2. Academic Validation
  3. KNDC1 attenuates fibrosis in nonalcoholic fatty liver disease by inhibiting glycolysis in hepatic stellate cells

KNDC1 attenuates fibrosis in nonalcoholic fatty liver disease by inhibiting glycolysis in hepatic stellate cells

  • Cell Signal. 2026 Jul:143:112487. doi: 10.1016/j.cellsig.2026.112487.
Juyi Li 1,  Yingqun Ni 2,  Rilong Huang 3,  Yuanyuan Zhang 4,  Junhua Wang 5,  Haiying Hu 5,  Meimei Li 5,  Huaizhen Liu 6
Affiliations

Affiliations

  • 1 Department of Endocrinology, Geriatrics Center, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui 230001, China; The First Clinical Medical College,Anhui University of Chinese Medicine, Hefei, Anhui 230038, China.
  • 2 Department of Endocrinology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui 230001, China; The First Clinical Medical College,Anhui University of Chinese Medicine, Hefei, Anhui 230038, China.
  • 3 Health Management Center, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui 230001, China; The First Clinical Medical College,Anhui University of Chinese Medicine, Hefei, Anhui 230038, China.
  • 4 Department of Endocrinology, Geriatrics Center, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui 230001, China.
  • 5 The First Clinical Medical College,Anhui University of Chinese Medicine, Hefei, Anhui 230038, China.
  • 6 Department of Endocrinology, Geriatrics Center, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui 230001, China; The First Clinical Medical College,Anhui University of Chinese Medicine, Hefei, Anhui 230038, China. Electronic address: [email protected].
PMID: 41833773 DOI: 10.1016/j.cellsig.2026.112487
Abstract

Background: Metabolic disruptions in non-alcoholic fatty liver disease (NAFLD) contribute to the progression of liver fibrosis. Kinase non-catalytic c-lobe domain containing 1 (KNDC1) is associated with intracellular signaling pathways. We investigated how KNDC1 regulates glycolysis and hepatic fibrosis.

Methods: Hepatic stellate cells (HSCs) stimulated with transforming growth factor-β1 (TGF-β1) and mice fed with high-fat and fructose diet were used as models for hepatic fibrosis. The impact of KNDC1 on glycolysis was assessed using Seahorse metabolic analyzer. And glucose uptake of HSCs was measured and visualized. Western blot and histological analysis were employed to examine the activity levels of hepatic fibrosis. Furthermore, proximity ligation assays, GST pull-down, and molecular docking were employed to identify the interaction between KRAS and glucose transporter 2 (GLUT2).

Results: KNDC1 inhibits glycolysis, blunts HSCs, thus alleviating hepatic fibrosis. In vitro, KNDC1 activates KRAS. Mechanistically, KRAS binds to GLUT2, preventing its membrane translocation, reducing glucose uptake, thereby inhibiting glycolysis.

Conclusions: We revealed a new molecular mechanism linking KNDC1 and GLUT2. Our research offers novel insights into the potential therapeutic applications of KNDC1 and glycolysis in the management of hepatic fibrosis in NAFLD.

Keywords

GLUT2; Glycolysis; KNDC1; KRAS; Liver fibrosis; Non-alcoholic fatty liver disease.

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