2. Academic Validation
  3. Cichoriin suppresses hepatic lipid accumulation and fibrosis in mice metabolic dysfunction associated steatohepatitis via the AMPK pathway

Cichoriin suppresses hepatic lipid accumulation and fibrosis in mice metabolic dysfunction associated steatohepatitis via the AMPK pathway

  • Biochem Pharmacol. 2025 Dec 10:245:117630. doi: 10.1016/j.bcp.2025.117630.
Yao Zhao 1,  Xinjie Luo 2,  Tian Li 3,  Xinling Wang 4,  Jianhua Yang 5,  Junping Hu 6
Affiliations

Affiliations

  • 1 Clinical Postdoctoral Research Station, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054 Xinjiang, PR China; Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054 Xinjiang, PR China.
  • 2 College of Pharmacy, Xinjiang Medical University, Urumqi 830017 Xinjiang, PR China.
  • 3 College of Basic Medicine, Xinjiang Medical University, Urumqi 830017 Xinjiang, PR China.
  • 4 College of Pharmacy, Xinjiang Medical University, Urumqi 830017 Xinjiang, PR China; Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017 Xinjiang, PR China.
  • 5 Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054 Xinjiang, PR China; Xinjiang Key Laboratory of Clinical Drug Research, Urumqi 830054 Xinjiang, PR China. Electronic address: [email protected].
  • 6 College of Pharmacy, Xinjiang Medical University, Urumqi 830017 Xinjiang, PR China; Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumqi 830017 Xinjiang, PR China. Electronic address: [email protected].
PMID: 41386558 DOI: 10.1016/j.bcp.2025.117630
Abstract

Previous studies highlight the critical role of AMP-activated protein kinase (AMPK) in hepatic lipid metabolism, yet natural activators for metabolic dysfunction-associated steatohepatitis (MASH) remain underexplored. This study investigated whether cichoriin from Cichorium intybus mitigates MASH fibrosis. C57BL/6J mice fed a Gubra-Amylin NASH diet for 20 weeks received cichoriin (100 or 200 mg/kg/day, oral gavage) for 6 weeks. Primary murine hepatocytes and hepatic stellate cells (HSCs) were co-cultured under fatty acid stimulation with cichoriin intervention to examine cellular mechanisms. AMPK dependency was validated using the pharmacological inhibitor Compound C. Cichoriin treatment significantly reduced hepatic steatosis, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and fibrotic markers while improving histological features. Mechanistically, molecular dynamics simulations indicated stable binding between cichoriin and AMPK. Cichoriin enhanced AMPK and Acetyl-CoA Carboxylase (ACC) phosphorylation, promoted fatty acid β-oxidation, suppressed lipogenesis, and reduced oxidative stress and pro-inflammatory cytokine production. Proteomic analysis revealed significant enrichment in AMPK-related and lipid metabolic pathways. Importantly, cichoriin decreased platelet-derived growth factor-AA (PDGF-AA) secretion by hepatocytes, thereby inhibiting HSCs activation and extracellular matrix deposition indirectly. Inhibition of AMPK via Compound C or siRNA knockdown reversed these protective effects, confirming AMPK dependency. This study demonstrates that cichoriin protects against MASH-associated liver injury through AMPK pathway activation and disruption of profibrotic hepatocyte-stellate cell signaling, supporting its development as a MASH fibrosis therapeutic.

Keywords

AMPK; Cichoriin; Hepatocyte-hepatic stellate cell crosstalk; Liver fibrosis; Metabolic dysfunction associated steatohepatitis.

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