Our outcomes revealed that SAM particularly when given at the starting phase downregulates ecCEBPA and UCA1 gene transcripts and ameliorate histopathological alterations in DEN-initiated HCC. Interestingly, SAM attenuates DEN-induced upregulation of PI3K/Akt protein expression. However, SAM upregulates the antioxidant enzymes mRNA transcripts and effectively diminishing DNA oxidation. The results of a DNA fragmentation assay further support the capacity of SAM to ameliorate DEN-induced hepatic malignancy. These results revealed the role of ecCEBPA and UCA1 in HCC and suggest that these lncRNAs may be helpful as prognostic and analytical biomarkers of HCC.