Antagonizing Activin A/p15INK4b Signaling as Therapeutic Strategy for Liver Disease

  • Cells. 2024 Apr 8;13(7):649. doi: 10.3390/cells13070649.
Sowmya Mekala  1 ,  Ravi Rai  1 ,  Samantha Loretta Reed  1 ,  Bill Bowen  1 ,  George K Michalopoulos  1  2  3 ,  Joseph Locker  1  2 ,  Reben Raeman  1  2 ,  Michael Oertel  1  2  3
Affiliations
  • 1. Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street-BST S-404, Pittsburgh, PA 15261, USA.
  • 2. Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • 3. McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
PMID: 38607090 DOI: 10.3390/cells13070649
Abstract

Background/aim: Activin A is involved in the pathogenesis of human liver diseases, but its therapeutic targeting is not fully explored. Here, we tested the effect of novel, highly specific small-molecule-based Activin A antagonists (NUCC-474/555) in improving liver regeneration following partial hepatectomy and halting fibrosis progression in models of chronic liver diseases (CLDs).

Methods: Cell toxicity of antagonists was determined in rat hepatocytes and Huh-7 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Hepatocytes and hepatic stellate cells (HSCs) were treated with Activin A and NUCC-555 and analyzed by reverse transcription-polymerase chain reaction and immunohistochemistry. Partial hepatectomized Fisher (F)344 rats were treated with NUCC-555, and bromodeoxyuridine (BrdU) incorporation was determined at 18/24/36/120/240 h. NUCC-555 was administered into thioacetamide- or carbon tetrachloride-treated F344 rats or C57BL/6 mice, and the fibrosis progression was studied.

Results: NUCC-474 showed higher cytotoxicity in cultured hepatic cells; therefore, NUCC-555 was used in subsequent studies. Activin A-stimulated overexpression of cell cycle-/senescence-related genes (e.g., p15INK4b, DEC1, Glb1) was near-completely reversed by NUCC-555 in hepatocytes. Activin A-mediated HSC activation was blocked by NUCC-555. In partial hepatectomized rats, antagonizing Activin A signaling resulted in a 1.9-fold and 2.3-fold increase in BrdU+ cells at 18 and 24 h, respectively. Administration of NUCC-555 in rats and mice with progressing fibrosis significantly reduced Collagen accumulation (7.9-fold), HSC activation indicated by reduced alpha smooth muscle actin+ and vimentin+ cells, and serum aminotransferase activity.

Conclusions: Our studies demonstrate that Activin A antagonist NUCC-555 promotes liver regeneration and halts fibrosis progression in CLD models, suggesting that blocking Activin A signaling may represent a new approach to treating people with CLD.

Keywords
activin antagonist; cell cycle arrest; liver fibrosis; liver regeneration; senescence.
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