Metabolomic profiling reveals ADB-BUTINACA-induced long-term hepatotoxicity

Abstract

The multi-organ toxicity of ADB-BUTINACA, a synthetic cannabinoid with high abuse potential, poses a public health risk. However, its long-term toxicological effects and metabolic mechanisms remain unclear. This study aimed to elucidate the hepatotoxic potential and metabolic disruption induced by ADB-BUTINACA through a 30-day oral exposure model in mice at doses of 0.1, 1, and 10 mg kg⁻¹·bw⁻¹. Serum biochemical analysis revealed elevated TNF-α, IL-6, total cholesterol, triglycerides, and LDL-C, indicating systemic inflammation and lipid dysregulation. Histopathological examination showed dose-dependent hepatocellular swelling, lipid droplet accumulation, and inflammatory infiltration. Non-targeted metabolomic profiling identified 60 significantly altered metabolites and 12 perturbed metabolic pathways, including unsaturated fatty acid biosynthesis, taurine metabolism, and the tricarboxylic acid (TCA) cycle. Notably, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and taurine were markedly reduced. RT-qPCR results showed that ADB-BUTINACA induced inhibition of TCA cycle and unsaturated fatty acid synthesis activity in the liver. Molecular docking demonstrated stable and competitive binding of ADB-BUTINACA to key metabolic enzymes: Fatty Acid Desaturase 2 (FADS2) and Elongation of Very Long Chain Fatty Acids Protein 2 (ELOVL2). This suggests interference with endogenous lipid regulatory processes. These findings elucidate the hepatotoxic mechanisms of ADB-BUTINACA and underscore its potential health risks as an emerging synthetic cannabinoid contaminant.