hADMSC-Evs attenuates depressive and anxiety − like behaviors in chronic liver disease via suppressing Liver-Brain Galectin3 signaling

Abstract

Chronic liver disease (CLD) is strongly associated with depression, affecting approximately 18–58% of patients and significantly worsening clinical outcomes. Although human adipose-derived mesenchymal stem cell extracellular vesicles (hADMSC-Evs) have demonstrated therapeutic potential in CLD, their ability to simultaneously alleviate depression in CLD remains unexplored. Here we report that hADMSC-Evs administration effectively attenuates both liver fibrosis and depression-like behavior in CLD mice. In addition, hADMSC-Evs treatment restored prefrontal cortical synaptic plasticity impairments observed in CLD mice. Integrated RNA-seq analysis and experimental validation identified hADMSC-Evs suppressed liver-brain Galectin3 signalling in CLD mice. Mechanistic investigations revealed that elevated circulating Galectin3 potentiates microglia-mediated synaptic pruning through complement pathway activation, thereby compromising synaptic structural integrity and promoting anxiety and depression-like phenotypes. This study provides mechanistic evidence supporting hADMSC-Evs as a dual-target therapeutic vehicle for CLD and its neuropsychiatric complications, while proposing Galectin3 mediated liver-brain axis dysregulation as a novel pathogenic mechanism underlying CLD-related depression. Our findings further highlight the therapeutic potential of modulating interorgan communication pathways through extracellular vesicle-based interventions.