This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "drug_induced_liver_injury#Hepatocyte Cell Death"). Conforming nodes should substitute the disorder-specific hepatotoxic driver (the particular drug and its proximal mechanism — reactive metabolite, BSEP inhibition, or immune-mediated idiosyncratic injury) while preserving the conserved metabolite/stress → mitochondrial dysfunction → hepatocyte death → inflammation → liver injury chain. The key conformance / central-effector target is "drug_induced_liver_injury#Hepatocyte Cell Death".
Human quad-culture Liver-Chip (Emulate/Wyss) for predictive hepatotoxicology
ORGAN ON CHIP
Microfluidic dual-channel human Liver-Chip populated with primary hepatocytes plus the three non-parenchymal liver cell types (liver sinusoidal endothelial cells, Kupffer cells, stellate cells) under continuous flow. A non-animal New Approach Methodology qualified against Innovation and Quality consortium criteria on a blinded benchmark drug set, with albumin synthesis, ALT release, morphological injury scoring, caspase 3/7 and TMRM mitochondrial imaging as readouts of the conserved DILI cascade.
Models:
Mitochondrial Dysfunction and Oxidative Stress, Hepatocyte Cell Death, Liver Injury and Acute Liver Failure
Ingber (Wyss Institute) is a co-author; this is the systematic qualification study for the liver organ-chip platform highlighted in the NAMeRS 2026 summit multi-organ-chip case study.
Curio Barrier Liver Chip with iPSC-derived human liver organoids
ORGAN ON CHIP
High-throughput microfluidic liver-on-a-chip (8 x 2 well "Curiochip" configuration) hosting three-dimensional liver organoids differentiated from human induced pluripotent stem cells. Sustains albumin secretion and cytochrome P450 activity for 28 days, enabling prolonged-exposure hepatotoxicity testing without primary human hepatocytes or animals.
Models:
Reactive Drug Metabolite Formation and Hepatocellular Stress, Hepatocyte Cell Death
Directly relevant to the NAMeRS 2026 summit project on 3D iPSC-hepatocyte models for gene-therapy liver safety; the model is fully human and animal-free.
Autologous HLA-genotyped liver organoid-CD8 T cell co-culture microarray
CO CULTURE
Matrix-free human liver organoid microarray co-cultured with autologous CD8-positive T cells derived from the same HLA-genotyped induced pluripotent stem cell donor. Reconstitutes antigen-specific adaptive immunity alongside hepatocytes, the component conventional hepatotoxicity models lack, and models idiosyncratic DILI in a genetically defined host context.
Models:
Sterile and Immune-Mediated Inflammatory Amplification, Hepatocyte Cell Death
Akura Twin 384-well liver fibrosis microphysiological system (HepaRG/THP-1 and hTERT-HSC microtissues)
CO CULTURE
High-throughput microphysiological system built on a 384-well microplate of 168 interconnected well pairs. HepaRG hepatocyte microtissues, with or without THP-1 monocytic cells, occupy the alpha well of each pair and hepatic stellate cell (hTERT-HSC) microtissues occupy the beta well. A non-animal New Approach Methodology in which methotrexate and acetaminophen are used as hepatotoxicant challenges alongside TGF-beta 1, with albumin synthesis and glucose/lactate sensing as cell-health readouts.
Models:
Hepatocyte Cell Death (perturbs), Sterile and Immune-Mediated Inflammatory Amplification (partially recapitulates)
Recorded here for its methotrexate and acetaminophen challenge arms. The same system is curated on Liver_Cirrhosis for the fibrosis arm - stellate activation, matrix output and TGF-beta perturbation - which is where the paper's primary claim sits.
Mitochondrial Dysfunction and Oxidative Stress
amplifier
Reactive metabolites and accumulated bile acids damage mitochondria, the organelle most central to hepatocyte bioenergetics, producing oxidative stress, impaired ATP synthesis, and mitochondrial permeability transition. This is the major amplifying event linking the proximal drug stress to hepatocyte death across hepatotoxic agents.
Downstream
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Hepatocyte Cell Death
Mitochondrial failure and oxidative stress precipitate hepatocyte necrosis and apoptosis.
Hepatocyte Cell Death
central effector
Mitochondrial failure and oxidative stress precipitate hepatocyte death by necrosis and apoptosis. This is the central effector step and the most common manifestation of DILI; conforming disorder nodes substitute the drug-specific upstream driver but converge here. It is the key conformance target of the module.
Downstream
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Sterile and Immune-Mediated Inflammatory Amplification
Hepatocyte death releases damage-associated signals that recruit and activate inflammatory cells.
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Liver Injury and Acute Liver Failure
Loss of hepatocyte mass produces clinically apparent liver injury.
Liver Injury and Acute Liver Failure
consequence
Accumulated hepatocyte loss and inflammation produce clinically apparent liver injury, manifesting as a hepatocellular, cholestatic, or mixed biochemical pattern, and in severe cases progressing to acute liver failure — the most feared consequence of DILI and a leading cause of drug attrition.