{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T22:36:33Z","timestamp":1786746993554,"version":"build-2736575974"},"reference-count":75,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ZonMW and BMBF joint InnoSysTox program","award":["114027005"],"award-info":[{"award-number":["114027005"]}]},{"name":"ZonMW and BMBF joint InnoSysTox program","award":["031L0243"],"award-info":[{"award-number":["031L0243"]}]},{"name":"European Union\u2019s Horizon 2020 Program Under the RISK-HUNT3R Initiative"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Drug-induced liver injury (DILI) arises from dynamic and time-dependent cellular stress responses that remain insufficiently captured by conventional single-timepoint toxicogenomic assessments. We systematically characterized temporal and concentration-dependent transcriptomic responses to the clinically relevant hepatotoxicants ketoconazole, diclofenac, and nitrofurantoin across 3 human liver in vitro models: primary human hepatocytes (PHH), hiPSC-derived hepatocyte-like cells (HLC), and HepG2 cells. Time-resolved RNA sequencing (0 to 48\u2009h) combined with likelihood ratio testing identified time-responsive genes (TRGs), which were subsequently integrated into TXG-MAPr gene co-expression modules to enable mechanistic interpretation at the network level. Across all models and compounds, a conserved core stress response was observed, characterized by activation of ER stress (ATF4), oxidative stress (NRF2), and heat shock (HSF1) pathways, whereas distinct model-specific adaptive programs reflected differences in metabolic competence and differentiation status. Mapping TRGs onto co-expression networks revealed coordinated temporal activation patterns and highlighted both shared and system-specific transcriptional programs. Concentration-response analysis at 24\u2009h demonstrated that module-level transcriptomic points of departure (tPODs) were highly reproducible across models for a subset of functionally annotated networks, particularly ER stress modules associated with hepatocellular injury in vivo. Notably, these modules showed substantial gene-level concordance across systems, supporting their biological robustness and translational relevance. These findings establish that time-resolved, network-based transcriptomics provides mechanistically grounded, reproducible, and quantitative endpoints that enhance cross-system comparability and offer a scalable framework for regulatory toxicology and next-generation chemical risk assessment.<\/jats:p>","DOI":"10.1093\/toxsci\/kfag088","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T11:41:35Z","timestamp":1784893295000},"source":"Crossref","is-referenced-by-count":0,"title":["Systematic comparison of temporal hepatotoxicant-induced gene network responses across 3 liver test systems"],"prefix":"10.1093","volume":"209","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6125-6147","authenticated-orcid":false,"given":"Tamara Y","family":"Danilyuk","sequence":"first","affiliation":[{"name":"Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden,","place":["The 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