Naringin mitigates paraquat-induced pulmonary epithelial-mesenchymal transition and fibrosis by modulating the NDRG1/JNK/PPARγ signaling pathway

Paraquat (PQ) is a widely used herbicide known to induce lung injury and fibrosis in humans. Naringin (Nar), a naturally occurring flavonoid, possesses anti-inflammatory and anti-fibrotic properties. This study explores the protective mechanisms of Nar against PQ-induced epithelial-mesenchymal transition (EMT) and pulmonary fibrosis, focusing on the N-Myc downstream-regulated gene 1 (NDRG1) and peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways. Results demonstrate that Nar treatment significantly suppresses the PQ-mediated increase in EMT and pro-fibrotic markers, such as TGF-β, Vimentin, Snail, N-cadherin, and α-SMA, while also reducing the release of pro-inflammatory and pro-fibrotic factors, including IL-6, TNF-α, IL-1β, TGF-β, and MMP-9. Additionally, Nar decreases NDRG1 levels and enhances PPARγ expression. Mechanistically, NDRG1 silencing led to diminished JNK activity, which restored PPARγ levels and alleviated the expression of EMT markers and cytochrome P450s (CYPs 1A2 and 2E1) in A549 cells. Furthermore, Nar effectively mitigated PQ-induced EMT, cellular migration, and invasion by downregulating NDRG1 and phosphorylated JNK while upregulating PPARγ. These findings highlight the critical involvement of the NDRG1/JNK/PPARγ signaling pathway in PQ-induced lung injury and suggest the therapeutic potential of Nar for pulmonary fibrosis.