Leucine-richα-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 pat...Leucine-richα-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 8.38μM.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.展开更多
基金supported by grants from the National Natural Science Foundation of China(32000998,32201240,and 81700638)The Young Elite Scientists Sponsorship Program by the Henan Association for Science and Technology(2022HYTP046)the China Postdoctoral Science Foundation(2021TQ0298).
文摘Leucine-richα-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 8.38μM.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.
