Nwd1 gene deletion triggers MASH-like pathology in mice: a new scientific breakthrough

Study highlights the role of the Nwd1 gene in liver disease, paving the way for new therapies and better liver health

2025-03-11

(Press-News.org)

Metabolic dysfunction-associated steatohepatitis (MASH) is a liver disease that progresses without symptoms and is associated with significant global public health concerns. It is prevalent in 30% of the population worldwide and poses a risk of advancing to cirrhosis and liver cancer. MASH is marked by lipid droplet accumulation in the liver, progressing from steatosis to inflammation and cell damage, ultimately leading to fibrosis, cirrhosis, and hepatocellular carcinoma. A clear understanding of cellular processes in MASH pathogenesis is essential for developing targeted therapies.

A key factor in the pathology of MASH is the disruption of endoplasmic reticulum (ER) homeostasis. The ER stores calcium ions (Ca2+) and plays a crucial role in regulating protein folding, lipid transfer, and organelle dynamics. The accumulation of unfolded or misfolded proteins in the ER activates a series of homeostatic responses known as ER stress, and sustained ER stress plays a role in the development of MASH. Recent studies indicate that the dysfunction of sarco/ER calcium ATPase (SERCA2), which regulates Ca2+ transport to the ER, can also induce ER stress, contributing to MASH.

In addition to SERCA2, previous research on NACHT and WD repeat domain-containing protein 1 (Nwd1) gene, which is part of the signal transduction ATPase family, has shown that it is localized in the ER and is expressed in both the liver and the brain. However, the role of the Nwd1 gene in SERCA2 activity and the pathogenesis of MASH remains unclear.

In a recent study, published on March 11, 2025, in Communications Biology, a team of scientists led by Professor Shin-ichi Sakakibara from the Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University, Japan, explored the physiological role of Nwd1 in MASH pathogenesis.

“The full mechanism behind the development of MASH remains unclear, and currently, only one therapeutic drug has been approved. Therefore, this study aimed to investigate the role of the Nwd1 gene in liver pathogenesis to identify potential new therapeutic targets. Our research is the first to explore the role of Nwd1 outside of the brain,” says Dr. Sakakibara.

The team created a Nwd1 knockout (Nwd1−/−) mice model using the CRISPR-Cas9 genome editing technique. They subsequently investigated the effects of Nwd1 deficiency on liver function and various cellular processes. The scientists found that Nwd1−/− mice exhibited liver pathologies, including excessive lipid accumulation, fibrosis, and heightened ER stress, mirroring MASH. Additionally, they saw a rise in pyroptosis—a form of programmed inflammatory cell death—in the livers of Nwd1−/− mice. Elevated levels of cleaved caspase-1 and increased leukocyte counts were also observed, indicating heightened inflammatory responses that further exacerbated liver damage. The researchers also discovered that Nwd1 interacts with SERCA2. They found that in the absence of Nwd1, SERCA2 activity was significantly reduced, leading to diminished ER Ca2+ storage and intensified ER stress. This stress was directly linked to the accumulation of lipid droplets in hepatocytes, a hallmark of MASH.

The first co-author, Dr. Seiya Yamada, stated, “These findings position Nwd1 as a potential regulator of liver homeostasis, particularly through its role in maintaining ER function and calcium balance.”

Overall, by demonstrating how Nwd1 deficiency disrupts these processes, the study offers fresh insights into MASH pathogenesis and underscores the therapeutic potential of targeting ER stress pathways.

“With MASH lacking effective treatments, understanding the molecular underpinnings of its development is crucial. This study paves the way for future research exploring Nwd1 as a therapeutic target, potentially leading to novel strategies to combat this growing public health issue,” concludes Dr. Yamada.

