Development of a Liver Fibrosis Treatment Targeting Inhibition of Hepatic Stellate Cell Activation

Chronic liver disease causes approximately 2 million deaths annually worldwide, accounting for nearly 4% of global mortality. Liver fibrosis is a central pathological feature driving the progression of chronic liver disease (CLD), irrespective of the underlying etiology-be it hepatitis viruses, alcohol consumption, or the increasingly prevalent metabolic dysfunction-associated steatosis. Liver fibrosis arises from a dysregulated wound-healing response following sustained liver injury and inflammation, leading to excessive extracellular matrix deposition that intersects normal liver architecture and function. Despite the significance of fibrosis in CLD progression, effective antifibrotic therapies have not been deduced. A limited subset of metabolic dysfunction-associated steatotic liver disease (MASLD) patients progresses to metabolic dysfunction-associated steatohepatitis (MASH) characterized by inflammation and fibrosis, which indicates that this progression involves specific triggering mechanisms or factors. Hepatic stellate cells (HSCs), located in the space of Disse as quiescent vitamin A-storing cells, are the key mediators of fibrosis. The activation and transdifferentiation of HSCs into myofibroblast-like cells following liver injury results in markedly increased collagen production. Our recent research has indicated that altered adenosine metabolism in hepatocytes leads to increased extracellular adenosine, which in turn drives the activation of HSCs, promoting the progression from MASLD to MASH. The regulatory mechanisms involving prostaglandin E2 and adenosine signaling in the activation of HSCs are complex and have not been fully elucidated. Further detailed investigations that would uncover the complete pathways controlling the activation of HSCs and enable the development of novel therapeutic strategies targeting liver fibrosis in CLD are warranted.