From network prediction to in vivo validation: luteolin attenuates cholestatic liver injury in association with PI3K/Akt/GSK-3β signalling modulation

  • Naunyn Schmiedebergs Arch Pharmacol. 2026 Jun 23. doi: 10.1007/s00210-026-05577-2.
Yuxin Wu  1  2 ,  Shiji Gong  3  4 ,  Xin Wu  3  4 ,  Wei Wang  1 ,  Dongming Zhang  5 ,  Jianxin Jia  6  7
Affiliations
  • 1. Department of General Surgery, Baotou Central Hospital, Baotou, 014040, Inner Mongolia Autonomous Region, China.
  • 2. Baotou Medical College, Baotou, 014040, Inner Mongolia Autonomous Region, China.
  • 3. Department of Human Anatomy, Baotou Medical College, Baotou, 014040, Inner Mongolia Autonomous Region, China.
  • 4. Key Laboratory of Human Anatomy, Education Department of Inner Mongolia Autonomous Region, Baotou, 014040, Inner Mongolia Autonomous Region, China.
  • 5. Department of General Surgery, Baotou Central Hospital, Baotou, 014040, Inner Mongolia Autonomous Region, China. [email protected].
  • 6. Department of Human Anatomy, Baotou Medical College, Baotou, 014040, Inner Mongolia Autonomous Region, China. [email protected].
  • 7. Key Laboratory of Human Anatomy, Education Department of Inner Mongolia Autonomous Region, Baotou, 014040, Inner Mongolia Autonomous Region, China. [email protected].
PMID: 42331983 DOI: 10.1007/s00210-026-05577-2
Abstract

Cholestatic liver disease (CLD) is characterized by inflammatory amplification, hepatic stellate cell activation and Collagen deposition. Luteolin is a natural flavonoid with reported anti-inflammatory and anti-fibrotic activities. Here, network pharmacology, molecular docking and experimental analyses were integrated to examine the effects of luteolin in CLD, with a focus on PI3K/Akt/GSK-3β-associated signalling. Target prediction identified 181 putative luteolin targets and 4,403 CLD-related targets, with 88 overlapping genes. In a bile duct ligation (BDL) rat model, luteolin treatment was associated with lower serum injury indices, reduced histopathological damage, decreased Collagen deposition and lower fibrosis-related readouts. Experimental analyses further showed that luteolin treatment was accompanied by lower phosphorylation-associated readouts along the PI3K/Akt/GSK-3β axis. Together, these findings support an association between luteolin treatment and attenuation of cholestatic liver injury and fibrosis, within a multi-target signalling context that includes PI3K/Akt/GSK-3β.

Keywords
Bile duct ligation; Cholestatic liver disease; Liver fibrosis; Luteolin; Network pharmacology; PI3K/Akt/GSK-3β signalling axis.
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