{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:13:31Z","timestamp":1785413611748,"version":"3.56.0"},"reference-count":56,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T00:00:00Z","timestamp":1781395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013948","name":"Tempus Public Foundation-Stipendium Hungaricum Scholarship","doi-asserted-by":"publisher","award":["-"],"award-info":[{"award-number":["-"]}],"id":[{"id":"10.13039\/501100013948","id-type":"DOI","asserted-by":"publisher"}]},{"award":["-"],"award-info":[{"award-number":["-"]}],"id":[{"id":"https:\/\/ror.org\/053mvwx19","id-type":"ROR","asserted-by":"publisher"}]},{"name":"DHET Academic Support Funding","award":["GINOP-2.3.3-15-2016-00020"],"award-info":[{"award-number":["GINOP-2.3.3-15-2016-00020"]}]},{"name":"Ministry of Culture and Innovation of Hungary from the National Research"},{"id":[{"id":"https:\/\/ror.org\/03vhmm238","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Proteomes"],"abstract":"<jats:p>Background: Fresh frozen tissues are considered the gold standard for proteomic analyses due to their superior preservation of protein integrity; however, their use is limited by the logistical and financial requirements of long-term cold storage. Formaldehyde-fixed paraffin-embedded (FFPE) tissues provide a practical alternative, owing to their stability and widespread availability in clinical settings. A critical step in FFPE proteomics is deparaffinization, which traditionally relies on organic solvents such as xylene, along with the efficient reversal of formaldehyde-induced crosslinks. Methods: In this study, we evaluated multiple FFPE protein extraction and digestion workflows including chaotropic, surfactant-based, and detergent-free approaches in combination with xylene-free deparaffinization strategies, using label-free data-independent acquisition (DIA) LC-MS\/MS. Results: Among the tested methods, a chaotropic, reductant, and surfactant-free in-solution digestion workflow demonstrated robust protein and peptide recovery. A modified version of this protocol further improved peptide coverage while maintaining comparable protein depth. The applicability of the optimized workflow was assessed using FFPE needle biopsy samples from control, hepatic steatosis, and liver fibrosis groups. Exploratory proteomic patterns were observed across conditions, with hepatic steatosis associated with early activation of stress-response pathways, while fibrosis showed evidence suggesting altered lipid metabolism. Conclusions: Overall, this study presents a simple, xylene-free, and MS-compatible workflow for FFPE proteomics that is suitable for low-input clinical samples and may support broader application of archival tissues in proteomic research.<\/jats:p>","DOI":"10.3390\/proteomes14020030","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:59:47Z","timestamp":1781503187000},"page":"30","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development of a Xylene-Free Sample Preparation Protocol for Quantitative Proteomics of Clinically Relevant Formaldehyde-Fixed Paraffin-Embedded Needle Biopsy Samples"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2580-1076","authenticated-orcid":false,"given":"Gontse Mabuse","family":"Moagi","sequence":"first","affiliation":[{"name":"Proteomics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Egyetem t\u00e9r 1, H-4032 Debrecen, Hungary"},{"name":"Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Egyetem t\u00e9r 1, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00edvia","family":"Beke","sequence":"additional","affiliation":[{"name":"Health Care Service and Units, Department of Pathology, Faculty of Medicine, University of Debrecen, Egyetem t\u00e9r 1, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor","family":"M\u00e9hes","sequence":"additional","affiliation":[{"name":"Health Care Service and Units, Department of Pathology, Faculty of Medicine, University of Debrecen, Egyetem t\u00e9r 1, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5584-6869","authenticated-orcid":false,"given":"G\u00e1bor","family":"Kecskem\u00e9ti","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, D\u00f3m Square 8, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8278-8038","authenticated-orcid":false,"given":"Zolt\u00e1n","family":"Szab\u00f3","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, D\u00f3m Square 8, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2139-8156","authenticated-orcid":false,"given":"Lilla","family":"Turi\u00e1k","sequence":"additional","affiliation":[{"name":"MTA-HUN-REN TTK Lend\u00fclet (Momentum) Glycan Biomarker Research Group, HUN-REN Research Centre for Natural Sciences, Magyar Tud\u00f3sok K\u00f6r\u00fatja 2, H-1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4373-2175","authenticated-orcid":false,"given":"\u00c9va","family":"Cs\u0151sz","sequence":"additional","affiliation":[{"name":"Proteomics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Egyetem t\u00e9r 1, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bertalan, P.M., Nokhoijav, E., Pap, \u00c1., Neagu, G.C., K\u00e1pl\u00e1r, M., Darula, Z., Kall\u00f3, G., Prokai, L., and Cs\u0151sz, \u00c9. 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