Metabolic dysfunction–associated steatohepatitis (MASH) is emerging as a new pillar of the pharmaceutical market. It is a disease in which fat accumulates in the liver and causes inflammation due to obesity, diabetes, and hyperlipidemia. Because there are almost no early symptoms, if left untreated it can progress through liver fibrosis to cirrhosis and liver cancer. Patient numbers are surging, but there is still no approved treatment.
Japanese scientists have uncovered at the cellular level how the liver hardens due to metabolic dysfunction–associated steatohepatitis. If a drug can be found that blocks the problematic signaling pathway, it is expected to become a new therapy to prevent or treat metabolic dysfunction–associated steatohepatitis.
A research team at Tokyo University of Science succeeded in precisely observing, using a human cell–based liver Organoid (organ mimic), the signals exchanged between damaged hepatocytes and surrounding stellate cells (astrocytes). They recreated the early stage of fibrosis, in which the liver hardens. The findings were published on Sept. in the international journal Stem Cell Reports.
The liver is an organ that regenerates well. But the situation changes if damage is repeated. When the extracellular matrix, a molecular complex formed to patch wounds, accumulates excessively, fibrosis progresses. If this process is not controlled, it leads to cirrhosis, in which the liver gradually hardens, and at the terminal stage there is no adequate treatment other than liver transplantation.
The team focused on the signals exchanged between hepatocytes and stellate cells. Stellate cells normally store and concentrate vitamin A, but when the liver is damaged, they are involved in fibrosis. Because most of these findings have been confirmed in animal experiments, it was unclear whether the same occurs in humans. The Tokyo University of Science team cultured human cells in 3D to create a liver-like Organoid and studied whether the same events occur in the human body.
First, they reverted fully matured human cells to the embryonic stem cell–like state of induced pluripotent stem cells (iPS cells). They then differentiated the iPS cells into hepatocyte- and stellate cell–like cells, combined the two, and cultured them in three dimensions. In this way, a liver Organoid that can substitute for the human liver in experiments was created.
In the liver Organoid, the team confirmed that when hepatocyte surface protein ICAM-1 receives the "repair command signal (IL-1β)" sent by stellate cells, extracellular matrix is produced in large quantities and hepatocyte proliferation is promoted. This is the first observation at the level of human cells of the actual signals between stellate cells and hepatocytes.
It is known that after liver injury, recovery proceeds first and then transitions to fibrosis. When the extracellular matrix accumulates excessively, it leads to fibrosis. This finding provides an experimental foundation for capturing, in human cells, what signals are exchanged during the transitional stage from recovery to fibrosis.
The team also reproduced a toxic reaction commonly seen in the human liver by administering the antipyretic and analgesic ingredient acetaminophen to iHSO. They then observed in real time the "early chain reaction" that progresses from hepatocyte injury to stellate cell activation and the triggering of fibrosis. Accordingly, the liver Organoid is also suggested as a potential evaluation platform to screen the toxicity of new drug candidates
The researchers expect that liver Organoids will help reveal why and how fibrosis starts and progresses in various liver diseases. Furthermore, they can be used to discover and test new drug candidates that suppress or reverse fibrosis. In other words, they can be used from basic research to drug development.
Kakinuma Sei, the professor who led the study, said, "We are now able to precisely observe the direct interactions between hepatocytes and stellate cells, laying the groundwork for developing treatments for various liver diseases."
References
Stem Cell Reports (2025), DOI: https://dx.doi.org/10.1016/j.stemcr.2025.102642