Identification of PIK3R5 as a hub in septic myocardial injury and the cardioprotective effects of Psoralidin

Myocardial injury is a severe complication of sepsis, resulting in substantial morbidity and mortality. Psoralidin (PSO), derived from the seeds of Psoralea corylifolia L., has garnered considerable attention due to its potent pharmacological effects, including anti-inflammatory and antibacterial effects. Our previous work conducted affirmed that PSO has a protective effect on sepsis and septic myocardial injury, however the specific molecular mechanisms need further clarification. This objective of this study was to use three analytic modalities and bioinformatics methods to identify potential targets, followed by experimental verification. A series of experiments methods (including echocardiography, HE, western blot, qPCR, RNA-seq, network pharmacology) were used to evaluate the effects of PSO against sepsis and septic myocardial injury in cecal ligation and puncture (CLP)-injured BALB/c mice and lipopolysaccharide (LPS)-injured HL-1 cardiomyocytes. Firstly, a group of sepsis-related genes were identified by integrating database surveys, RNA-seq analysis, and weighted gene co-expression network analysis (WCGNA). Subsequently, the pharmacological targets of PSO were predicted. Furthermore, the identification of phosphoinositide 3- kinase regulatory subunit 5 (PIK3R5) as a crucial hub gene was accomplished via protein-protein interaction network and molecular docking approach. In vivo experiments showed that PSO treatment alleviated septic myocardial injury, as evidenced by improved cardiac function indicators and inflammation response. Similar results were obtained in vitro experiments. Importantly, the expression of PI3KR5 was decreased in the myocardium and cardiomyocytes, and the effect was reversed by PSO treatment. This study systematically revealed the key targets of PSO in the treatment of septic myocardial injury. These findings offer valuable insights into disease-drug targets, which have certain clinical significance to exploring disease biomarkers and potential therapeutic targets for septic patients.