Liver fibrosis, a pathological condition in which the liver becomes stiff and scarred,
commonly develops in the progression of chronic liver diseases such as chronic hepatitis
and metabolic dysfunction-associated steatohepatitis (MASH). Because advanced fibrosis
can lead to cirrhosis or liver cancer, understanding the underlying mechanisms is critical for
developing effective therapies.
A research team led by Dr. Takao Seki (Assistant Professor) and Dr. Hiroyasu Nakano
(Specially Appointed Professor) at the Faculty of Medicine, Toho University, has uncovered
a previously unknown intercellular network that promotes liver fibrosis. Their findings
highlight the critical roles of hepatic stellate cells and two key molecules: the growth factor
FGF18 and the pro-fibrotic mediator osteopontin (OPN).
Under normal physiological conditions, hepatic stellate cells remain quiescent and serve to
store vitamin A. However, upon liver injury, they transform into myofibroblasts that actively
produce collagen and other extracellular matrix components, contributing to fibrosis. This
study reveals how these stellate cells influence each other to propagate fibrotic activity.
The researchers first demonstrated that stimulation of activated hepatic stellate cells with
FGF18 significantly enhances the production of OPN. They further showed that OPN acts
on neighboring quiescent stellate cells to induce their activation, establishing a positive
feedback loop. Interestingly, OPN does not act on already activated cells but specifically
targets quiescent ones, effectively spreading fibrosis in a stepwise manner from cell to cell.
Using a mouse model of liver fibrosis, the team found that OPN transmits signals via a cell
surface receptor called integrin, highlighting how molecular "communication" among
stellate cells drives the fibrotic process.
These findings identify a novel self-amplifying intercellular communication system in liver
fibrosis, mediated by FGF18 and OPN. Rather than being a consequence of a single
molecule, fibrosis is shown to be a dynamic and coordinated response involving cell–cell
signaling and environmental cues. This discovery offers a new perspective on the
pathogenesis of liver fibrosis.
The FGF18–OPN axis is also a promising therapeutic target. Because FGF18 selectively
acts on hepatic stellate cells, therapies based on this pathway may offer cell-specific
interventions that avoid the broad effects of conventional liver-targeted drugs.
This research was published in the international journal iScience in June 2026. The study
was conducted in collaboration with Dr. Yuichi Tsuchiya (Associate Professor, Faculty of
Pharmaceutical Sciences, Toho University) and Dr. Minoru Tanaka (Division Chief, National
Center for Global Health and Medicine Research Institute).
