Oh, Yumin Park, Ogyi Swierczewska, Magdalena Hamilton, James P. Park, Jong-Sung Kim, Tae Hyung Lim, Sung-Mook Eom, Hana Jo, Dong Gyu Lee, Choong-Eun Kechrid, Raouf Mastorakos, Panagiotis Zhang, Clark Hahn, Sei Kwang Jeon, Ok-Cheol Byun, Youngro Kim, Kwangmeyung Hanes, Justin Lee, Kang Choon Pomper, Martin G. Gao, Bin Lee, Seulki 2024-01-20T04:01:17Z 2024-01-20T04:01:17Z 2021-09-04 2016-07 0270-9139 https://pubs.kist.re.kr/handle/201004/123914 Liver fibrosis is a common outcome of chronic liver disease that leads to liver cirrhosis and hepatocellular carcinoma. No US Food and Drug Administration-approved targeted antifibrotic therapy exists. Activated hepatic stellate cells (aHSCs) are the major cell types responsible for liver fibrosis; therefore, eradication of aHSCs, while preserving quiescent HSCs and other normal cells, is a logical strategy to stop and/or reverse liver fibrogenesis/fibrosis. However, there are no effective approaches to specifically deplete aHSCs during fibrosis without systemic toxicity. aHSCs are associated with elevated expression of death receptors and become sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death. Treatment with recombinant TRAIL could be a potential strategy to ameliorate liver fibrosis; however, the therapeutic application of recombinant TRAIL is halted due to its very short half-life. To overcome this problem, we previously generated PEGylated TRAIL (TRAIL(PEG)) that has a much longer half-life in rodents than native-type TRAIL. In this study, we demonstrate that intravenous TRAILPEG has a markedly extended half-life over native-type TRAIL in nonhuman primates and has no toxicity in primary human hepatocytes. Intravenous injection of TRAILPEG directly induces apoptosis of aHSCs in vivo and ameliorates carbon tetrachloride-induced fibrosis/cirrhosis in rats by simultaneously down-regulating multiple key fibrotic markers that are associated with aHSCs. Conclusion: TRAIL-based therapies could serve as new therapeutics for liver fibrosis/cirrhosis and possibly other fibrotic diseases. English WILEY-BLACKWELL APOPTOSIS-INDUCING LIGAND IN-VIVO FIBROSIS CANCER COMBINATION MECHANISMS THERAPY PHARMACOKINETICS TOXICITY PATHWAYS Systemic PEGylated TRAIL Treatment Ameliorates Liver Cirrhosis in Rats by Eliminating Activated Hepatic Stellate Cells Article 10.1002/hep.28432 1 HEPATOLOGY, v.64, no.1, pp.209 - 223 HEPATOLOGY 64 1 209 223 scie scopus 000379233400025 2-s2.0-84976498736 Gastroenterology & Hepatology Gastroenterology & Hepatology Article APOPTOSIS-INDUCING LIGAND IN-VIVO FIBROSIS CANCER COMBINATION MECHANISMS THERAPY PHARMACOKINETICS TOXICITY PATHWAYS TRAIL PEGylation Liver Cirrhosis Hepatic Stellate Cell