Downregulated expression of serum exosome-derived miR-375-3p alleviates interface hepatitis and promotes fibrosis regression in patients with chronic hepatitis B

INTRODUCTION: Chronic liver inflammation leads to fibrosis, cirrhosis and hepatocellular carcinoma. Serum alanine aminotransferase is the most widely used indicator of liver inflammatory injury, but it does not accurately reflect the extent of chronic liver inflammation. The role of exosomes in chronic liver inflammation and fibrosis has gained significant interest. This study aimed to investigate the association between serum exosome-derived miRNAs and chronic liver inflammation injury in chronic hepatitis B (CHB) patients with significant fibrosis, and to evaluate their potential clinical value. METHODS: Using serum samples collected from healthy adults and patients with paired histologic CHB and significant fibrosis. Transcriptome analysis was conducted to identify dysregulated exosome-derived miRNAs associated with chronic liver inflammation. These were validated by lipopolysaccharide/ D-galactosamine-induced acute liver injury in mice and CCl 4 -induced cirrhosis in rat models, and 80 CHB patients with paired histologic after a 72-week treatment. RESULTS: Exosome-derived miR-375-3p was positively associated with interface hepatitis, as determined by transcriptomic screening. Its upregulation was associated with severe interface hepatitis in the mouse and rat models. In the validation cohort, a high proportion of patients in the high-expression group demonstrated severe interface hepatitis (85%, p =0.022), while the low-expression group showed a higher proportion of interface hepatitis improvement (80%, p =0.002) and regression of fibrosis (70%, p <0.001). DISCUSSION: The expression level of serum exosome-derived miR-375-3p was positively associated with interface hepatitis and is independently associated with the prognosis of interface hepatitis and fibrosis in patients with CHB and significant fibrosis.