Tier 4 — mechanistic

Transcriptome-based repurposing of apigenin as a potential anti-fibrotic agent targeting hepatic stellate cells

Daniel F. Hicks, Nicolas Goossens, Ana Blas-García, Takuma Tsuchida, Benjamin Wooden, Michael C. Wallace, Natalia Nieto, Abigale Lade, Benjamin Redhead, Arthur I. Cederbaum, Joel T. Dudley, Bryan C. Fuchs, Youngmin A. Lee, Yujin Hoshida, Scott L. Friedman
Scientific Reports 2017 7:42563

Bibliography

PubMed
PMID 28256512
PubMed Central
PMC5335661
DOI
10.1038/srep42563
Funding
Supported by Icahn School of Medicine Medical Student Research Office, Spanish and Geneva research support, FLAGS/Nuovo-Soldati foundations, NIH/NIDDK DK099558, ERC-2014-AdG-671231HEPCIR, Irma T. Hirschl Trust, US Department of Defense W81XWH-16-1-0363, NIH DK56621 and AA020709.
Competing interests
The authors declared no competing financial interests.

Study snapshot

DesignConnectivity Map transcriptomic drug-repurposing screen with in vitro validation and observational transcriptomic correlation
ModelRat-derived HSC activation signature; human TWNT-4 hepatic stellate cells; existing transcriptome data from 216 patients with HCV-related compensated cirrhosis
SampleNine prioritized compounds were experimentally tested; human prognostic association used an existing cohort of 216 patients, but those patients were not treated with apigenin.
InterventionApigenin 2.5-200 micromolar in TWNT-4 cells, with key non-toxic mechanistic comparisons around 10-20 micromolar.
Duration24-hour in vitro apigenin treatment for key stellate-cell assays; observational human transcriptome follow-up was separate from apigenin exposure.
EndpointsCOL1A1 expression; PDGFRB expression; Cell viability; HSC activation signature reversal; C1QTNF2 target identification; C1QTNF2 association with cirrhosis outcomes

What the study showed, in plain terms

Researchers used a transcriptome drug-repurposing screen to look for compounds that might reverse the gene-expression pattern of activated hepatic stellate cells, the main collagen-producing cells in liver fibrosis. Apigenin emerged as a top candidate and reduced collagen I expression in a human stellate-cell line. A human cirrhosis dataset helped support the biological relevance of a proposed mediator, C1QTNF2, but no patients were actually given apigenin.

Key findings

Apigenin was one of the highest-ranked compounds in the Connectivity Map screen and was the only experimentally tested hit that reduced COL1A1 to a level comparable with sorafenib. The effect was dose-dependent and present at the protein level; 10 micromolar apigenin also reduced PDGFRB without clear toxicity below 20 micromolar. C1QTNF2 was proposed as a mediator and its expression correlated with better outcomes in an existing 216-patient cirrhosis cohort.

What this study can and cannot tell us

The anti-fibrotic apigenin experiment was in vitro. The human cohort was used only for prognostic gene-expression association and does not provide evidence that apigenin treats fibrosis in people. Poor solubility was identified as a translational limitation, and immune-related actions were not captured by the cell system.

Editorial review

Reviewed by the Biohack Blueprint research team

Last verified

Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology