{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T06:04:10Z","timestamp":1790229850769,"version":"4.1.0"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Drug\u2010induced liver injury (DILI) is a leading cause of acute liver failure (ALF) and a major obstacle in drug development, reflecting the lack of robust, mechanism\u2010based biomarkers. Human\n                      <jats:italic>in vitro<\/jats:italic>\n                      systems, coupled with unbiased omics, provide controlled, human\u2010relevant and mechanistically informative platforms that can accelerate biomarker discovery. Here, we explore quantitative toxicoproteomics of paracetamol (acetaminophen; APAP)\u2010exposed HepG2 cells as a platform for the identification of candidate translational biomarkers of APAP\u2010liver injury and recovery.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      HepG2 cells were exposed to the APAP IC\n                      <jats:sub>50<\/jats:sub>\n                      concentration for 8 h (injury phase), followed by drug withdrawal and a 24 h recovery phase. Injury\u2010induced cell responses were evaluated through RT\u2010qPCR analysis and intracellular ROS quantification. Proteomic changes associated with injury and recovery were characterized by quantitative LC\u2010MS\/MS and selected proteins were validated by immunoblotting.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LC\u2010MS\/MS quantified 1,478 proteins and revealed increased protein secretion upon APAP exposure. Notably, comparison of the proteomic dataset against published proteomic profiles of a large cohort of ALF patients supported the potential clinical relevance of the obtained signature. Injury\u2010phase upregulated proteins, including KRT18 and HMGB1, recapitulated known clinical DILI biomarkers. Similarly, recovery\u2010phase was marked by clinical markers of liver regeneration,\n                      <jats:italic>e.g<\/jats:italic>\n                      ., AFP, APOA1 and HP, enabling discrimination between injury and regeneration. HPD, S100A6 and TXNRD1 emerged as candidate diagnostic biomarkers, whilst SERPINA1 and complement components (C3, C5) showed prognostic potential.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Collectively, this study demonstrated how toxicoproteomics applied to human\n                      <jats:italic>in vitro<\/jats:italic>\n                      hepatic models, validated against clinical evidence, provide a relevant platform for the discovery of novel translational biomarkers of liver injury and recovery.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1819323","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:39:52Z","timestamp":1790228392000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Toxicoproteomics of APAP-exposed HepG2 cells identifies candidate translational biomarkers of liver injury and recovery"],"prefix":"10.3389","volume":"17","author":[{"given":"Ana S.","family":"Serras","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa","place":["Lisbon, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9rgio P.","family":"Cam\u00f5es","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa","place":["Lisbon, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Vitorino","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Mass Spectrometry Center, Department of Chemistry, University of Aveiro","place":["Aveiro, Portugal"]},{"name":"Department of Surgery and Physiology, Cardiovascular R&D Center, Faculty of Medicine, University of Porto","place":["Oporto, Portugal"]},{"name":"Department of Medical Sciences, Institute of Biomedicine iBiMED, University of Aveiro","place":["Aveiro, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana P.","family":"Miranda","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa","place":["Lisbon, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1016\/j.jhep.2019.02.014","article-title":"EASL clinical practice guidelines: drug-Induced liver injury","volume":"70","author":"Andrade","year":"2019","journal-title":"J. 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