Researchers at Waseda University in Japan have identified a gene that, when rendered nonfunctional in mice, causes the rodents to develop telltale signs of the liver disease metabolic dysfunction-associated steatohepatitis (MASH). The result suggests that the protein made by the gene, known as Nwd1, and other molecules it interacts with could be worthwhile targets for new MASH therapies.
The scientists published their work in Communications Biology on March 11.
The research team had previously found that the signaling protein Nwd1, which has the full name NACHT and WD repeat domain-containing protein 1, is mainly made in the brain and liver. Though they knew the protein was important for brain development, its function in the liver was uncertain.
Using CRISPR gene editing, the team disrupted the Nwd1 gene’s sequence in mice so that it no longer worked properly. When they did, they saw that the rodents’ liver cells became enlarged with fat molecules and their livers became covered in scar tissue.
These effects closely mimic those of MASH, where patients’ livers become full of fat deposits, which can later progress to scarring, cirrhosis and possibly liver failure.
The loss of Nwd1’s regulatory role in turn decreased activity of a protein called SERCA2 ATPase, the researchers found, which lowered the amount of calcium inside the cells’ endoplasmic reticula (ER). The ER is an important organelle that mediates protein folding and lipid transfer, the authors note, and disruption in its activity has been linked to MASH. SERCA2, too, has been identified as a potential target for MASH therapeutics.
Further unraveling the function of Nwd1 “could provide clues to understanding the mechanisms of MASH pathogenesis and developing therapeutic strategies for MASH associated with ER stress,” the authors wrote.
Many companies have tried and failed to develop MASH drugs over the years, with the first success coming in March 2024 with the FDA approval of Madrigal Pharmaceuticals’ Rezdiffra (resmetirom). Before Rezdiffra finally broke through, companies ranging from pharma giants like Pfizer and Bristol Myers Squibb to biotechs like Genfit and NGM Biopharmaceuticals had all tried and failed to get their own MASH drugs over the finish line.
A study published in January estimated that cases of MASH will rise substantially in the U.S. in the coming decades, from 14.9 million adults in 2020 to 23.2 million by 2050.
Rezdiffra has thus far been a success in this growing market, bringing in $180 million in sales in its first nine months.