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Some life-threatening acute hepatitis originates from drug-induced liver injury (DILI). Carbon tetrachloride (CCl₄)-induced acute liver injury in mice is the widely used model of choice to study acute DILI, which pathogenesis involves a complex interplay of oxidative stress, necrosis, and apoptosis. Since the receptor interacting protein kinase-1 (RIPK1) is able to direct cell fate towards survival or death, it may potentially affect the pathological process of xenobiotic-induced liver damage. Two different mouse lines, either deficient for <i>Ripk1</i> specifically in liver parenchymal cells (<i>Ripk1</i>^LPC-KO) or for the kinase activity of RIPK1 (<i>Ripk1</i>^K45A, kinase dead), plus their respective wild-type littermates (<i>Ripk1</i>^fl/fl, <i>Ripk1</i>^wt/wt), were exposed to single toxic doses of CCl₄. This exposure led in similar injury in <i>Ripk1</i>^K45A mice and their littermate controls. However, <i>Ripk1</i>^LPC-KO mice developed more severe symptoms with massive hepatocyte apoptosis as compared to their littermate controls. A pretreatment with a TNF-α receptor decoy exacerbated liver apoptosis in both <i>Ripk1</i>^fl/fl and <i>Ripk1</i>^LPC-KO mice. Besides, a FasL antagonist promoted hepatocyte apoptosis in <i>Ripk1</i>^fl/fl mice but reduced it in <i>Ripk1</i>^LPC-KO mice. Thus, the scaffolding properties of RIPK1 protect hepatocytes from apoptosis during CCl₄ intoxication. TNF-α and FasL emerged as factors promoting hepatocyte survival. These protective effects appeared to be independent of RIPK1, at least in part, for TNF-α, but dependent on RIPK1 for FasL. These new data complete the deciphering of the molecular mechanisms involved in DILI in the context of research on their prevention or cure.