Integrating network pharmacology, molecular docking, machine learning, and experimental validation: puerarin improves sepsis-induced acute kidney injury via the Sirt1-Nrf2-HO-1 pathway.

Acute kidney injury (AKI) associated with sepsis has a high clinical mortality rate, and there is a lack of effective therapeutic targets; uncontrolled oxidative stress and inflammatory responses are central pathological mechanisms. The Sirt1-Nrf2-HO-1 pathway plays a key role in renal antioxidant and anti-inflammatory protection. Although puerarin possesses anti-inflammatory and antioxidant activity, its specific molecular mechanisms for improving sepsis-induced AKI have not yet been fully elucidated. The aim of this study was to determine whether puerarin protects against sepsis-induced AKI by activating the Sirt1-Nrf2-HO-1 pathway and to establish a theoretical foundation for its clinical application. Using network pharmacology, we identified Sirt1, Nrf2, and HO-1 as key targets linked to oxidative stress and inflammation. Molecular docking suggested that puerarin binds well to all three proteins. In both cell and animal studies, we found that puerarin activates the Sirt1-Nrf2-HO-1 pathway, which in turn improves kidney function, reduces tissue damage, and lowers oxidative stress and inflammation. Our findings suggest that puerarin protects against sepsis-induced AKI by triggering the Sirt1-Nrf2-HO-1 pathway, pointing to this signaling axis as a possible target for treatment.