Molecular mechanism of paraquat-induced ferroptosis leading to pulmonary fibrosis mediated by Keap1/Nrf2 signaling pathway

Abstract

Paraquat (PQ) is a widely used and highly toxic pesticide that is often actively ingested and causes pulmonary fibrosis in patients. Ferroptosis is a regulated form of non-apoptotic cell death associated with iron-dependent lipid peroxidation. Previous studies have shown that ferroptosis is involved in the occurrence and development of acute lung injury (ALI). In this study, a model rat with inflammatory response, oxidative stress, lipid peroxidation, and pulmonary fibrosis was successfully established by PQ administration. The occurrence of ferroptosis in PQ model rats was confirmed by TUNEL staining, iron ion detection, and Ferroptosis related biomarkers detection. Western blotting (WB) and real-time PCR (RT-PCR) showed that the expression of Keap1 was significantly up-regulated and the expression of Nrf2 was significantly down-regulated in the lung tissue of PQ rats. Further transcriptomics and proteomics confirmed: (1) Enrichment of molecular processes related to iron ion binding; (2) Keap1 may promote Nrf2 ubiquitination and lead to Nrf2 degradation; (3) There is functional enrichment in ferroptosis related pathways. Our results suggest that PQ can regulate Keap1/Nrf2 signaling pathway, leading to increased lipid peroxidation and abnormal iron uptake, thereby inducing iron death and exacerbating the progression of pulmonary fibrosis. Our study provides new insights into PQ-induced pulmonary fibrosis. Graphical abstract

Ferroptosis in organ fibrosis: From mechanisms to therapeutic medicines

“…[ 68 ] Moreover, ferroptosis was also proved to be responsible for PM2.5-mediated pulmonary fibrosis and heavy metals-induced pulmonary fibrosis. [69,70] To our knowledge, several ferroptosis pathways associated with pulmonary fibrosis have been revealed, including NCOA4-mediated ferritinophagy, [ 71 ] miR-150–5p/ SLC38A1 signaling, [ 72 ] Keap1/Nrf2 signaling, [ 73 ] cGAS/ STING signaling, [ 74 ] Nrf2/HO-1 signaling, [ 75 ] Wnt5a/Ca 2+ signaling, [ 76 ] USP3/Sirt3/p53 signaling, [ 77 ] EMPA/Nrf2/ SLC7A11 signaling, [ 78 ] and ACSL4-dependent ferroptosis pathway ( Figure 3B ).…”