BACKGROUND AND AIMS: MicroRNAs (miRNAs) are short non-coding oligonucleotides involved in the post-transcriptional regulation of gene expression. We investigated the association between the miRNome profile of circulating extracellular vesicles (EVs) and metabolic derangements, circulating and hepatic pro-inflammatory cytokines, and liver damage across the histological spectrum of metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: EV miRNAs expression was determined by NGS (NextSeq550, Illumina Inc) in 228 biopsy-proven MASLD patients. In vivo metabolic studies were performed in a subgroup of 54 patients by tracer infusion ([6,6-H]glucose and [H]glycerol) to assess glucose and lipid fluxes and insulin resistance (IR) in the adipose tissue. RESULTS: Seven miRNAs (miR-27b-3p, miR-30a-5p, miR-122-5p, miR-375-3p, miR-103a-3p, let-7d-5p, and let-7f-5p) were differentially expressed according to the diagnosis of steatohepatitis and the presence of significant fibrosis (F ≥ 2), thus marking subjects with 'at-risk MASH'. In the metabolic studies, the above-reported miRNAs had the strongest associations with lipid metabolism: miR-122-5p and miR-375-3p levels directly correlated with circulating free fatty acids (FFAs) and adipose tissue (AT)-IR, while let-7d-5p and let-7f-5p inversely correlated with lipolysis, FFAs, and progressively decreased according to AT-IR severity. In addition, let-7d-5p and let-7f-5p inversely correlated with the circulating and hepatic expression of pro-inflammatory cytokines, which increased by increasing degrees of AT-IR. CONCLUSIONS: Our results suggest an intertwined connection between miR-122-5p, miR-375-3p, and the let-7 family in modulating lipid derangements and inflammatory pathways in patients with 'at-risk MASH', paving the basis for further studies aiming at investigating their potential therapeutic value.