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Navitoclax improves acute-on-chronic liver failure by eliminating senescent cells in mice
Yusuke Watanabe1,2, Hiroyuki Abe2, Naruhiro Kimura2
1Division of Preemptive Medicine for Digestive Disease and Healthy Active Life, School of Medicine, Niigata University, Niigata, Japan.
Aim:
Acute-on-chronic liver failure (ACLF), a disease with poor prognosis, is reportedly caused by cellular senescence due to mitochondrial dysfunction. In this study, we described and analyzed the underlying mechanism of a novel approach for ACLF using ABT263/navitoclax (Navi) that selectively eliminates senescent cells.
Methods:
Irradiation-induced senescent hepatocytes were used for in vitro evaluation of the effects of Navi on ACLF (n = 6 for each group). Lipopolysaccharide- and carbon tetrachloride-induced ACLF mouse model was used for in vivo evaluation of the effects of Navi administration compared with the control using one-way or two-way analysis of variance, followed by Student's t-test or Kruskal-Wallis test. The effects on the senescence-associated secretory phenotype (n = 8 for each group) and mitochondrial functions, including adenosine triphosphate concentration and membrane potential (n = 8 for each group), were investigated using real-time polymerase chain reaction, immunohistochemistry, and enzyme analysis.
Results:
Navi eliminated irradiation-induced senescent hepatocytes in vitro, leading to non-senescent hepatocyte proliferation. Navi eliminated senescent cells in the liver in vivo, resulting in downregulation of mRNA expression of senescence-associated secretory phenotype factors, a decrease of liver enzymes, and upregulated proliferation of non-senescent cells in the liver. Regarding mitochondrial functional assessment in the liver, adenosine triphosphate concentration and membrane potential were upregulated after Navi administration in vitro and in vivo.
Conclusions:
Navi may ameliorate ACLF damage by eliminating senescent cells in the liver, downregulating senescence-associated secretory phenotype factors, and upregulating mitochondrial functions. We believe that this novel approach using Navi will pave the way for ACLF treatment.
Insights
ABT263/navitoclax (Navi) eliminates senescent liver cells, improving mitochondrial function and promoting hepatocyte proliferation. This novel approach shows promise for treating acute-on-chronic liver failure (ACLF).
Area of Science:
- Hepatology and Cellular Senescence
- Mitochondrial Biology and Disease Mechanisms
- Pharmacological Interventions in Liver Disease
Background:
- Acute-on-chronic liver failure (ACLF) is a severe condition with a poor prognosis.
- Cellular senescence, driven by mitochondrial dysfunction, is implicated in ACLF pathogenesis.
- Targeting senescent cells represents a potential therapeutic strategy for ACLF.
Purpose of the Study:
- To investigate the efficacy of ABT263/navitoclax (Navi) in eliminating senescent cells in ACLF.
- To elucidate the underlying mechanisms by which Navi ameliorates ACLF.
- To evaluate the impact of Navi on liver cell proliferation and mitochondrial function.
Main Methods:
- In vitro studies using irradiation-induced senescent hepatocytes to assess Navi's effects.
- In vivo studies utilizing a mouse model of ACLF (induced by lipopolysaccharide and carbon tetrachloride).
- Analysis of senescence-associated secretory phenotype (SASP) factors, liver enzymes, and mitochondrial functions (ATP concentration, membrane potential).
Main Results:
- Navi effectively eliminated senescent hepatocytes in vitro, promoting non-senescent cell proliferation.
- In vivo, Navi treatment reduced senescent cells in the liver, downregulated SASP factors, decreased liver enzymes, and increased hepatocyte proliferation.
- Navi administration significantly upregulated mitochondrial ATP concentration and membrane potential both in vitro and in vivo.
Conclusions:
- ABT263/navitoclax (Navi) demonstrates potential in ameliorating ACLF by clearing senescent liver cells.
- Navi's mechanism involves suppressing SASP factors and restoring mitochondrial function.
- This senolytic approach offers a promising new avenue for ACLF therapeutic development.
