This multiscale mechanistic liver lobule model is composed of various interacting cell types, such as hepatocytes, residential Kupffer cells and macrophages. It captures hepatocellular acetaminophen (APAP) metabolism, DNA damage response activation, necrotic cell death, macrophage recruitment and the regulation of hepatocellular senescence and proliferation, with qualitatively different outcomes as a function of the initial APAP concentration in blood plasma.