AP39 through AMPK-ULK1-FUNDC1 pathway regulates mitophagy, inhibits pyroptosis, and improves doxorubicin-induced myocardial fibrosis

AP39 through AMPK-ULK1-FUNDC1 pathway regulates mitophagy, inhibits pyroptosis, and improves doxorubicin-induced myocardial fibrosis

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Summary: Doxorubicin induces myocardial injury and fibrosis.Still, no effective interventions are available.AP39 is an H2S donor that explicitly targets mitochondria.This study investigated whether AP39 could improve doxorubicin-induced myocardial fibrosis.Doxorubicin induced significant myocardial fibrosis while suppressing mitophagy-related proteins and elevating pyroptosis-related proteins.

Conversely, AP39 reverses these effects, enhancing mitophagy and inhibiting pyroptosis.In vitro experiments revealed that AP39 read more inhibited H9c2 cardiomyocyte pyroptosis, improved doxorubicin-induced impairment of mitophagy, reduced ROS levels, ameliorated the mitochondrial membrane potential, and upregulated AMPK-ULK1-FUNDC1 expression.In contrast, AMPK inhibitor (dorsomorphin) and ULK1 inhibitor (SBI-0206965) reversed AP39 antagonism of doxorubicin-induced FUNDC1-mediated impairment of mitophagy and secondary cardiomyocyte pyroptosis.These results suggest that mitochondria-targeted H2S can antagonize doxorubicin-induced pyroptosis and impaired google pixel 7 freedom mitophagy in cardiomyocytes via AMPK-ULK1-FUNDC1 and ameliorated myocardial fibrosis and remodeling.