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Although the precise molecular mechanisms underlying PLD remain incompletely elucidated, it is documented that PLD is frequently induced by cationic amphiphilic compounds. To facilitate the identification of potential PLD inducers across diverse groups of chemicals, the development of novel high-throughput screening methodologies is imperative. Here, an\n                    <jats:italic>in vitro<\/jats:italic>\n                    human liver cell culture system was established for PLD screening, employing the fluorescence-based LipidTox assay in differentiated HepaRG cells in a\u00a096-well format. Cells were treated with a selection of 35 compounds characterized as either PLD inducers or non-inducers, based on previously published\n                    <jats:italic>in vivo<\/jats:italic>\n                    data. Concentration-response curves of phospholipid accumulation were assessed and the results were compared with existing\n                    <jats:italic>in vivo, in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in silico<\/jats:italic>\n                    datasets. The findings confirm the applicability of the LipidTOX assay in differentiated HepaRG cells as a reliable\n                    <jats:italic>in vitro<\/jats:italic>\n                    -based high-throughput screening method for PLD prediction, achieving an overall predictivity of 86%.\n                  <\/jats:p>","DOI":"10.1007\/s00204-025-04254-2","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T08:01:18Z","timestamp":1765353678000},"page":"1023-1032","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["New approach methodologies for metabolic disruption: a high-throughput human liver cell phospholipidosis assay"],"prefix":"10.1007","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1308-453X","authenticated-orcid":false,"given":"Neele","family":"Wewer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3810-027X","authenticated-orcid":false,"given":"Albert","family":"Braeuning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2699-677X","authenticated-orcid":false,"given":"Dajana","family":"Lichtenstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"issue":"23","key":"4254_CR1","doi-asserted-by":"publisher","first-page":"5533","DOI":"10.1016\/j.febslet.2006.08.061","volume":"580","author":"N Anderson","year":"2006","unstructured":"Anderson N, Borlak J (2006) Drug-induced phospholipidosis. 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