Hicks, Daniel F.Goossens, NicolasBlas-García, AnaTsuchida, TakumaWooden, BenjaminWallace, Michael C.Nieto, NataliaLade, AbigaleRedhead, BenjaminCederbaum, Arthur IDudley, Joel T.Fuchs, BryanLee, Youngmin A.Hoshida, YujinFriedman, Scott L.2017-04-062017Hicks, D. F., N. Goossens, A. Blas-García, T. Tsuchida, B. Wooden, M. C. Wallace, N. Nieto, et al. 2017. “Transcriptome-based repurposing of apigenin as a potential anti-fibrotic agent targeting hepatic stellate cells.” Scientific Reports 7 (1): 42563. doi:10.1038/srep42563. http://dx.doi.org/10.1038/srep42563.http://nrs.harvard.edu/urn-3:HUL.InstRepos:32071894We have used a computational approach to identify anti-fibrotic therapies by querying a transcriptome. A transcriptome signature of activated hepatic stellate cells (HSCs), the primary collagen-secreting cell in liver, and queried against a transcriptomic database that quantifies changes in gene expression in response to 1,309 FDA-approved drugs and bioactives (CMap). The flavonoid apigenin was among 9 top-ranked compounds predicted to have anti-fibrotic activity; indeed, apigenin dose-dependently reduced collagen I in the human HSC line, TWNT-4. To identify proteins mediating apigenin’s effect, we next overlapped a 122-gene signature unique to HSCs with a list of 160 genes encoding proteins that are known to interact with apigenin, which identified C1QTNF2, encoding for Complement C1q tumor necrosis factor-related protein 2, a secreted adipocytokine with metabolic effects in liver. To validate its disease relevance, C1QTNF2 expression is reduced during hepatic stellate cell activation in culture and in a mouse model of alcoholic liver injury in vivo, and its expression correlates with better clinical outcomes in patients with hepatitis C cirrhosis (n = 216), suggesting it may have a protective role in cirrhosis progression.These findings reinforce the value of computational approaches to drug discovery for hepatic fibrosis, and identify C1QTNF2 as a potential mediator of apigenin’s anti-fibrotic activity.en-USJournal Article2017-04-0610.1038/srep42563