Activation of NR1H3 signaling pathways by psoralidin attenuates septic myocardial injury.

Sepsis can cause various organ dysfunction, which heart failure may be associated with significant mortality. Recently, natural plant extracts have gradually attracted people's attention in the clinical treatment of cardiovascular diseases. Psoralidin (PSO) is one of the main bioactive compounds from the seeds of Psoralea corylifolia L and exhibits remarkable protective effects in diseases, including cancer, osteoporosis, and depression. Recently, NR1H3 is one of the emerging nuclear receptors targets for the various drugs. This study first reported the porotective role of PSO in septic myocardial injury, which was mainly attributed to the NR1H3-dependent manner. NR1H3 knockout mice subjected to cecal ligation and puncture (CLP) were used to investigate the involvement of NR1H3 in PSO protection. Our results showed that PSO prominently improved cardiac function, attenuated inflammation, inhibited oxidative stress, improved mitochondrial function, regulated ERS, suppressed apoptosis, and particularly increased NR1H3 and p-AMPK levels. However, NR1H3 knockout reversed the positive role of PSO in septic mice. Furthermore, activation of NR1H3 by T0901317 also increased the activity of AMPK and ACC in the HL-1 cardiomyocytes, indicating the regulatory relationship between NR1H3 and AMPK signaling. Together, this study demonstrated the beneficial effect of PSO in septic myocardial injury through activation of NR1H3/AMPK pathway. [Display omitted] • Psoralidin (PSO) treatment elevated the survival rate and improved cardiac function in CLP mice. • The protective mechanisms of PSO were contributed to the attenuated inflammation, oxidative stress, and apoptosis, improved mitochondrial function, and regulated ERS. • NR1H3 knockout nullified the protective roles of PSO against sepsis. • RNA-seq illustrated the comprehensive transcriptome regulated by PSO in CLP mice. • This study demonstrated the beneficial effect of PSO in septic myocardial injury through activation of NR1H3 pathway. [ABSTRACT FROM AUTHOR]