Multi-omics integration reveals sex-based differences in the circulating extracellular vesicle lipidome and miRNome of alcohol use disorder patients

Background Integrated multi-omics and extracellular vesicle (EV) analysis are emerging as powerful, complementary strategies for biomarker discovery. These approaches offer promising tools to enhance early detection, diagnosis, and treatment of alcohol use disorder (AUD), a prevalent and globally significant neuropsychiatric condition. Methodology Here we applied an integrated miRNomic and lipidomic approach to analyze plasma EVs from AUD patients and controls of both sexes to gain a comprehensive understanding of the underlying molecular mechanisms. Results We identified an AUD signature with predictive potential for diagnostic and prognostic applications. Individual features (e.g., hsa-miR-99b-3p, hsa-miR-556-5p, Cer_NDS d39:1, and PI 18:0_18:2) represented important components; however, the strength of this signature lay in the combined profile rather than isolated markers. We also revealed an AUD-sex signature that provided insight into how biological responses to alcohol differ between females and males (including features such as hsa-miR-1301-3p and PC 39:4), which also underscored the power of multi-omic integration. The individual miRNome approach also revealed an opposite functional alteration by sex in various alcohol related systems, such as pathways associated with immunity, oxidative stress, and autophagy. Conclusions While addressing the long-standing underrepresentation of females in alcohol-related research, this collective work also represents the first study to integrate EV-derived miRNA and lipid data to uncover sex-related pathophysiological pathways in AUD. Together, our findings underscore the added value of multi-omics integration in identifying clinically relevant molecular signatures of disease; this sex-informed approach offers a promising path toward more personalized diagnostic tools and therapeutic strategies in AUD.