EV-derived miR-186-5p alleviates APAP-induced liver injury by the suppression of CXCL1

Acetaminophen (APAP) overdose is the major cause of drug-induced liver injury (DILI) and acute liver failure (ALF), and patients with advanced APAP toxicity rarely benefit from N-acetylcysteine (NAC), which is the first-line agent used in the clinic. Mesenchymal stromal cells (MSCs) and their extracellular vesicles (MSC-EVs) have shown promising effects in the treatment of DILI by decreasing neutrophil infiltration. However, the specific mechanism underlying the therapeutic effects of MSCs or MSC-EVs still needs to be elucidated. In this study, by using RNA-seq, we found that CXCL1, which is a chemoattractant for neutrophils, is a key molecule in MSC-mediated amelioration of DILI, and by luciferase reporter assay, we verified that MSC-EV-derived miR-186-5p binds to the 3’-UTR of CXCL1 to inhibit its expression in hepatocytes. Neutralizing CXCL1 reduces APAP-induced liver damage in vivo, and the agomir miR-186-5p shows excellent potential in the treatment of DILI. Overall, these findings suggest that the use of MSC-EVs may be a promising novel strategy for preventing DILI and that targeting the miR-186-5P/CXCL1 axis is a feasible approach for improving the efficacy of MSCs in the treatment of DILI. To investigate the potential target genes that whose expression is altered after MSC treatment, we performed RNA sequencing on liver tissues from the control (CTRL) group, the APAP+PBS (APAP_PBS) group, and the APAP +MSC (APAP_MSC) group 24h after APAP administration.