Acetaminophen (APAP) is one of the few recommended analgesic and antipyretic drugs in some critical cases such as viral disease COVID‐19. However, the unrestricted use of APAP develops liver disorders. Hepatotoxicity and liver injury can also be induced by ionizing radiation (IR) during radiotherapy. The data of the current study represents that treatment of rats with either APAP‐overdose, or gamma‐irradiation (R) induces hepatotoxicity, results in significant increases of the hepatic‐enzymes activities (ALT, AST, ALP, GGT, LDH, and MDH), as well as enhancement of triglycerides, total cholesterol levels, combined with declines in albumin and total protein contents. An enhancement of the lipid peroxides (malondialdehyde; MDA), and nitric oxide levels along with a decline of reduced glutathione contents and suppression of superoxide dismutase, catalase, and glutathione peroxidase activities are also observed within the liver tissues of intoxicated animals. TNF‐α, IL‐1β, IL‐6, iNOS, Cytochrome P450 2E1 (CYP2E1), miR‐802 gene expression, NF‐κB, and calcium levels are up‐regulated, while Nuclear factor erythroid‐related factor‐2 (Nrf2), Hemoxygenase‐1 (HO‐1) protein and gene expressions, as well as, glutamate‐cysteine ligase catalytic subunit (GCLC), NAD(P)H‐Quinone oxidoreductase (NQO1), and miR‐122 gene expressions are down‐regulated in the livers of intoxicated animals. All these parameters show significant improvement in R/APAP intoxicated animals. Curcumin pretreatment develops an amelioration of these effects in APAP‐overdose, R‐exposure, or R/APAP treatments. In conclusion, oral administration of curcumin shows hepatoprotective effects against APAP‐overdose induced hepatic damage in normal and gamma‐irradiated rats through prospective regulation of the therapeutic targets CYP2E1, Nrf2, and NF‐κB, via organizing the miR‐122 and miR‐802 gene expression.
