Berberine attenuates sepsis-associated myocardial injury and mitochondrial dysfunction through the AMPK/PGC-1α/NRF2 signaling pathway.

Abstract

Berberine (Ber), a bioactive isoquinoline alkaloid derived from traditional Chinese herbs, has shown protective effects against sepsis-associated myocardial injury, although its underlying mechanisms remain unclear. This study investigated whether Ber attenuates LPS-induced myocardial injury by preserving mitochondrial function. Lipopolysaccharide (LPS)-induced rat endotoxemia model and LPS-treated H9C2 cells, inflammation, oxidative stress, mitochondrial function, and signaling pathways. RNA sequencing combined with pathway enrichment analyses was performed to identify the molecular targets of Ber, followed by validation using RT-qPCR, western blotting, pharmacological inhibition, and siRNA-mediated gene silencing. Ber markedly attenuated LPS-induced myocardial injury, inflammatory responses, oxidative stress, and mitochondrial dysfunction in vivo and in vitro, as evidenced by improved ATP production and mitochondrial integrity. Transcriptomic analysis showed that Ber reversed LPS-induced dysregulation of inflammatory and metabolic pathways. Based on transcriptomic findings together with prior evidence, the AMPK/PGC-1α/NRF2 signaling axis was selected for further validation. Pharmacological inhibition of AMPK signaling or genetic silencing of PGC-1α partially attenuated the mitochondrial protective effects of Ber, accompanied by reduced NRF2 expression and impaired antioxidant responses. These findings suggest that Ber attenuates sepsis-associated myocardial injury and mitochondrial dysfunction, at least in part through activation of the AMPK/PGC-1α/NRF2 signaling axis. This study provides mechanistic evidence supporting Ber as a potential modulator of mitochondrial dysfunction during sepsis-associated myocardial injury and highlights mitochondrial regulation as a potential target for further investigation.