***

Reference

Authors: Seiya Yamada1,2*, Hayato Ogawa1, Miona Funato1, Misaki Kato1, Kazuhiko Nakadate3, Tomoya Mizukoshi1, Kiyoharu Kawakami3, Ryosuke Kobayashi4, Takuro Horii4, Izuho Hatada4,5, and Shin-ichi Sakakibara1

Title of original paper: Induction of MASH-like pathogenesis in the Nwd1−/− mouse liver

Journal: Communications Biology

DOI: 10.1038/s42003-025-07717-5

Affiliations

1Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University, Japan

2Neuroscience Center, HiLIFE - Helsinki Institute of Life Science, University of Helsinki, Finland

3Department of Basic Biology, Educational and Research Center for Pharmacy, Meiji Pharmaceutical University, Japan

4Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Japan

5Viral Vector Core, Gunma University Initiative for Advanced Research (GIAR), Gunma, Japan

About Waseda University

Located in the heart of Tokyo, Waseda University is a leading private research university that has long been dedicated to academic excellence, innovative research, and civic engagement at both the local and global levels since 1882. The University has produced many change-makers in its history, including nine prime ministers and many leaders in business, science and technology, literature, sports, and film. Waseda has strong collaborations with overseas research institutions and is committed to advancing cutting-edge research and developing leaders who can contribute to the resolution of complex, global social issues. The University has set a target for achieving a zero-carbon campus by 2032, in line with the Sustainable Development Goals (SDGs) adopted by the United Nations in 2015.

To learn more about Waseda University, visit https://www.waseda.jp/top/en

About Professor Shin-ichi Sakakibara

Shin-ichi Sakakibara is a professor at the Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University. He earned his Ph.D. from the University of Tokyo and specializes in neuroscience, focusing on neural development, molecular biology, histology, and neuroanatomy. He has an exceptional academic record with 50 papers in Scopus and over 4,350 citations, reflected in an h-index of 23, showcasing his significant impact in the field. He holds professional memberships in organizations such as the Japan Neuroscience Society, the Japan Society for Neurochemistry, and the Society for Neuroscience. His research interests include neuroanatomy, neural stem cells, neurogenesis, and glial cells.

END

[Attachments] See images for this press release:

Nwd1 gene deletion triggers MASH-like pathology in mice: a new scientific breakthrough 2

Nwd1 gene deletion triggers MASH-like pathology in mice: a new scientific breakthrough 3

ELSE PRESS RELEASES FROM THIS DATE:

First burials: Neanderthal and Homo sapiens interactions in the Mid-Middle Palaeolithic Levant

2025-03-11

The first-ever published research on Tinshemet Cave reveals that Neanderthals and Homo sapiens in the mid-Middle Paleolithic Levant not only coexisted but actively interacted, sharing technology, lifestyles, and burial customs. These interactions fostered cultural exchange, social complexity, and behavioral innovations, such as formal burial practices and the symbolic use of ochre for decoration. The findings suggest that human connections, rather than isolation, were key drivers of technological and cultural advancements, highlighting the Levant as a crucial crossroads in early human history. Link to the images: https://drive.google.com/drive/folders/19p__omKCSSPkGBI3b8beF1QXqeRahGk1?usp=drive_link ...

Machine learning models fail to detect key health deteriorations, Virginia Tech research shows

2025-03-11

xIt would be greatly beneficial to physicians trying to save lives in intensive care units if they could be alerted when a patient’s condition rapidly deteriorates or shows vitals in highly abnormal ranges. While current machine learning models are attempting to achieve that goal, a Virginia Tech study recently published in Communications Medicine shows that they are falling short with models for in-hospital mortality prediction, which refers to predicting the likelihood of a patient dying in the hospital, failing to recognize ...

Women with PVD often underdiagnosed & undertreated, highlighting need for more research

2025-03-11

Statement Highlights: Peripheral vascular disease (PVD)—a condition affecting arteries, veins and the lymphatic systems throughout the body—has significant differences in incidence, risk factors, diagnosis, treatment and outcomes in women vs. men. Women with PVD often experience subtle or atypical symptoms, which can lead to underdiagnosis or delay in diagnosis, and they are less likely to receive guideline-recommended treatments. Targeted screening, tailored treatment strategies and increased representation of women in clinical trials are critical priorities to addressing these gaps ...

