Drug induced hepatotoxicity is a common cause of acute liver injury. Acetaminophen (paracetamol, N 
acetyl p-acetaminophen, APAP) is a widely used analgesic and antipyretic drug. However, its 
overdose is one of the main cause of acute liver failure. The current study is an attempt to investigate 
the different mechanisms of APAP-induced hepatoxicity including inflammatory response, oxidative 
stress and different cell death pathways and the ability of necrostatin-1 to antagonize the APAPinduced hepatoxicity. Materials and methods: thirty adult male albino rats were used and divided 
into 3 equal groups: control groups, paracetamol treated group (APAP group): each rat received 
paracetamol (APAP) dissolved in saline at a dose level of 2 gm/kg body weight given as a single dose 
orally by oral gavage, paracetamol + necrostatin-1(RIPK1 inhibitor) (APAP+Necrostatin-1 group): 
each rat of this group received pretreatment of necrostatin-1 at a dose level of 1.8 mg/kg taken as a 
single IP injection1 hour before receiving APAP as the previous regimen. An overnight fast and blood 
samples from jugular vein were obtained. Blood samples were collected for the assay of serum liver 
enzymes, serum lipid profile, serum tumor necrosis factor alpha (TNF-α), serum interleukin-33 (IL33) and serum reduced glutathione (GSH). Histological examination of the liver, and immune-staining 
for caspase-3 was also done. Results and conclusion: The liver is a particular target for drug toxicity 
because of its role in clearing and metabolizing chemicals. The pathophysiology and intrinsic 
mechanisms underlying paracetamol (APAP) induced hepatotoxicity are different because aetiologies 
and mechanisms vary between oxidative stress, inflammation and cell death including apoptosis, 
necrosis and necroptosis. Necrostatin-1 is proved to have antioxidant, anti-inflammatory, antiapoptotic and anti-necroptotic effect that antagonize APAP-injurious effect.