Sauchinone preserves cardiac function in doxorubicin-induced cardiomyopathy by inhibiting the NLRP3 inflammasome

Abstract

Background: Doxorubicin (Dox)-induced cardiomyopathy (DIC) is characterized by severe myocardial damage that can progress to dilated cardiomyopathy and potentially lead to heart failure. No effective prevention or treatment strategies are available for DIC. Sauchinone, a diastereomeric lignan isolated from Saururus chinensis, is known for its notable anti-inflammatory effects. However, a paucity of research on sauchinone in relation to heart disease exists, particularly regarding its role in DIC, which remains unclear.

Purpose: This study aimed to assess the therapeutic potential of sauchinone in alleviating cardiac injury and elucidate its potential molecular mechanism in DIC.

Methods: Male C57BL/6J mice were used to construct chronic and acute DIC models in vivo. The mice were administered sauchinone intragastrically concurrently with the first injection of Dox to evaluate the therapeutic effect of sauchinone on DIC. H9c2, a rat cardiomyocyte cell line, was treated with various concentrations of sauchinone in conjunction with Dox to assess the protective effects of sauchinone on cardiomyocyte injury in vitro.

Results: Supplementation with exogenous sauchinone mitigated Dox-induced cardiac atrophy, cardiac fibrosis, and ventricular remodeling, while preserving cardiac function. Sauchinone reduced Dox-induced abnormal apoptosis both in vitro and in vivo. Additionally, sauchinone restored mitochondrial function and decreased reactive oxygen species levels, which may be attributed to its activation of nuclear factor erythroid 2-related factor 2 (NRF2) signaling, thereby attenuating Dox-induced oxidative damage. Furthermore, sauchinone significantly inhibited the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and reduced the cardiac infiltration of inflammatory factors, thereby alleviating oxidative stress and inhibiting the progression of DIC. The NLRP3 agonist nigericin abolished DIC progression, while the NLRP3 antagonist MCC950 further enhanced the beneficial effects of sauchinone on DIC progression both in vivo and in vitro.

Conclusions: The key novel finding of the present study is that the use of sauchinone, a diastereomeric lignan isolated from Saururus chinensis, effectively limits the progression of DIC. Specifically, sauchinone not only alleviates Dox-induced chronic cardiac injury but also significantly delays the progression of acute DIC. Mechanistically, inactivation of the NLRP3 inflammasome and NRF2-mediated antioxidant pathways have been identified as two critical signaling pathways regulated by sauchinone, which plays a vital role in blocking the progression of DIC. Sauchinone holds promise as a potential therapeutic approach for DIC or dilated cardiomyopathy.

Keywords: Doxorubicin-induced cardiomyopathy; Inflammation; NLRP3 inflammasome; NRF2; Sauchinone.