β-caryophyllene mitigates oxidative stress, inflammation and fibrosis by activating cannabinoid-2 receptors in murine model of high-fat diet/streptozotocin-induced nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological condition, frequently arising as a complication of type 2 diabetes mellitus (T2DM), and is characterized by hepatic steatosis. NAFLD has become a significant global public health concern. Its progression involves a complex interplay of lipid accumulation, oxidative stress, inflammation, and fibrosis. The condition is strongly linked to central obesity, dyslipidaemia, hypertension, hyperglycaemia, and altered liver function tests. Currently, the primary treatment strategy centers on weight reduction through lifestyle and dietary modifications. Growing evidence highlighting the role of dietary cannabinoids in liver diseases and diabetes that led to investigations into β-caryophyllene (BCP), a naturally occuring cannabinoid type-2 (CB2) receptor agonist in NAFLD. This study inveyigated the effects of BCP in a mouse model of NAFLD induced by a high-fat diet (HFD)/streptozotocin (STZ) administration. Following onset of diabetes, mice received a 12-week oral BCP (50 mg/kg). BCP reduced liver injury markers, mitigated hepatic oxidative stress by inhibiting the expression of NADPH oxidase 2 and NADPH oxidase 4 and activating Nrf2 signaling. BCP also inhibited inflammation and down-regulated inflammasome activation and suppressed hepatic fibrosis and endothelial-to-mesenchymal transition mediating inhibition of TGF-β/Smad signaling. To elucidate CB2R-dependent mechanism of BCP, T2DM mice were pretreated with AM630, a CB2R antagonist. Pharmacological challenge with AM630 abrogated the beneficial effects of BCP in T2DM mice. Taken together, BCP improved hepatic impairment efficiently in diabetic mice by suppressing oxidative stress, inflammation, and fibrosis mediating CB2R-dependent mechanisms. These results suggest that CB2R activation may represent a novel therapy for NAFLD with diabetes. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany