Sinomenine Ameliorates Mitochondrial Dysfunction in PD-1 Inhibitor-Induced Myocardial Injury in Mice via the TLR4/NF-κB Pathway.

Abstract

Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment but can cause severe cardiotoxicity. Anti-inflammatory and cardioprotective effects of sinomenine have been documented in existing research. However, it remains unclear what role sinomenine plays in myocardial injury induced by PD-1 inhibitors. Myocardial injury in mice, induced by PD-1 inhibitors, was used to establish an experimental model. After administering sinomenine to the mice, assessments of cardiac function were conducted using echocardiographic techniques. Histological examination and ELISA were performed to evaluate myocardial injury, inflammation, and mitochondrial dysfunction. The expression of key proteins in the TLR4/NF-κB pathway was determined via Western blotting. Treatment with sinomenine notably enhanced cardiac function and mitigated myocardial injury in mice subjected to PD-1 inhibitors. It also attenuated myocardial inflammation and mitochondrial dysfunction. Mechanistic studies shed light on the fact that the activation of the TLR4/NF-κB pathway was inhibited by sinomenine. The alleviation of PD-1 inhibitor-induced myocardial injury by sinomenine is achieved through the reduction of inflammation and the restoration of mitochondrial function, with this process being regulated by the inhibition of the TLR4/NF-κB signaling pathway. These observations imply that sinomenine has the potential to serve as a therapeutic option for managing cardiotoxicity linked to immune checkpoint inhibitors.