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Although biologic therapies have significantly improved outcomes for patients with moderate to severe disease, certain anatomical regions often remain resistant to treatment. Given the observed variability in treatment response depending on lesion location, we aimed to explore anatomical site-specific differences in the skin transcriptome. Methods: Using a non-invasive tape-stripping technique, we collected and analyzed 44 psoriatic plaque samples from the scalp, trunk, upper extremities, and lower extremities, followed by differential gene expression and gene ontology analysis. Moreover, we included 80 samples obtained from healthy skin biopsies (GSE54456) to conduct an inflammation-controlled approach. We used two different approaches, an intra-disease approach, in which anatomically different sites were compared, and an inflammation-controlled approach, in which the inflammation bias was reduced. Results: Our findings indicate distinct molecular signatures and biological pathways across different anatomical sites, including differential expression of SERPINB7 and miRNAs such as miR-205 and miR-203a, along with different pathways. Furthermore, our results emphasized the heterogeneity of psoriasis and suggested that site-specific molecular mechanisms may contribute to variations in disease manifestation and treatment response. Conclusions: This study highlights the need for more personalized, site-specific therapeutic strategies. It should be considered an exploratory pilot study, and larger studies with paired samples from multiple anatomical sites within the same patients are needed to validate the identified transcriptomic signatures.<\/jats:p>","DOI":"10.3390\/jcm15114034","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T16:06:08Z","timestamp":1779465968000},"page":"4034","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptomic Profiling of Psoriatic Lesions by Tape-Stripping Reveals Site-Specific Differences"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1954-1416","authenticated-orcid":false,"given":"Maru\u0161ka","family":"Marovt","sequence":"first","affiliation":[{"name":"Department of Dermatovenerology, University Medical Centre Maribor, 2000 Maribor, Slovenia"},{"name":"Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7921-6565","authenticated-orcid":false,"given":"Martina","family":"Kru\u0161i\u010d","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4208-9683","authenticated-orcid":false,"given":"Mario","family":"Gorenjak","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pij Bogomir","family":"Marko","sequence":"additional","affiliation":[{"name":"Department of Dermatovenerology, University Medical Centre Maribor, 2000 Maribor, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1624-9428","authenticated-orcid":false,"given":"Uro\u0161","family":"Poto\u010dnik","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia"},{"name":"Faculty of Chemistry and Chemical Engineering, University of Maribor, 2000 Maribor, Slovenia"},{"name":"Department for Science and Research, University Medical Centre Maribor, 2000 Maribor, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S0140-6736(07)61128-3","article-title":"Pathogenesis and clinical features of psoriasis","volume":"370","author":"Griffiths","year":"2007","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1001\/jama.2020.4006","article-title":"Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review","volume":"323","author":"Armstrong","year":"2020","journal-title":"JAMA"},{"key":"ref_3","first-page":"1","article-title":"Rapid Efficacy of riSankizumab in pretibial psoriasis invOLVEment: RESOLVE","volume":"13","author":"Bernardini","year":"2024","journal-title":"Drugs Context"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"39","DOI":"10.2147\/BTT.S252578","article-title":"Biologic Treatments of Psoriasis: An Update for the Clinician","volume":"15","author":"Brownstone","year":"2021","journal-title":"Biol. 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