Cirsium setidens attenuates doxorubicin-induced cardiotoxicity by modulating oxidative stress and inflammatory pathways

Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its clinical application is limited by cardiotoxicity associated with oxidative stress, inflammation, and apoptosis. Cirsium setidens ( C. setidens ), a traditional Korean edible plant, is known for its antioxidant and anti-inflammatory properties. This study investigated the cardioprotective potential of C. setidens aqueous extract (CSA) against DOX-induced cardiotoxicity (DICT). Metabolite profiling used UPLC-QTOF/MS revealed that CSA contains diverse bioactive compounds, predominantly amino acids and phenolic constituents, including flavonoids, coumarins, cinnamic acid derivatives, and higenamine. Cardiotoxic H9c2 cardiomyocytes and DOX-induced mouse model were used to investigate the in vitro and in vivo effects of CSA, respectively. CSA protected H9c2 cells against DICT while further enhancing DOX's anticancer effect in MDA-MB-231 cells. Moreover, CSA markedly attenuated DOX-induced cardiac dysfunction and myocardial injury, including electrocardiographic abnormalities and myocardial fibrosis. Mechanistically, CSA exerted its cardioprotective effects through coordinated regulation of the ROS-inflammation signaling axis. CSA suppressed inflammatory gene expression, including Il-1β , Il-6 , Tnf-α , Ifn-γ , and Mcp-1 . Concurrently, it activated the Nrf1/Nrf2 antioxidant signaling pathways, restoring the expression of downstream antioxidant genes such as Sod1 , Sod2 , and Ho-1 . In addition, CSA modulated apoptosis-related genes by downregulating Bax , Casp9 , Casp3 , and Parp2 , while upregulating anti-apoptotic genes Bcl2 and Bcl-xl . CSA demonstrates cardioprotective efficacy against DOX-induced cardiotoxicity by modulating ROS-inflammation-related oxidative and inflammatory pathways, supporting its potential for functional food applications. Cirsium setidens aqueous extract (CSA) mitigates doxorubicin-induced cardiotoxicity by activating Nrf1/Nrf2 antioxidant signaling and suppressing NF-κB–mediated inflammation and apoptosis. These findings suggest that CSA is a promising food-derived cardioprotective agent for chemotherapy-induced cardiac injury. • Cirsium setidens aqueous extract (CSA) attenuated doxorubicin-induced cardiotoxicity. • CSA restored ECG parameters and reduced myocardial fibrosis in DOX-treated mice. • CSA activated Nrf1/Nrf2 antioxidant signaling and suppressed NF-κB-mediated inflammation. • CSA regulated apoptotic genes, enhancing Bcl2/Bcl-xl and inhibiting Bax/Casp3/Casp9 pathways. • Multi-component flavonoids and phenolic acids in CSA act synergistically for cardioprotection.