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Seven clusters were identified based on clinical, biochemical, and histological features reflecting drug toxic mechanisms:<jats:list list-type=\"simple\">\n              <jats:list-item>\n                <jats:p>Cluster 0 (Control): Drugs with no known steatotic effects or clinical evidence of DIFLD.<\/jats:p>\n              <\/jats:list-item>\n              <jats:list-item>\n                <jats:p>Cluster 1: Drugs with mild pro-steatotic effects, exacerbating existing metabolic steatosis without significant liver enzyme elevation.<\/jats:p>\n              <\/jats:list-item>\n              <jats:list-item>\n                <jats:p>Cluster 2: Compounds causing moderate steatosis with mild hepatocellular damage, occasional enzyme increases, and delayed onset.<\/jats:p>\n              <\/jats:list-item>\n              <jats:list-item>\n                <jats:p>Cluster 3: Agents causing severe mitochondrial dysfunction, ATP depletion, and lactic acidosis, initially without inflammation.<\/jats:p>\n              <\/jats:list-item>\n              <jats:list-item>\n                <jats:p>Cluster 4: Drugs inducing inflammatory steatohepatitis with moderate elevations of liver enzymes (ALT, AST, ALP 90\u2013700 U\/L) but preserved liver function.<\/jats:p>\n              <\/jats:list-item>\n              <jats:list-item>\n                <jats:p>Cluster 5: Drugs causing severe steatohepatitis with marked enzyme elevation (ALT, AST\u2009&gt;\u2009700 U\/L) indicating significant liver injury and inflammation.<\/jats:p>\n              <\/jats:list-item>\n              <jats:list-item>\n                <jats:p>Cluster 6: Compounds causing steatohepatitis with additional cholestasis and elevated bilirubin (&gt;\u200911\u00a0mg\/dL).<\/jats:p>\n              <\/jats:list-item>\n            <\/jats:list>\n          <\/jats:p>\n          <jats:p>Clusters 1 and 2 primarily impair \u03b2-oxidation and mitochondrial respiration, linked to high lipophilicity and typically lower daily doses. Cluster 3 involves mitochondrial DNA depletion and impaired lipid export. Clusters 4 and 5 combine mitochondrial and nuclear receptor disruption, often linked to higher daily doses. Cluster 6 combines steatosis-promoting mechanisms with bile acid transport disruption. This classification improves understanding of DIFLD phenotypes by linking clinical manifestations with drug physicochemical properties and toxicological mechanisms, aiding diagnosis and risk assessment of drug-induced steatosis.<\/jats:p>","DOI":"10.1007\/s00204-025-04178-x","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T18:09:59Z","timestamp":1758046199000},"page":"5075-5091","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Ontogeny of drug-induced fatty liver disease (DIFLD): from key initiating events to disease phenotypes"],"prefix":"10.1007","volume":"99","author":[{"given":"Ernesto","family":"L\u00f3pez-Pascual","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Moreno-Torres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Moro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Rapisarda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Ortega-Vallbona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Serrano-Candelas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Gozalbes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramiro","family":"Jover","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5635-8365","authenticated-orcid":false,"given":"Jos\u00e9 V.","family":"Castell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"key":"4178_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.aohep.2021.100451","volume":"24","author":"L Agoglia","year":"2021","unstructured":"Agoglia L, Carolina Cardoso A, C NL et al (2021) P-88 Evaluation of steatosis and liver fibrosis in patients with psoriasis: the impact of methotrexate and metabolic factors on the severity of the disease. 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