Integrating metabolomics and network pharmacology to explore Rhizoma Coptidis extracts against sepsis-associated acute kidney injury

• SA-AKI was effectively alleviated with RCE treatment. • 25 differential metabolites related to the pathological processes of SA-AKI and the effects of RCE were identified. • A compound-metabolite-target-disease network was constructed to explore the mechanisms of RCE against SA-AKI. • RCE may mitigate SA-AKI through regulating these 17 overlapping target proteins in the network. Sepsis remains the most common cause of acute kidney injury (AKI) in critically ill patients, increasing the risk of in-hospital and long-term death. Rhizoma Coptidis (RC), a classical traditional Chinese herb, exhibits anti-inflammatory and antioxidant properties in various diseases including sepsis. This study aimed to investigate the protective effects of RC extracts (RCE) against sepsis-associated acute kidney injury (SA-AKI) and explore the underlying mechanisms with metabolomics-based network pharmacology. The results showed that RCE improved renal function and histological injury and decreased reactive oxygen species (ROS) production in SA-AKI. Using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS), 25 differential metabolites were identified that had a close connection with the pathological processes of SA-AKI and the effects of RCE. Afterward, a compound-metabolite-target-disease network was constructed and 17 overlapping target proteins of the components of RCE, the differential metabolites, and the disease-related genes were discovered. Among these overlapping target proteins, RCE increased the nuclear translocation of nuclear factor-erythroid 2-related factor-2 (Nrf2), the protein expression of heme oxygenase-1 (HO-1), the mRNA expression of peroxisome proliferator activated receptor α (PPARα) and reduced nitric oxide synthase 2 (NOS2) activity. In addition, molecular docking revealed that both berberine and quercetin could bond with NOS2 and PPARα, respectively. Therefore, RCE demonstrated protective effects for SA-AKI through the regulation of metabolism and different signaling pathways.