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

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.