Targeted degradation of LRG1 to attenuate renal fibrosis.

ABSTRACT: Leucine-rich α-2 glycoprotein 1 (LRG1), a secreted glycoprotein, has been identified as significantly upregulated in renal fibrosis, potentially exacerbating the condition by enhancing TGF-β-Smad3-dependent signaling pathways. Herein, utilizing our developed LRG1-targeting peptide for LRG1 recruitment and lenalidomide for E3 ubiquitin ligase engagement, we developed an advanced proteolysis targeting chimera, ^ETTAC-2, specifically designed for LRG1 degradation. Our cellular degradation assays validated that ^ETTAC-2 effectively degraded LRG1 through a proteasome-dependent mechanism, achieving half-maximal degradation at a concentration of 8.38 µM. Furthermore, anti-fibrotic experiments conducted both in vitro and in vivo revealed that ^ETTAC-2 ef

SUBMITTER: Fan L 

PROVIDER: S-EPMC11378895 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature