LY-res-3

Hepatic fibrosis is characterized by persistent hepatocyte injury and activation of hepatic stellate cells (HSCs), leading to excessive extracellular matrix deposition and impaired liver function. 5-hydroxytryptamine (5-HT) promotes HSCs activation and fibrogenesis via the 5-HT_2A receptor (5-HT_2AR, a GPCR). Herein, we developed novel bifunctional lysosome-targeting chimeras (LYTACs) by conjugating a potent 5-HT_2AR antagonist to a triantennary N-acetylgalactosamine (tri-GalNAc) ligand by using precisely optimized linkers. LY-res-3 induced potent, rapid, and selective degradation of endogenous 5-HT_2AR in asialoglycoprotein receptor (ASGPR)-positive hepatocytes. Mechanistic studies confirmed that LY-res-3 mediates inhibition of TGF-β release in hepatocytes, with this activity strictly dependent on ASGPR-mediated 5-HT_2AR endocytosis, followed by lysosomal degradation. Crucially, the bifunctional molecule concurrently maintained significant antagonism against 5-HT_2AR in activated HSCs, effectively blocking TGF-β downstream signaling. By combining targeted degradation with receptor antagonism, this strategy establishes a novel therapeutic modality targeting hepatocyte-HSCs crosstalk in liver fibrosis. Furthermore, it provides a powerful and generalizable method for developing hepatic-selective degraders against other challenging GPCRs implicated in liver fibrosis.