Chicory Extract Alleviates Anthracycline-Induced Cardiotoxicity by Inhibiting Mitochondrial Damage via the UCP2/NLRP3 Pathway

Doxorubicin (Dox)-induced cardiotoxicity (DIC) was characterized by severe myocardial damage that might progress to irreversible heart failure. There were limited options available for the prevention and treatment of DIC. Chicory (<i>Cichorium intybus</i> L.) has demonstrated notable cardioprotective effects. However, its potential to mitigate DIC remains unexplored. This study aimed to assess the therapeutic potential of chicory in alleviating DIC and elucidate its active ingredients and potential molecular mechanism. Male Sprague-Dawley (SD) rats were used to construct DIC models. The rats were prophylactically gavaged chicory to evaluate the therapeutic effect of chicory on DIC. The UPLC-QExactivePlus system was used for the subsequent analysis of heart tissue samples to reveal the potential active ingredients of chicory. The binding of chicory components to uncoupling protein 2 (UCP2) and NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) was validated using surface plasmon resonance (SPR). Highly binding ingredients were then utilized in an H9c2 cell model to validate underlying mechanisms. Chicory alleviated Dox-induced cardiac dysfunction and myocardial structural injury, and reversed mitochondrial damage. These protective effects may be attributed to its activation of UCP2 and inhibition of NLRP3 signaling, thereby attenuating Dox-induced cardiac oxidative damage and inflammatory infiltration. Additionally, a total of 15 chemical compositions of chicory into rat heart tissue were characterized. SPR validation demonstrated that nine compounds targeting UCP2 and NLRP3 increased survival rates in Dox-induced H9c2 cells, reduced oxidative and inflammatory levels, and improved mitochondrial function. Chicory could effectively alleviate DIC by reducing oxidative stress, inflammation, and preserving mitochondrial function. These findings offer a novel insight into chicory's clinical relevance in DIC management. Targeting UCP2 to regulate the NLRP3 pathway highlights chicory as a promising therapeutic strategy for preventing and treating DIC.