Nanchangmycin regulates FYN, PTK2, and MAPK1/3 to control the fibrotic activity of human hepatic stellate cells
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Evaluation Summary:
The manuscript by Li et al. identifies the polyether ionophore nanchangmycin as a novel anti-fibrotic compound through a comprehensive chemical library screen. Given the lack of clinically available treatments for liver fibrosis, the anti-activation properties of nanchangmycin could represent a novel therapeutic avenue for the treatment of this disease.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Abstract
Chronic liver injury causes fibrosis, characterized by the formation of scar tissue resulting from excessive accumulation of extracellular matrix (ECM) proteins. Hepatic stellate cell (HSC) myofibroblasts are the primary cell type responsible for liver fibrosis, yet there are currently no therapies directed at inhibiting the activity of HSC myofibroblasts. To search for potential anti-fibrotic compounds, we performed a high-throughput compound screen in primary human HSC myofibroblasts and identified 19 small molecules that induce HSC inactivation, including the polyether ionophore nanchangmycin (NCMC). NCMC induces lipid re-accumulation while reducing collagen expression, deposition of collagen in the extracellular matrix, cell proliferation, and migration. We find that NCMC increases cytosolic Ca 2+ and reduces the phosphorylated protein levels of FYN, PTK2 (FAK), MAPK1/3 (ERK2/1), HSPB1 (HSP27), and STAT5B. Further, depletion of each of these kinases suppress COL1A1 expression. These studies reveal a signaling network triggered by NCMC to inactivate HSC myofibroblasts and reduce expression of proteins that compose the fibrotic scar. Identification of the antifibrotic effects of NCMC and the elucidation of pathways by which NCMC inhibits fibrosis provide new tools and therapeutic targets that could potentially be utilized to combat the development and progression of liver fibrosis.
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Evaluation Summary:
The manuscript by Li et al. identifies the polyether ionophore nanchangmycin as a novel anti-fibrotic compound through a comprehensive chemical library screen. Given the lack of clinically available treatments for liver fibrosis, the anti-activation properties of nanchangmycin could represent a novel therapeutic avenue for the treatment of this disease.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This well written manuscript by Li et al. utilizes a comprehensive chemical screening library to identify compounds with anti-fibrotic activity in hepatic stellate cells. The authors were thorough in their investigation using both in vitro and ex vivo strategies in rodent and human cells. The authors identify the polyether ionophore nanchangmycin as possessing novel anti-fibrotic activities. The authors go on to show that nanchangmycin inhibits multiple aspects of hepatic stellate cell activation including migration, proliferation and activation genes. Finally, the authors provide a cellular/molecular mechanism underlying the anti-activation properties of nanchangmycin through inhibition of several signaling cascades. This study is of high priority given the lack of therapeutic options for the treatment of …
Reviewer #1 (Public Review):
This well written manuscript by Li et al. utilizes a comprehensive chemical screening library to identify compounds with anti-fibrotic activity in hepatic stellate cells. The authors were thorough in their investigation using both in vitro and ex vivo strategies in rodent and human cells. The authors identify the polyether ionophore nanchangmycin as possessing novel anti-fibrotic activities. The authors go on to show that nanchangmycin inhibits multiple aspects of hepatic stellate cell activation including migration, proliferation and activation genes. Finally, the authors provide a cellular/molecular mechanism underlying the anti-activation properties of nanchangmycin through inhibition of several signaling cascades. This study is of high priority given the lack of therapeutic options for the treatment of hepatic fibrosis.
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Reviewer #2 (Public Review):
The manuscript aims at identifying compounds with liver antifibrogenic effect. To do so the authors perform a high-throughput drug screening on HSCs, the main fibrogenic cell type of the liver. The manuscript is a good resource for further studies on liver fibrosis, since it provides information on the effect of an important number of drugs on HSCs. However, the authors use only one readout (cytoplasmic lipid accumulation) for the first screening to evaluate the effect of drugs on HSCs, so for most compounds the data available is limited, and drugs acting though other mechanisms beside the accumulation of lipid droplets may not be detected. Moreover, the manuscript provides robust data that NCMC regulate HSCs activation.
The approach of the study is very interesting and provides novel information for the …
Reviewer #2 (Public Review):
The manuscript aims at identifying compounds with liver antifibrogenic effect. To do so the authors perform a high-throughput drug screening on HSCs, the main fibrogenic cell type of the liver. The manuscript is a good resource for further studies on liver fibrosis, since it provides information on the effect of an important number of drugs on HSCs. However, the authors use only one readout (cytoplasmic lipid accumulation) for the first screening to evaluate the effect of drugs on HSCs, so for most compounds the data available is limited, and drugs acting though other mechanisms beside the accumulation of lipid droplets may not be detected. Moreover, the manuscript provides robust data that NCMC regulate HSCs activation.
The approach of the study is very interesting and provides novel information for the field. Overall, the authors obtained 19 compounds with a potential antifibrogenic effect, based on the effects on HSCs. However, it is surprising that out of more than 15000 compounds only 19 reduced the activation of HSCs.
The results on the effect of NCMC on HSCs are robust. However, there is no information on the induction of a quiescent phenotype, or on the effects of NCMC on disease models.
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Reviewer #3 (Public Review):
Li et al. used a high throughput screening method and identified Nanchangmycin can inhibit hepatic stellate cell (HSC) activation and induced their inactivation through in vitro cell culture experiment. The study also determined that Nanchangmycin can increase cytosolic Ca concentration and inhibit FYN, FAK, and ERK activities, which are crucial for HSC activation. These findings suggest that Nanchangmycin has potential to treat liver fibrosis. Overall, the study should be of interest to the researchers who seek novel agents for treating liver fibrosis.
Strengths
1. The study used a high throughput screening method to identify Nanchangmycin from 15,867 compounds.
2. The study determined the effect of Nanchangmycin on HSC inactivation by assessing ECM production, HSC migration, and proliferation.
3. The study …Reviewer #3 (Public Review):
Li et al. used a high throughput screening method and identified Nanchangmycin can inhibit hepatic stellate cell (HSC) activation and induced their inactivation through in vitro cell culture experiment. The study also determined that Nanchangmycin can increase cytosolic Ca concentration and inhibit FYN, FAK, and ERK activities, which are crucial for HSC activation. These findings suggest that Nanchangmycin has potential to treat liver fibrosis. Overall, the study should be of interest to the researchers who seek novel agents for treating liver fibrosis.
Strengths
1. The study used a high throughput screening method to identify Nanchangmycin from 15,867 compounds.
2. The study determined the effect of Nanchangmycin on HSC inactivation by assessing ECM production, HSC migration, and proliferation.
3. The study determined the effect of Nanchangmycin on and regulation of cytosolic Ca concentration and activation of FYN, FAK, ERK pathways.Weaknesses
1. The study did not validate whether Nanchangmycin has a therapeutic effect using in vivo liver fibrosis model.
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