{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T07:27:59Z","timestamp":1792481279896,"version":"4.5.0"},"reference-count":108,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T00:00:00Z","timestamp":1715299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (FIS), Spain","award":["Nr. PI20\/00690"],"award-info":[{"award-number":["Nr. PI20\/00690"]}]},{"name":"CIBERHED (ISCIII, Madrid)","award":["Nr. PI20\/00690"],"award-info":[{"award-number":["Nr. PI20\/00690"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Drug induced fatty liver disease (DIFLD) is a form of drug-induced liver injury (DILI), which can also be included in the more general metabolic dysfunction-associated steatotic liver disease (MASLD), which specifically refers to the accumulation of fat in the liver unrelated to alcohol intake. A bi-directional relationship between DILI and MASLD is likely to exist: while certain drugs can cause MASLD by acting as pro-steatogenic factors, MASLD may make hepatocytes more vulnerable to drugs. Having a pre-existing MASLD significantly heightens the likelihood of experiencing DILI from certain medications. Thus, the prevalence of steatosis within DILI may be biased by pre-existing MASLD, and it can be concluded that the genuine true incidence of DIFLD in the general population remains unknown. In certain individuals, drug-induced steatosis is often accompanied by concomitant injury mechanisms such as oxidative stress, cell death, and inflammation, which leads to the development of drug-induced steatohepatitis (DISH). DISH is much more severe from the clinical point of view, has worse prognosis and outcome, and resembles MASH (metabolic-associated steatohepatitis), as it is associated with inflammation and sometimes with fibrosis. A literature review of clinical case reports allowed us to examine and evaluate the clinical features of DIFLD and their association with specific drugs, enabling us to propose a classification of DIFLD drugs based on clinical outcomes and pathological severity: Group 1, drugs with low intrinsic toxicity (e.g., ibuprofen, naproxen, acetaminophen, irinotecan, methotrexate, and tamoxifen), but expected to promote\/aggravate steatosis in patients with pre-existing MASLD; Group 2, drugs associated with steatosis and only occasionally with steatohepatitis (e.g., amiodarone, valproic acid, and tetracycline); and Group 3, drugs with a great tendency to transit to steatohepatitis and further to fibrosis. Different mechanisms may be in play when identifying drug mode of action: (1) inhibition of mitochondrial fatty acid \u03b2-oxidation; (2) inhibition of fatty acid transport across mitochondrial membranes; (3) increased de novo lipid synthesis; (4) reduction in lipid export by the inhibition of microsomal triglyceride transfer protein; (5) induction of mitochondrial permeability transition pore opening; (6) dissipation of the mitochondrial transmembrane potential; (7) impairment of the mitochondrial respiratory chain\/oxidative phosphorylation; (8) mitochondrial DNA damage, degradation and depletion; and (9) nuclear receptors (NRs)\/transcriptomic alterations. Currently, the majority of, if not all, adverse outcome pathways (AOPs) for steatosis in AOP-Wiki highlight the interaction with NRs or transcription factors as the key molecular initiating event (MIE). This perspective suggests that chemical-induced steatosis typically results from the interplay between a chemical and a NR or transcription factors, implying that this interaction represents the primary and pivotal MIE. However, upon conducting this exhaustive literature review, it became evident that the current AOPs tend to overly emphasize this interaction as the sole MIE. Some studies indeed support the involvement of NRs in steatosis, but others demonstrate that such NR interactions alone do not necessarily lead to steatosis. This view, ignoring other mitochondrial-related injury mechanisms, falls short in encapsulating the intricate biological mechanisms involved in chemically induced liver steatosis, necessitating their consideration as part of the AOP\u2019s map road as well.<\/jats:p>","DOI":"10.3390\/ijms25105203","type":"journal-article","created":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T09:22:52Z","timestamp":1715332972000},"page":"5203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Drug-Induced Fatty Liver Disease (DIFLD): A Comprehensive Analysis of Clinical, Biochemical, and Histopathological Data for Mechanisms Identification and Consistency with Current Adverse Outcome Pathways"],"prefix":"10.3390","volume":"25","author":[{"given":"Ernesto","family":"L\u00f3pez-Pascual","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Valencia, 46010 Valencia, Spain"},{"name":"Joint Research Unit in Experimental Hepatology, Health Research Institute La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3254-7372","authenticated-orcid":false,"given":"Ivan","family":"Rienda","sequence":"additional","affiliation":[{"name":"Pathology Department, Hospital Universitario y Polit\u00e9cnico La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6091-0888","authenticated-orcid":false,"given":"Judith","family":"Perez-Rojas","sequence":"additional","affiliation":[{"name":"Pathology Department, Hospital Universitario y Polit\u00e9cnico La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Rapisarda","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Valencia, 46010 Valencia, Spain"},{"name":"Joint Research Unit in Experimental Hepatology, Health Research Institute La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9902-8868","authenticated-orcid":false,"given":"Guillem","family":"Garcia-Llorens","sequence":"additional","affiliation":[{"name":"Joint Research Unit in Experimental Hepatology, Health Research Institute La Fe, 46026 Valencia, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4914-5804","authenticated-orcid":false,"given":"Ramiro","family":"Jover","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Valencia, 46010 Valencia, Spain"},{"name":"Joint Research Unit in Experimental Hepatology, Health Research Institute La Fe, 46026 Valencia, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1179-6430","authenticated-orcid":false,"given":"Jos\u00e9 V.","family":"Castell","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Valencia, 46010 Valencia, Spain"},{"name":"Joint Research Unit in Experimental Hepatology, Health Research Institute La Fe, 46026 Valencia, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,10]]},"reference":[{"key":"ref_1","first-page":"318","article-title":"Deciphering the Liver Enigma: Distinguishing Drug-Induced Liver Injury and Metabolic Dysfunction-Associated Steatotic Liver Disease\u2014A Comprehensive Narrative Review","volume":"2","year":"2023","journal-title":"Explor. 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