Induction of MASH-like pathogenesis in the Nwd1-/- mouse liver

  • Commun Biol. 2025 Mar 11;8(1):348. doi: 10.1038/s42003-025-07717-5.
Seiya Yamada  1  2 ,  Hayato Ogawa  3 ,  Miona Funato  3 ,  Misaki Kato  3 ,  Kazuhiko Nakadate  4 ,  Tomoya Mizukoshi  3 ,  Kiyoharu Kawakami  4 ,  Ryosuke Kobayashi  5 ,  Takuro Horii  5 ,  Izuho Hatada  5  6 ,  Shin-Ichi Sakakibara  7
Affiliations
  • 1. Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan. [email protected].
  • 2. Neuroscience Center, HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland. [email protected].
  • 3. Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan.
  • 4. Department of Functional Morphology, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
  • 5. Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.
  • 6. Viral Vector Core, Gunma University Initiative for Advanced Research (GIAR), Gunma, Japan.
  • 7. Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan. [email protected].
PMID: 40069352 DOI: 10.1038/s42003-025-07717-5
Abstract

Endoplasmic reticulum (ER) stores CA2+ and plays crucial roles in protein folding, lipid transfer, and it's perturbations trigger an ER stress. In the liver, chronic ER stress is involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Dysfunction of sarco/endoplasmic reticulum calcium ATPase (SERCA2), a key regulator of CA2+ transport from the cytosol to ER, is associated with the induction of ER stress and lipid droplet formation. We previously identified NACHT and WD repeat domain-containing protein 1 (Nwd1) localized at the ER and mitochondria. However, the physiological significance of Nwd1 outside the brain remains unclear. In this study, we revealed that Nwd1-/- mice exhibited pathological manifestations comparable to MASH. Nwd1 interacts with SERCA2 near ER membranes. Nwd1-/- livers exhibited reduced SERCA2 ATPase activity and a smaller CA2+ pool in the ER, leading to an exacerbated state of ER stress. These findings highlight the importance of SERCA2 activity mediated by Nwd1 in the pathogenesis of MASH.

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