MiR-106b-5p protects against drug-induced liver injury by targeting vimentin to stimulate liver regeneration.

Abstract

Understanding the endogenous mechanism of adaptive response to drug-induced liver injury (arDILI) may discover innovative strategies to manage DILI. To gain mechanistic insight into arDILI, we investigated exosomal miRNAs in the adaptive response to toosendanin-induced liver injury (TILI) of mice. Exosomal miR-106b-5p was identified as a specific regulator of arDILI by comprehensive miRNA profiling. Outstandingly, miR-106b-5p agomir treatment alleviated TILI and other DILI by inhibiting apoptosis and promoting hepatocyte proliferation. Conversely, antagomir treatments had opposite effects, indicating that miR-106b-5p protects mice from liver injury. Injured hepatocytes released miR-106b-5p-enriched exosomes taken up by surrounding hepatocytes. Vim (encodes vimentin) was identified as an important target of miR-106b-5p by dual luciferase reporter and siRNA assays. Furthermore, single-cell RNA-sequencing analysis of toosendanin-injured mouse liver revealed a cluster of Vim + hepatocytes; nonetheless declined following miR-106b-5p cotreatment. More importantly, Vim knockout protected mice from acetaminophen poisoning and TILI. In the clinic, serum miR-106b-5p expression levels correlated with the severity of DILI. Indeed, liver biopsies of clinical cases exposed to different DILI causing drugs revealed marked vimentin expression among harmed hepatocytes, confirming clinical relevance. Together, we report mechanisms of arDILI whereby miR-106b-5p safeguards restorative tissue repair by targeting vimentin.