Cannabigerol attenuates liver fibrosis via AMPK activation: Regulation of lipid metabolism, inflammation, and hepatic stellate cell activation

Liver fibrosis, driven by lipid dysregulation and chronic inflammation, remains a major global health burden with limited therapeutic options. This study investigates the therapeutic potential of cannabigerol (CBG), a minor non-psychoactive phytocannabinoid, in mitigating hepatic lipid accumulation and inflammation. In hepatocytes exposed to palmitic and oleic acids (PA/OA), CBG significantly reduced lipid accumulation by suppressing lipogenesis and enhancing lipophagy. Mechanistic studies revealed that CBG directly activated AMP-activated protein kinase (AMPK), as confirmed by in vitro activity assay and molecular docking study. Additionally, CBG markedly suppressed the expression of pro-inflammatory cytokines (IL6, IL1B, and TNFA) and attenuated the activation of hepatic stellate cells. Importantly, both the lipid-lowering and anti-inflammatory effects of CBG were abolished by co-treatment with the AMPK inhibitor compound C, confirming AMPK as a central mediator of actions of CBG. These findings highlight CBG as a promising therapeutic candidate for liver fibrosis, offering dual modulation of lipid metabolism and inflammatory signaling via AMPK activation.