Food additive β-caryophyllene mitigates alcoholic steatohepatitis by dual modulation of inflammation and lipid metabolism: A diet-based intervention strategy

Abstract

Alcoholic steatohepatitis (ASH) represents the excessive lipid accumulation and inflammatory infiltration in the spectrum of Alcohol-associated liver disease (ALD). Unfortunately, there are currently no FDA-approved drugs for the treatment of ASH. This study aims to demonstrate the practicability of β-caryophyllene (BCP), an FDA-approved food flavoring agent, against ASH and exploring its underlying mechanisms related to lipid metabolism regulation and inflammation. Bioinformatics analysis revealed BCP was closely associated with lipid metabolic pathways and alcoholic liver disease. In the mouse model of chronic and binge ethanol feeding, BCP demonstrated significant therapeutic effects, including alleviating histopathological changes, reducing lipid accumulation, decreasing inflammatory cell infiltration and subsequent release of inflammatory cytokines. Additionally, BCP suppressed the formation of neutrophil extracellular traps (NETs). BCP modulated the expression of sterol-regulatory element binding protein 1 (SREBP1) and Peroxisome proliferator-activated receptor α (PPARα) in AML12 hepatocytes, suggesting its role in lipid metabolism regulation. Furthermore, BCP inhibited the expression of Toll-like receptor 4 (TLR4), Purinergic ligand-gated ion channel 7 receptor (P2X7R), Nucleotide-binding domain-(NOD-) like receptor protein 3 (NLRP3) inflammasome in mouse peritoneal macrophages (MPMs) , thereby reducing the production of inflammatory cytokines. Our findings highlight the potential of BCP as a natural dietary supplement or functional food ingredient for mitigating lipid accumulation and inflammation in ASH. This study provides a promising option for the development of nutraceutical interventions or dietary strategies to combat ASH.