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Metabolic dysfunction-associated steatohepatitis (MASH) is increasingly recognized as a complex, polygenic condition impacted by numerous genetic factors, although the precise influence of these genes on disease progression remains largely undefined. Recent research efforts have focused on the NACHT and WD repeat domain-containing protein 1 (Nwd1) gene, revealing its significant role in liver disease mechanisms. This discovery marks a pivotal advancement in developing new therapeutic strategies for MASH.
MASH is a silent liver disease that has serious implications for public health worldwide, affecting approximately 30% of the global population. If unchecked, it can progress to more severe conditions, such as cirrhosis and liver cancer. The disease is characterized by the accumulation of lipid droplets in the liver, which can escalate from simple fat storage (steatosis) to inflammation, cellular damage, fibrosis, and ultimately lead to serious complications like hepatocellular carcinoma. Gaining insight into the cellular mechanisms behind MASH is vital for creating effective targeted treatments.
A primary contributor to MASH pathology is the disruption of endoplasmic reticulum (ER) homeostasis. The ER is essential for calcium ion (Ca2+) storage and plays a fundamental role in managing protein folding, lipid movement, and organelle interactions. An overload of misfolded or improperly folded proteins triggers ER stress, and persistent stress has been linked to MASH. Emerging evidence suggests that dysfunctions in sarco/ER calcium ATPase (SERCA2), which is responsible for transporting Ca2+ into the ER, can also lead to ER stress and foster MASH development.
In addition to its connection with SERCA2, the Nwd1 gene, which is expressed in the liver and brain, has been studied for its role in various physiological processes. However, the specific contributions of Nwd1 to SERCA2 activity and MASH pathogenesis have remained unclear.
A recent publication in Communications Biology, dated March 11, 2025, and led by Professor Shin-ichi Sakakibara from Waseda University, explores the role of Nwd1 in MASH. Dr. Sakakibara highlights the urgent need for further understanding of MASH, noting that only a single therapeutic option exists. “Our study aimed to elucidate the role of the Nwd1 gene in liver disease, opening new avenues for potential therapeutic interventions and marking the first exploration of Nwd1 outside the central nervous system,” said Dr. Sakakibara.
Utilizing CRISPR-Cas9 genome editing, the research team created a knockout model for the Nwd1 gene, referred to as Nwd1−/− mice. They assessed the implications of Nwd1 deficiency on liver function and cellular dynamics. Notably, the Nwd1−/− mice displayed significant liver abnormalities characteristic of MASH, which included excessive lipid buildup, fibrosis, and increased ER stress. The study also identified elevated levels of pyroptosis—a form of inflammatory cell death— in these mice, alongside higher counts of cleaved caspase-1 and increased leukocyte presence, signaling heightened inflammatory activity that worsened liver damage. The investigation unveiled that Nwd1 interacts with SERCA2, and in its absence, the activity of SERCA2 decreased significantly, which resulted in impaired ER Ca2+ storage and intensified ER stress. This stress was directly tied to the accumulation of lipid droplets in liver cells, a primary feature of MASH.
Dr. Seiya Yamada, the first co-author of the study, remarked, “Our findings establish Nwd1 as a potential key player in maintaining liver homeostasis through its influence on ER function and calcium regulation.”
In summary, this research sheds light on how the lack of Nwd1 disrupts various liver processes, offering new perspectives on the pathogenesis of MASH and highlighting the possibility of targeting ER stress pathways as a therapeutic strategy.
Dr. Yamada concluded, “In the absence of effective treatments for MASH, comprehending the molecular basis of its progression is vital. This study sets the groundwork for upcoming investigations into Nwd1 as a therapeutic target, potentially ushering in innovative approaches to address this escalating public health concern.”
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