2. Academic Validation
  3. Vitamin D supplementation ameliorates ductular reaction, liver inflammation and fibrosis in mice by upregulating TXNIP in ductular cells

Vitamin D supplementation ameliorates ductular reaction, liver inflammation and fibrosis in mice by upregulating TXNIP in ductular cells

  • Nat Commun. 2025 May 13;16(1):4420. doi: 10.1038/s41467-025-59724-z.
Eun Bok Baek # 1 2,  Hyuk Soo Eun # 3 4,  Jun-Yeop Song # 1,  Eun-Ju Hong 1,  Se-Hee Park 5,  Poornima Kumbukgahadeniya 1,  Sang-Min Park 6,  Seok-Hwan Kim 7,  Soon Ok Kim 8,  Ha Neul Kim 8,  Young-Eun Cho 9,  Young-Suk Won 10,  Hyo-Jung Kwon 11
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea.
  • 2 Department of Physiology, College of Medicine, Jeju National University, Jeju, Republic of Korea.
  • 3 Department of Internal Medicine, School of Medicine, Chungnam National University, Daejeon, Republic of Korea.
  • 4 Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea.
  • 5 Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, Republic of Korea.
  • 6 College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
  • 7 Department of Surgery, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
  • 8 Department of Medical Sciences, Chungnam National University, Daejeon, Republic of Korea.
  • 9 Department of Food and Nutrition, Andong National University, Andong, Republic of Korea.
  • 10 Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, Republic of Korea. yswon@kribb.re.kr.
  • 11 College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea. hyojung@cnu.ac.kr.
  • # Contributed equally.
PMID: 40360509 DOI: 10.1038/s41467-025-59724-z
Abstract

Ductular reaction is associated with liver disease progression, but there are no drugs targeting ductular reaction. Vitamin D deficiency is common in chronic liver diseases and related to disease progression, but the underlying mechanisms by which vitamin D regulates liver diseases progression remain unclear. Here, we show that vitamin D plasma levels are negatively correlated with the degree of ductular reaction in patients with chronic liver diseases. 1,25(OH)2D3, the active form of vitamin D, reduces 3,5-diethoxycarbonyl-1,4-dihydrocollidin (DDC)-induced ductular reaction, liver inflammation, and fibrosis in female mice and upregulates the vitamin D target gene, TXNIP (encoding thioredoxin-interacting protein), in ductular cells. Cholangiocyte-specific Txnip-knockout female mice are more susceptible to DDC-induced ductular reaction, inflammation, and fibrosis. Deletion of Txnip in cholangiocytes promotes proliferation and suppressed death. Furthermore, Txnip deficiency increases TNF-α and TGF-β secretion by cholangiocytes to stimulate Kupffer cells and hepatic stellate cells, consequently leading to inflammation and Collagen deposition. Biliary Txnip deficiency abolishes the protective effects of vitamin D, and TXNIP overexpression attenuates DDC-induced ductular reaction and inflammation and fibrosis. Collectively, our findings identify new mechanism how vitamin D ameliorates liver diseases and suggest that the vitamin D/TXNIP axis is a therapeutic target for addressing ductular reaction and liver diseases.

Figures
Products