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Despite evidence of its cytotoxic, genotoxic, endocrine-disrupting, and immunomodulatory effects, its molecular mechanisms of toxicity remain incompletely understood, limiting mechanistically informed risk assessment. As evidence suggests that AOH acts as a multi-kinase inhibitor, this study aimed to expand its kinase target spectrum through integrated computational and experimental approaches. Ligand-based screening of structurally characterized kinase\u2013ligand complexes, followed by molecular docking, molecular dynamics simulations, and free-energy calculations, identified phosphoinositide 3-kinase (PI3K) as a promising target. Functional validation was performed in Caco-2 and HT-29 human intestinal cells exposed to AOH (1\u201320\u00a0\u03bcM) for up to 5\u00a0h. PI3K activity was assessed by quantifying phosphorylation of its downstream effector Akt by Western blot, while AOH metabolism was characterized by liquid chromatography\u2013tandem mass spectrometry. AOH induced a concentration-dependent reduction in phosphorylated Akt in Caco-2 cells at concentrations \u2265 10\u00a0\u03bcM without affecting total Akt, whereas no inhibition was observed in HT-29 cells. Immunofluorescence microscopy revealed decreased global protein phosphorylation in Caco-2 cells but increased phosphorylation in HT-29 cells. These contrasting responses were associated with differences in phase II metabolism, with extensive glucuronidation and sulfation occurring only in HT-29 cells. Computational analyses indicated that these metabolites exhibit reduced fitting into the ATP-binding pocket of PI3K. Overall, the findings identify PI3K as a novel molecular target of AOH and demonstrate that cellular metabolism critically determines its kinase-inhibitory activity.\n                  <\/jats:p>","DOI":"10.1007\/s00204-026-04608-4","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:02:50Z","timestamp":1792792970000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Target fishing in the \u201ckinome\u201d: integrated in silico\/in vitro discovery of novel kinase inhibitory activities of alternariol"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4876-8057","authenticated-orcid":false,"given":"Francesco","family":"Crudo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3666-2631","authenticated-orcid":false,"given":"Lorenzo","family":"Pedroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florinda","family":"Perugino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1485-7805","authenticated-orcid":false,"given":"Florian","family":"Call","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5913-6066","authenticated-orcid":false,"given":"Eszter","family":"Borsos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Rieger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8633-5458","authenticated-orcid":false,"given":"Giorgia","family":"Del Favero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6568-2944","authenticated-orcid":false,"given":"Doris","family":"Marko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Dall\u2019Asta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1901-3317","authenticated-orcid":false,"given":"Luca","family":"Dellafiora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,23]]},"reference":[{"issue":"2","key":"4608_CR1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","volume":"1","author":"MJ Abraham","year":"2015","unstructured":"Abraham MJ, Murtola T, Schulz R et al (2015) Gromacs: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. 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