Genkwanin alleviates paraquat-induced acute lung injury by activating SIRT1-mediated Nrf2/HO-1 signaling pathway.

Paraquat (PQ) mainly damages the lungs, leading to acute lung injury (ALI) and even pulmonary fibrosis. Genkwanin (GEN) is demonstrated to possess anti-inflammatory and antioxidant activities in several diseases. This study aims to elucidate the protective effect of GEN against PQ-induced ALI and to decipher its underlying molecular mechanism. C57BL/6 J mice were injected intraperitoneally with 20 mg/kg PQ to induce an in vivo ALI model. BEAS-2B cells were treated with PQ to mimic an in vitro ALI model. The results showed that GEN alleviated PQ-induced lung pathologic damage, lung injury score, wet/dry weight ratio, myeloperoxidase (MPO) activity, and inflammatory cytokine production. GEN inhibited the expression of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) and enhanced the activities of superoxide dismutase (SOD) and catalase (CAT) in lung tissues of PQ-treated mice. Also, GEN decreased PQ-induced apoptosis of lung tissues by downregulating Bax and Cleaved caspase 3 and elevating Bcl-2. Moreover, GEN repressed inflammatory factor levels, reactive oxygen species (ROS) production, and apoptosis in PQ-stimulated BEAS-2B cells. Additionally, GEN treatment led to the increase of sirtuin 1 (SIRT1) expression in both PQ-treated mice and BEAS-2B cells. Inhibition of SIRT1 largely reversed the inhibitory effects of GEN on PQ-induced inflammation, oxidative stress, and apoptosis in mice and cells. Furthermore, GEN activated the Nrf2/HO-1 signaling by upregulating SIRT1 in mice and BEAS-2B cells administered with PQ. In conclusion, GEN ameliorates lung inflammation, oxidative stress, and apoptosis in PQ-induced ALI by inducing SIRT1 to activate the Nrf2/HO-1 signaling. Our findings highlight the potential of GEN to resist PQ poisoning.