Recently, the research team led by Sun Jianbo, Qi Lianwen, and Liu Qun published their latest findings in the prestigious Journal of the American Chemical Society. The paper, titled “Bifunctional LYTAC Mediates Hepatocytes-Hepatic Stellate Cells Crosstalk by Regulating 5-HT2A Receptor Degradation and Antagonism to Synergistically Ameliorate Hepatic Fibrosis,” details their groundbreaking work. Zhou Xinyue (2021 direct Ph.D. student), Xu Zhongyuan (2023 Ph.D. student), and Liu Xiwen (2023 master's student) from our university served as co-first authors. Professors Sun Jianbo, Liu Qun, and Qi Lianwen are the corresponding authors, with China Pharmaceutical University listed as the first corresponding institution.
Liver fibrosis represents a pivotal pathological process in the progression of various chronic liver diseases, characterized by parenchymal cell injury and sustained activation of hepatic stellate cells (HSCs), leading to excessive extracellular matrix deposition and loss of liver function. This study demonstrates that the serotonin 2A receptor (5-HT2AR) is a critical regulator of liver fibrosis progression. Liver injury significantly upregulates 5-HT2AR expression on both hepatocytes and HSCs, thereby exacerbating inflammation and promoting HSC activation. However, existing 5-HT2AR small-molecule antagonists exhibit limited efficacy due to insufficient target specificity or extensive tissue distribution.
Addressing these critical scientific challenges, the team employed a lysosome-targeting chimeric (LYTAC) strategy. They linked Tri-GalNAc—the ligand for the hepatocyte-specific sialic acid glycoprotein receptor (ASGPR)—to the 5-HT2AR small-molecule antagonist analog18, designing and synthesizing a series of LYTACs that degrade 5-HT2AR specifically on hepatocytes. Results indicate that LY-res-3 exhibits optimal 5-HT2AR degradation efficacy and possesses dual intervention mechanisms: (1) Targeting hepatic parenchymal cell 5-HT2AR to induce lysosomal degradation, thereby inhibiting TGF-β release and reducing HSC activation; (2) Binds to 5-HT2AR on HSCs, continuously antagonizing the receptor and thereby inhibiting the TGF-β signaling pathway. This dual-functional LYTAC improved liver fibrosis in mice through synergistic antagonism and degradation of hepatic 5-HT2AR. In summary, this study provides a novel approach for simultaneously intervening in hepatocytes and HSCs to influence intercellular interactions, offering an innovative strategy for targeting 5-HT2AR in the treatment of liver fibrosis.
This research was supported by the National Natural Science Foundation of China and the Special Fund for Basic Research of Central Universities.
Original link: https://doi.org/10.1021/jacs.5c13607
