Troxerutin attenuates paclitaxel-induced cardiotoxicity through modulation of ferroptosis and GRP78/ATF6/CHOP signaling in rats.

Paclitaxel (PXT) is an effective chemotherapeutic agent whose clinical use is limited by serious cardiotoxic effects, including arrhythmias, myocardial infarction, and heart failure. Troxerutin (TXR) is a bioflavonoid with demonstrated cardioprotective properties in various cardiac injury models, including cardioprotective effects in doxorubicin-induced myocardial injury, as well as diabetic myocardiopathy. This study, therefore, investigates whether TXR can mitigate PXT-induced cardiotoxicity and explores the underlying protective mechanisms. Male Wistar rats were treated with either PXT (7.5 mg/kg/week, i.p.) and/or TXR (150 mg/kg/day, oral) for 28 days. TXR restored the histological structure of the myocardial tissues, as well as heart weight and heart index, which were disrupted following PXT treatment. In addition, TXR alleviated PXT-induced elevation of cardiac damage indicators such as Troponin I and CK-MB. Furthermore, TXR counteracted the PXT effect on cardiac iron deposits and mitigated PXT-induced imbalance of redox homeostasis as evidenced by the abridged reactive oxygen species level, raised levels of the antioxidant enzymes glutathione peroxidase-4, catalase and superoxide dismutase, attenuating ferroptosis induced by PXT. Besides, TXR ameliorated PXT-induced endoplasmic reticulum (ER) stress as indicated by reduced ER stress markers C/EBP homologous protein, activating transcription factor-6, and glucose regulatory protein-78. Moreover, TXR hindered apoptosis induced by PXT, as evidenced by its effect on the BAX and BCL-2 expressions. Importantly, TXR did not abrogate the anticancer activity of PXT in cultured human MDA-MB cells. In conclusion, TXR hindered the cardiotoxicity of PXT and showed cardioprotective effects via its inhibitory actions on ER stress, ferroptosis, oxidative stress, and apoptosis.