New Irresistible Materials CEO to drive commercialization and market adoption

2025-03-11

University of Birmingham spin-out Irresistible Materials Ltd (IM), a leader in the development of novel resist materials for extreme ultraviolet (EUV) lithography, has announced the appointment of Dinesh R. Bettadapur as its new chief executive officer (CEO) and board director. Bettadapur brings a wealth of business experience and strategic vision to the company, having previously held leadership roles at ASML, Intel, and Lam Research, as well as multiple Silicon Valley startups where he enabled significant business growth leading to three successful exits. In his new role, Bettadapur will lead IM’s business strategy and commercial engagements ...

Gold mining in the Peruvian Amazon has done more damage to peatlands in the last two years than in the previous three decades 

2025-03-11

New research published in the academic journal Environmental Research Letters reveals that artisan gold mining in the southern Peruvian Amazon has caused more destruction to carbon-rich peatlands in the past two years than in the previous three decades combined, posing a serious threat to the environment and climate.   For decades, small-scale gold mining has thrived along the rivers of the Madre de Dios region, driven by gold frequently found in the surrounding soils. While the deforestation caused by mining has already resulted in significant carbon emissions, scientists have now discovered that the damage ...

Cheap and environmentally friendly – the next generation LEDs may soon be here

2025-03-11

Cost, technical performance and environmental impact – these are the three most important aspects for a new type of LED technology to have a broad commercial impact on society. This has been demonstrated by researchers at Linköping University in a study published in Nature Sustainability. “Perovskite LEDs are cheaper and easier to manufacture than traditional LEDs, and they can also produce vibrant and intense colours if used in screens. I’d say that this is the next generation ...

Rare frog rediscovered after 130 years

2025-03-11

A team of researchers has rediscovered a frog species which has not been seen in more than 130 years. First described in 1902, Alsodes vittatus had evaded detection since then, despite multiple search efforts. The researchers discovered two populations of the frog at the southeastern end of the ancient Hacienda San Ignacio de Pemehue in La Araucanía Region, Chile. The rediscovery is an important milestone for South American herpetology and the conservation of biodiversity in the southern cone. The frog Alsodes vittatus is an elusive creature – described in 1902, it managed to go undetected for more than a century. Now, after a decade of investigation, a research team ...

Earth's 'dirty mirror' effect is accelerating climate change

2025-03-11

Earth is absorbing more sunlight and trapping more heat than it releases into space, causing our planet to warm up at an increasing rate. New research shows that cloudy areas over oceans are reflecting less sunlight to space than before, adding to heating from rising greenhouse gas levels and causing climate change to accelerate. The study, published today (Tuesday, 11 March) in Environmental Research Letters, found this dimming effect was occurring in several regions, including cloudy areas off the coasts of California and Namibia, ...

Breakthrough in next-generation polio vaccines

2025-03-11

A more affordable, lower-risk polio vaccine is on the horizon, research led by the University of Leeds has found. Researchers have taken a major step towards producing a more affordable and lower-risk polio vaccine using virus-like particles (VLPs). These particles mimic the outer protein shell of poliovirus, but are empty inside. This means there is no risk of infection, but the VLP still causes the immune system to respond. Now, a research project led by Professor David Rowlands, Emeritus Professor of Molecular Virology at the University of Leeds, has tested the effectiveness of using different yeast, insect, mammalian and ...

A call for federally funded pediatric firearm injury prevention research

2025-03-11

BOSTON, MASSACHUSETTS – Firearm-related injuries are the leading cause of death among children and adolescents in the United States, yet research on firearm injury prevention receives significantly less federal funding compared to other major pediatric health concerns. A new paper published in Pediatrics underscores the critical need for an enhanced federal investment in firearm injury prevention research to address the rising rates of fatalities and injuries. “Expanding the field of firearm injury ...