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The underlying cellular and molecular mechanisms behind this association remain elusive. Herein, a human skin model to assess the photocarcinogenic effects of HCT is established. Skin biopsies collected from human body donors are treated with HCT and irradiated with 300 mJ\/cm<jats:sup>2<\/jats:sup> low dose UVA or UVB or with 5\u2009J\/cm<jats:sup>2<\/jats:sup> high dose UVA. In HCT-treated biopsies but not in control, low dose UVA irradiation results in activation and nuclear translocation of the tumor-suppressor protein p53 accompanied by an upregulated gene expression of p53-negative regulator <jats:italic>MDM2<\/jats:italic>. High dose UVA additionally provokes DNA damage and initiation of pro-inflammatory gene expression. In contrast, UVB induces pronounced DNA damage, p53 protein activation, gene expression of <jats:italic>MDM2<\/jats:italic> and inflammatory marker genes in both HCT-treated biopsies and untreated control. In summary, in HCT-treated skin biopsies, activation of the p53-MDM2 axis, induction of DNA damage, and inflammatory response depends on UVA-dosage and may influence skin carcinogenesis over time. This human model eliminates the need for animal testing and mitigates species difference, offering a valuable tool for future drug development and safety testing.<\/jats:p>","DOI":"10.1038\/s42003-025-08064-1","type":"journal-article","created":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T19:29:37Z","timestamp":1746559777000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Assessing phototoxic drug properties of hydrochlorothiazide using human skin biopsies"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6946-9825","authenticated-orcid":false,"given":"Mathias","family":"Hohl","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felix","family":"G\u00f6tzinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone","family":"J\u00e4ger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lea","family":"Wagmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6059-1671","authenticated-orcid":false,"given":"Mert","family":"Tokcan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Tschernig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00f6rg","family":"Reichrath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9325-2658","authenticated-orcid":false,"given":"Jan M.","family":"Federspiel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9921-4284","authenticated-orcid":false,"given":"Peter","family":"Boor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4377-6784","authenticated-orcid":false,"given":"Markus R.","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4425-549X","authenticated-orcid":false,"given":"Felix","family":"Mahfoud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2976-2514","authenticated-orcid":false,"given":"Michael","family":"B\u00f6hm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,6]]},"reference":[{"key":"8064_CR1","doi-asserted-by":"crossref","unstructured":"Pedersen, S. 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These authors declare the following competing interests: F.G. has received speaker honoraria from AstraZeneca and has been supported by the German Heart Foundation (F\/61\/21). J.M.F. received funding of the German Cardiology Society during parts of the study (project number: 04\/2022). F.M. is supported by Deutsche Gesellschaft f\u00fcr Kardiologie (DGK), Deutsche Forschungsgemeinschaft (SFB TRR219, Project-ID 322900939), and Deutsche Herzstiftung. Saarland University has received scientific support from Ablative Solutions, Medtronic and ReCor Medical. Until May 2024, F.M. has received speaker honoraria\/consulting fees from Ablative Solutions, Amgen, Astra-Zeneca, Bayer, Boehringer Ingelheim, Inari, Medtronic, Merck, ReCor Medical, Servier, and Terumo. MB reports personal fees from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Edwards, Medtronic, Novartis, Servier, and Vifor. JR received funding from the J\u00f6rg Wolff foundation.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"705"}}