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

Alcoholic steatohepatitis (ASH) represents excessive lipid accumulation and inflammatory infiltration in the spectrum of alcohol-associated liver diseases (ALDs). Unfortunately, currently, there are no FDA-approved drugs for the treatment of ASH. Thus, this study was aimed at demonstrating 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 that BCP was closely associated with lipid metabolic pathways and alcoholic liver diseases. In a 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 the regulation of lipid metabolism. Furthermore, BCP inhibited the expression of toll-like receptor 4 (TLR4), purinergic ligand-gated ion channel 7 receptor (P2X7R), and nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasomes 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.