Fig. 9: Schematic showing that EPRS1-mediated fibroblast activation and mitochondrial dysfunction induce kidney fibrosis.
From: EPRS1-mediated fibroblast activation and mitochondrial dysfunction promote kidney fibrosis
Our results indicate that EPRS1 can mediate kidney fibrosis. EPRS1 is an enzyme that catalyzes the binding of proline to tRNAPro. EPRS1 of the multi-tRNA synthetase complex (MSC) translationally synthesizes proline-rich profibrotic proteins. However, the EPRS1 inhibitor inhibits hydroxyproline. EPRS1 also activates the TGF-β pathway. EPRS1 can translocate to the cell membrane and bind to TGF-β receptor 1 (TβRI), resulting in downstream pathways. Our results demonstrated that EPRS1 is linked to three different pathways associated with kidney fibrosis. EPRS1 regulates the phosphorylation of STAT3 and Smad3. The nuclear localization of p-STAT3 and p-Smad3 induces the transcription of profibrotic genes. This pathway leads to fibroblast activation, resulting in increased ECM production, cell proliferation, and tissue remodeling. p-STAT3 affects mitochondrial reactive oxygen species (ROS) generation45,46. Eventually, ROS lead to mitochondrial dysfunction in cells. However, EPRS1 inhibition not only transcriptionally reduces p-Smad3 and p-STAT3 but also improves mitochondrial dysfunction. As a result, EPRS1 inhibition reduces kidney fibrosis through transcriptional and translational regulation. MSC multi-tRNA synthetase complex, ECM extracellular matrix, EMT epithelial‒mesenchymal transition, FMT fibroblast–mesenchymal transition, Pro proline, ROS reactive oxygen species. This figure was created with Biorender.com.
