Conclusion: These results suggest that Lys6-linked polyubiquitination of ASK1 by TRAF6 represents a mechanism underlying ASK1 activation in hepatocytes and a key driving force of proinflammatory and profibrogenic responses in NASH.
FBXW5 is the central component of the SCF complex (SCF<sup>Fbxw5</sup> ) that directly interacts with and ubiquitinates ASK1 in hepatocytes during NASH development.
Conclusion: Hepatocyte Dusp9 prevents NAFLD and NASH progression in mice, including lipid accumulation, glucose metabolism disorders, and enhanced inflammation and liver fibrosis, in an ASK1-dependent manner; these findings suggest that Dusp9 may be a promising therapeutic target for the treatment of NAFLD and NASH.
Here we demonstrate that overexpression of Cxcl1 in the liver alone promotes steatosis-to-NASH progression in HFD-fed mice by inducing neutrophil infiltration, oxidative stress, and stress kinase (such as ASK1 and p38MAPK) activation.
Apoptosis signal-regulating Kinase 1 (ASK1) has been confirmed as a potential therapeutic target for the treatment of non-alcoholic steatohepatitis (NASH) disorder and the discovery of ASK1 inhibitors has attracted increasing attention.
In human livers of lean and obese subjects, ASK1 expression correlated negatively with liver fat content and NASH scores, but positively with markers for autophagy.
Selonsertib, a serine/threonine kinase inhibitor, targets apoptosis signal-regulating kinase 1 (ASK1) and is now in phase III clinical trial for the treatment of non-alcoholic steatohepatitis (NASH).
In human livers of lean and obese subjects, ASK1 expression correlated negatively with liver fat content and NASH scores, but positively with markers for autophagy.
These results implicate TNFAIP3 as a functionally important endogenous suppressor of ASK1 hyperactivation in the pathogenesis of NASH and identify it as a potential new molecular target for NASH therapy.
Among a variety of medications in development, four agents such as OCA, elafibranor, ASK1 inhibitor, and CVC are currently being evaluated in an international phase 3 trial for the treatment of NASH.
Antioxidants such as vitamin E, and more recently anti-inflammatory agents such as apoptosis signal-regulating kinase 1 inhibitors show promise as therapy for NASH.
As inflammation and apoptosis are key features of NASH agents modulating these pathways are of interest; CCR2/5 antagonists downregulate inflammatory pathways and reduce fibrosis with caspase and apoptosis signal-regulating kinase 1 inhibitors reducing apoptosis and fibrosis.