The dynamic trajectory of circulating exosome components in high-fat diet-induced metabolic-associated steatotic liver disease and its modulation by curcuminoids.

BACKGROUND AND OBJECTIVE: Circulating exosomes have emerged as promising non-invasive carriers of disease biomarkers, particularly in metabolic-associated steatotic liver disease (MASLD). Curcuminoids derived from Curcuma longa L. have shown potential in regulating lipid metabolism. However, most studies focus on late-stage disease, overlooking the dynamic metabolic changes during early progression, and the effect of curcuminoids on circulating exosomal components remains unknown. This study aimed to characterize the dynamic trajectory of circulating exosome components in high-fat diet (HFD)-induced MASLD and to evaluate its modulation by curcuminoids. METHODS: A time-course mouse model of HFD-induced MASLD was established over 12 weeks. Untargeted metabolomics combined with temporal clustering analysis and nanoparticle tracking analysis was used to profile dynamic changes in circulating exosomal lipids and identify candidate biomarkers. Subsequently, the curcuminoids were administered preventively to HFD-fed mice, and targeted metabolomic analysis of the selected biomarkers was performed to assess intervention-induced alterations and their correlation with exosome particle concentration. RESULTS: Seventy-one time-independent differential metabolites were identified between HFD and control groups. Temporal clustering analysis revealed distinct dynamic patterns of 43 metabolites between MASLD and control mice. Correlation analysis with exosome secretion dynamics identified 36 metabolites significantly associated with exosomal particle concentration, among which 26 were ultimately selected as robust lipid biomarkers. The curcuminoids significantly ameliorated MASLD-related phenotypes, including serum lipids, liver enzymes, hepatic steatosis, and brown adipose tissue injury. Quantitative analysis further showed that 22 of the 26 biomarkers were significantly downregulated by curcuminoids, with these changes correlating with exosomal particle concentration. CONCLUSION: This study provides a comprehensive temporal landscape of exosomal metabolite changes during MASLD progression and demonstrates that curcuminoids intervention is associated with modulation of disease progression, paralleled by downregulation of exosome-associated lipid metabolites. The identified metabolites represent potential early-stage, non-invasive biomarkers for MASLD that warrant further validation in human cohorts and offer preliminary experimental evidence for the effects of the curcuminoids in MASLD.