{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:58:43Z","timestamp":1787029123784,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012247","name":"Program of Shanghai Academic\/Technology Research Leader","doi-asserted-by":"crossref","award":["23XD1460600"],"award-info":[{"award-number":["23XD1460600"]}],"id":[{"id":"10.13039\/501100012247","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Activation of hepatic stellate cells (HSCs) featuring upregulated expression of \u03b1-smooth muscle actin (\u03b1-SMA) is recognized as a key driver for hepatic fibrosis, which provides a promising strategy for seeking anti-liver fibrogenic agents via suppressing the activation event. In this study, we designed and synthesized twenty-eight cordycepin derivatives through structural modifications at the C2 position and the C6-NH2 group of the purine moiety. These compounds were screened for their inhibitory effects on HSC activation by detecting the mRNA expression of \u03b1-SMA using quantitative real-time polymerase chain reaction (qPCR) in the LX-2 cell model. Most compounds displayed inhibitory activity comparable to cordycepin, with compound 3a bearing a C2-chloro and a N6-methyl-N6-(2-chlorobenzyl) substituent, demonstrating enhanced in vitro anti-fibrotic effect. This compound was able to dose-dependently downregulate \u03b1-SMA and collagen-I at both mRNA and protein levels, inhibited LX-2 cell migration, and exhibited improved metabolic stability in liver microsomes. The Western blotting result also indicated that 3a could activate the AMPK signaling pathway. Overall, these results suggest 3a may serve as a lead compound for further investigation.<\/jats:p>","DOI":"10.3390\/molecules31020264","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T08:17:32Z","timestamp":1768292252000},"page":"264","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Design, Synthesis, and Anti-Hepatic Fibrosis Evaluation of Cordycepin Derivatives"],"prefix":"10.3390","volume":"31","author":[{"given":"Wenfang","family":"Pan","sequence":"first","affiliation":[{"name":"Lingang Laboratory, Shanghai 200031, China"},{"name":"School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Liu","sequence":"additional","affiliation":[{"name":"Lingang Laboratory, Shanghai 200031, China"},{"name":"School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China"},{"name":"Stake Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanchen","family":"Zhong","sequence":"additional","affiliation":[{"name":"Lingang Laboratory, Shanghai 200031, China"},{"name":"School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bixi","family":"Tang","sequence":"additional","affiliation":[{"name":"Lingang Laboratory, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zang","sequence":"additional","affiliation":[{"name":"Lingang Laboratory, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanchao","family":"Xie","sequence":"additional","affiliation":[{"name":"Lingang Laboratory, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41575-020-00372-7","article-title":"Molecular and cellular mechanisms of liver fibrosis and its regression","volume":"18","author":"Kisseleva","year":"2021","journal-title":"Nat. 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