In conclusion, our study provides evidence that miR-125b-5p can alleviate LPS/D-GalN-induced ALF by regulating the Keap1/Nrf2/HO-1 signaling pathway, and therefore, regulation of miR-125b-5p and its downstream target Keap1 may serve as an alternative intervention for liver failure. Here, NFE2L2 is linked to liver failure.