Targeted degradation of LRG1 to attenuate renal fibrosis.

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, ET TAC-2, specifically designed for LRG1 degradation. Our cellular degradation assays validated that ET TAC-2 effectively degraded LRG1 through a proteasome-dependent mechanism, achieving halfmaximal degradation at a concentration of 8.38 μM. Furthermore, anti-fibrotic experiments conducted both in vitro and in vivo revealed that ET TAC-2 efficiently induced LRG1 degradation in fibrotic kidneys. This action effectively inhibited the TGF-β-Smad3 signaling pathway and diminished the secretion of fibrosis-associated proteins, consequently attenuating the progression of renal fibrosis. Our study highlights the pivotal role of LRG1 in renal fibrosis and positions ET TAC-2 as a promising therapeutic candidate for targeted LRG1 intervention. [ABSTRACT FROM AUTHOR]