Liver-specific deletion of the N6-methyladenosine methyltransferase complex member, Mettl14, in a mouse model demonstrates progressive liver injury and marked nuclear heterotypia in hepatocytes. This phenotype correlates with significant changes in the transcriptomic profile relative to wild-type mouse liver, and changes in localization of the transcription / export machinery (TREX) complex as visualized by immunofluorescence. Mettl14 deletion liver also exhibits exacerbated injury to toxicity-based liver injury models, but shows no significant difference in regeneration after physical injury as modeled by partial hepatectomy. Deletion of the N6-methyladenosine recognizing proteins Ythdf1 and Ythdf2, both alone and together, impacts response to toxicity-based liver injury. This affects both liver mass regeneration and total mouse weight maintenance and recovery post-surgery. Dual deletion of Ythdf1 and Ythdf2 in liver tissue leads to liver damage in the steady state, and significantly exacerbated damage after liver injury models relative to either Ythdf1 or Ythdf2 deletion alone.