In summary, we have demonstrated that in RRV-induced murine BA, HMGB1, which is initially released from injured cholangiocytes, is an inflammatory initiator; and our findings that HMGB1 promotes maturation and activation of NK cells via the TLRs-MAPK signaling pathways and that the role of NK cell maturation in the immunological gap of BA provide new approaches into the mechanistic study of NK cell-mediated RRV-induced BA. Here, HMGB1 is linked to breast angiosarcoma.