Abstract

Influenza A virus (IAV) A/PR/8/34 is a major cause of acute lung injury (ALI), with limited anti-inflammatory and antioxidant therapies. Curculigoside (CUR), a natural polyphenol, has anti-inflammatory and antioxidant activities, but its mechanisms remain unclear. This study investigated CUR’s protective role in IAV-induced ALI. In vitro, A549 and MDCK cells were infected with IAV to assess CUR’s effects on cell viability, inflammation, oxidative stress (OS), and barrier proteins using CCK-8 assay, ELISA, immunofluorescence, and Western blot. An IAV-induced ALI mouse model evaluated lung pathology, cytokines, OS markers, and barrier integrity. The Nrf2 inhibitor ML385 was applied to verify mechanistic involvement. CUR inhibited IAV replication, reduced cytopathic effects, and improved cell survival. It dose-dependently decreased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), COX-2 and iNOS, suppressed ROS and MDA, increased SOD and GSH, and restored ZO-1 and Occludin expression. In vivo, CUR alleviated weight loss, lung injury, edema, and inflammatory infiltration, while enhancing antioxidant defenses and barrier integrity. Mechanistically, CUR downregulated Keap1, promoted Nrf2 nuclear translocation, and activated Nrf2 signaling. ML385 partly reversed these effects, confirming Nrf2 involvement. CUR protects against IAV-induced ALI by inhibiting viral replication, reducing inflammation and OS, and preserving barrier function through activation of the Keap1/Nrf2 pathway.