Piperlongumine alleviates viral myocarditis by inhibiting pyroptosis through NF-κB pathway

Viral myocarditis (VMC) is a cardiac condition characterized by inflammation of the myocardium due to viral infection. It is a significant cause of sudden cardiac death in young adults, and effective treatments remain limited. Inflammatory caspase-mediated pyroptosis serves as a host defense mechanism against pathogens and is crucial in the pathogenesis of VMC. Piperlongumine (PL), an amide alkaloid derived from Piper longum l., exhibits notable anti-inflammatory properties. However, there has been no reported research on the use of PL for the treatment of VMC.

To explore the role of PL in inhibiting VMC by regulating cardiomyocyte pyroptosis and the potential molecular mechanism.

To evaluate the effect of PL on VMC, we established the VMC mouse model through intraperitoneal injection of coxsackie virus B3 (CVB3) for in vivo experiments. Subsequently, we assessed body weight, cardiac histopathological changes, cardiac function, and cardiomyocyte pyroptosis in VMC mice following PL treatment using hematoxylin and eosin (HE) staining, echocardiography, real-time quantitative PCR (RT-qPCR), and western blot analysis. The impact of PL on mouse cardiac muscle cell line (HL-1) pyroptosis was evaluated through the cell counting kit-8 assay kit (CCK8), RT-qPCR, immunofluorescence, and western blot. Additionally, network pharmacology was employed to preliminarily analyze the cellular pathways by which PL reduces VMC via the inhibition of pyroptosis, and the results of this analysis were validated through western blot.

In vivo experimental results demonstrated that following PL treatment, symptoms in VMC mice were significantly alleviated, cardiac function was restored, inflammation in cardiac tissue was reduced, and both myocardial cell pyroptosis and levels of inflammatory factors were notably decreased. Similar findings were observed in vitro. Network pharmacology analysis indicated that the NF-κB pathway may serve as a critical target for PL treatment of VMC. Furthermore, in vitro experiments revealed that the specific NF-κB pathway inhibitor MG132 can significantly inhibit CVB3-induced pyroptosis. Additionally, PL could reduce the phosphorylation levels of key molecules in the NF-κB signal pathway in a dose dependent manner.

In summary, this study presents evidence that PL ameliorates cardiomyocyte injury and enhances cardiac function in VMC mice, by reducing pyroptosis through the inhibition of the NF-κB pathway. These findings offer new insights for the potential of PL in VMC treatment.