A recent scientific breakthrough sheds light on a critical aspect of metabolic dysfunction-associated steatohepatitis (MASH), a liver disease affecting 30% of the global population. This condition, often asymptomatic, can progress to severe health issues such as cirrhosis and liver cancer. The study, conducted by researchers from Waseda University, Japan, delves into the role of the Nwd1 gene in liver pathogenesis. By examining Nwd1's interaction with SERCA2 and its impact on endoplasmic reticulum (ER) stress, the research offers new insights into potential therapeutic targets for MASH.

MASH is characterized by the accumulation of lipid droplets in the liver, leading to inflammation and cell damage. A key factor in this progression is the disruption of ER homeostasis, which regulates calcium ions and protein folding. Sustained ER stress plays a significant role in the development of MASH. Recent studies have shown that the dysfunction of sarco/ER calcium ATPase (SERCA2), responsible for Ca2+ transport to the ER, can induce ER stress, contributing to MASH pathology.

In March 2025, a team led by Professor Shin-ichi Sakakibara published findings in Communications Biology that explored the physiological role of Nwd1 in MASH. Using CRISPR-Cas9 genome editing, they created a Nwd1 knockout mouse model to investigate the effects of Nwd1 deficiency on liver function. The study revealed that Nwd1−/− mice exhibited liver abnormalities, including excessive lipid accumulation, fibrosis, and heightened ER stress, mirroring MASH symptoms. Additionally, there was an increase in pyroptosis, a form of programmed inflammatory cell death, along with elevated levels of cleaved caspase-1 and increased leukocyte counts, indicating heightened inflammatory responses that exacerbated liver damage.

The researchers also discovered that Nwd1 interacts with SERCA2. 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. Dr. Seiya Yamada, the first co-author, highlighted that these findings position Nwd1 as a potential regulator of liver homeostasis, particularly through its role in maintaining ER function and calcium balance.

This study provides fresh insights into MASH pathogenesis and underscores the therapeutic potential of targeting ER stress pathways. With effective treatments for MASH still lacking, understanding the molecular mechanisms behind its development is crucial. This research paves the way for future investigations into Nwd1 as a therapeutic target, potentially leading to novel strategies to combat this growing public health issue.