Gnetum montanum extract attenuates lipopolysaccharide induced acute lung inflammation through Nrf2 and heme oxygenase 1 mediated redox modulation in macrophages

The Nrf2/HO-1 pathway is a promising therapeutic target for inflammatory disease management. Stilbene derivatives can activate this pathway and exert potent anti-inflammatory effects. Gnetum montanum Markgr., a stilbene-rich medicinal plant traditionally used in Vietnam, China, and Other Asian countries for the treatment of inflammatory disorders, has not been systematically investigated for its anti-inflammatory properties or underlying mechanisms. Our study evaluated the protective effects of a stilbene-rich G. montanum extract (SGME) against inflammatory responses in vitro and in vivo. In lipopolysaccharide (LPS)-activated raw 264.7 macrophages, SGME significantly suppressed the expression and production of pro-inflammatory mediators by inhibiting NF-κB activation. In bone marrow-derived macrophages, SGME effectively prevented polarization toward the pro-inflammatory M1 phenotype. Mechanistically, SGME promoted Nrf2 nuclear translocation, leading to the upregulation of HO-1 and Other Nrf2 target genes, attenuating LPS-induced oxidative stress in macrophages. Both Nrf2 knockdown and pharmacological inhibition significantly diminished these protective effects, confirming Nrf2’s pivotal role. Notably, in an oropharyngeal LPS-induced acute lung inflammation model, SGME reduced leukocyte infiltration, suppressed excessive cytokine production, and alleviated oxidative stress, accompanied by increased expression of Nrf2-dependent antioxidant genes, including Cat, Sod2, and Hmox1. These findings demonstrate that SGME exerts potent anti-inflammatory effects via Nrf2 pathway activation, warranting further studies to evaluate its therapeutic potential in inflammation-related diseases.