Piceatannol ameliorates intestinal barrier dysfunction in urosepsis by modulating the Nrf2/ROS/NF-κB pathway.

Urosepsis is a life-threatening condition. Intestinal barrier dysfunction in sepsis drives disease progression and significantly determines mortality. Piceatannol exhibits potent anti-oxidative and anti-inflammatory activities and protects intestinal barrier homeostasis; however, its role and mechanisms in urosepsis-induced intestinal barrier dysfunction remain unclear. This study aimed to investigate the therapeutic potential of PIC in intestinal injury during urosepsis. Molecular docking was performed to evaluate the interaction between PIC and nuclear factor E2-related factor 2 (Nrf2) proteins, revealing a binding energy of -6.7 kcal/mol for the Nrf2-PIC complex. A murine urosepsis model was established by lipopolysaccharide (LPS) injection into the renal pelvis, while an in vitro model used LPS-stimulated human colon epithelial NCM460 cells. PIC treatment significantly attenuated LPS-induced intestinal barrier dysfunction and suppressed oxidative stress and inflammatory responses in both models. Mechanistically, PIC modulated the activation of the Nrf2/reactive oxygen species (ROS)/NF-κB pathway, which is closely associated with oxidative stress and inflammation. Notably, pretreatment with the Nrf2 inhibitor ML385 partially blocked the protective effects of PIC on the intestinal barrier, along with its antioxidant and anti-inflammatory effects. Collectively, these findings demonstrate that PIC ameliorates intestinal barrier dysfunction by attenuating LPS-triggered oxidative stress and inflammatory responses via modulation of the Nrf2/ROS/NF-κB pathway in both NCM460 cells and uroseptic mice.