Honokiol reduces acute lung injury by modulating macrophage polarization via the p62/keap1/Nrf2 axis

Purpose Acute lung injury (ALI) is a severe syndrome causing respiratory failure with limited therapeutic options. This study aimed to investigate the protective effect of honokiol against lipopolysaccharide (LPS)-induced ALI and its underlying mechanism, focusing on macrophage polarization via the p62/Keap1/Nrf2 axis. Methods In vivo , mice (n = 6/group) received LPS to induce ALI and were treated with honokiol with/without the Nrf2 inhibitor ML385. Lung injury, inflammation, and BALF macrophage phenotypes (CD86 + M1, CD206 + M2) were assessed. In vitro , LPS/IFN-γ-stimulated RAW264.7 (and co-cultured BEAS-2B) were treated with honokiol or ML385. Protein expression, cytokines, and cell viability were analyzed. Results Honokiol significantly alleviated lung pathological damage and edema (wet/dry ratio, P < 0.05), and reduced serum TNF-α, IL-6, IL-1β, and LDH (P < 0.05). It promoted a shift from M1 to M2 macrophages in vivo (P < 0.05) and in vitro. Mechanistically, honokiol activated the p62/Keap1/Nrf2 pathway, inhibited the NLRP3 inflammasome, and suppressed inflammatory secretion. These protective effects were attenuated by ML385. In co-culture, honokiol improved BEAS-2B viability (P < 0.05) and reduced damage, an effect reversed by ML385. Conclusion Honokiol improves lung injury by regulating the p62/Keap1/Nrf2 signaling axis, promoting CD206+ macrophage polarization, and reducing the inflammatory response in ALI, thereby ameliorating lung injury. This study provides a scientific basis for honokiol as a potential therapeutic agent for the treatment of ALI.