factors of Nrf2, the role of this pathway in the antioxidant activity of fisetin in RPE cells is still unclear.…”

Role of Ferroptosis in Fibrotic Diseases

“…Further studies showed that fisetin protects against DOX-induced cardiomyopathy by inhibiting ferroptosis via SIRT1/Nrf2 signaling pathway activation. 103 Salidroside, an extraction from traditional Chinese medicine Rhodiola rosea, also significantly attenuated ferroptosis and fibrosis in a mice model of DIC. However, the molecular mechanism is different; the antiferroptotic effects of salidroside are mediated by activating AMPK-dependent signaling pathways including regulating abnormal fatty acid metabolism and maintaining mitochondrial function.…”

Relevance of Ferroptosis to Cardiotoxicity Caused by Anthracyclines: Mechanisms to Target Treatments

“…In addition, Nrf2 can be activated by deacetylation of SIRT1, and Fisetin activated Nrf2 by up-regulating the expression of SIRT1, leading to the up-regulation of HO-1, FTH1, TfR1, and FPN, and exerting an anti-ferroptosis effect. After being transfected with SIRT1 and Nrf2 siRNA, the anti-ferroptosis effect of Fisetin was abolished in H9C2 cells ( 105 ).…”