Schematic overview summarizing the findings within this investigation. APAP-in-duced hepatic apoptosis and necrosis in the fed CD-1 mouse model, which can be quantified by the serum biomarker K18. This is accompanied by the caspase-dependent oxidation of HMGB1 (HMGB1-SO3H), which prevents an inflammatory response. The fasting of mice before APAP induces a depletion in basal hepatic ATP levels, which does not permit apoptosis activation and HMGB1 oxidation. The resulting reduced HMGB1 (HMGB1-SH) activates inflammatory cells and promotes the hepatic inflammatory response after hepatocyte death, leading to exacerbated injury.