{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:20:05Z","timestamp":1790814005353,"version":"4.1.0"},"reference-count":93,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Parul University","award":["RDC\/IMSL\/148"],"award-info":[{"award-number":["RDC\/IMSL\/148"]}]},{"name":"European Regional Development Funds (FEDER) and AEI.","award":["the General Research Plan grants PID2021-126289OA-I00 and PID2023-149956OB-I00"],"award-info":[{"award-number":["the General Research Plan grants PID2021-126289OA-I00 and PID2023-149956OB-I00"]}]},{"name":"UE and Xunta de Galicia (Spain).","award":["grant ED431C 2022\/46\u2014Competitive Reference Groups. GRC"],"award-info":[{"award-number":["grant ED431C 2022\/46\u2014Competitive Reference Groups. GRC"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sepsis is a life-threatening condition driven by a dysregulated immune response, leading to systemic inflammation and multi-organ failure. Among the key molecular regulators, S100A8\/A9 has emerged as a critical damage-associated molecular pattern (DAMP) protein, amplifying pro-inflammatory signaling via the Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) pathways. Elevated S100A8\/A9 levels correlate with disease severity, making it a promising biomarker and therapeutic target. To unravel the role of S100A8\/A9 in sepsis, we integrate scRNA-seq and RNA-seq approaches. scRNA-seq enables cell-type-specific resolution of immune responses, uncovering cellular heterogeneity, state transitions, and inflammatory pathways at the single-cell level. In contrast, RNA-seq provides a comprehensive view of global transcriptomic alterations, allowing robust statistical analysis of differentially expressed genes. The integration of both approaches enables precise deconvolution of immune cell contributions, validation of cell-specific markers, and identification of potential therapeutic targets. Our findings highlight the S100A8\/A9-driven inflammatory cascade, its impact on immune cell interactions, and its potential as a diagnostic and prognostic biomarker in sepsis. Eight protein targets resulted from the integrative transcriptomics studies (corresponding to S100A8, S100A9, S100A6, NAMPT, FTH1, B2M, KLF6 and SRGN) have been used to predict interaction affinities with 2958 ChEMBL approved drugs, by using a pre-trained AI models (PLAPT) in order to point directions on drug repurposing in sepsis. The strongest predicted interactions have been confirmed with molecular docking and molecular dynamics analysis. This study underscores the power of combining high-throughput transcriptomics to advance our understanding of sepsis pathophysiology and develop precision medicine strategies.<\/jats:p>","DOI":"10.3390\/ijms262211186","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T15:03:15Z","timestamp":1763564595000},"page":"11186","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Integrated Transcriptomic Analysis of S100A8\/A9 as a Key Biomarker and Therapeutic Target in Sepsis Pathogenesis and AI Drug Repurposing"],"prefix":"10.3390","volume":"26","author":[{"given":"Kirtan","family":"Dave","sequence":"first","affiliation":[{"name":"Parul Institute of Applied Sciences, Department of Life Sciences, Parul University, Vadodara 391760, India"},{"name":"Bioinformatics Laboratory, Research & Development Cell, Parul University, Vadodara 391760, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1428-1790","authenticated-orcid":false,"given":"Alejandro","family":"Pazos-Garc\u00eda","sequence":"additional","affiliation":[{"name":"RNASA, CITIC, Computer Science Faculty, University of A Coru\u00f1a, 15071 A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natia","family":"Tamarashvili","sequence":"additional","affiliation":[{"name":"School of Medicine, New Vision University, 0159 Tbilisi, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6194-5329","authenticated-orcid":false,"given":"Jose","family":"V\u00e1zquez-Naya","sequence":"additional","affiliation":[{"name":"RNASA, CITIC, Computer Science Faculty, University of A Coru\u00f1a, 15071 A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5628-2268","authenticated-orcid":false,"given":"Cristian R.","family":"Munteanu","sequence":"additional","affiliation":[{"name":"RNASA, CITIC, Computer Science Faculty, University of A Coru\u00f1a, 15071 A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1586\/eri.12.50","article-title":"Sepsis, severe sepsis and septic shock: Changes in incidence, pathogens and outcomes","volume":"10","author":"Martin","year":"2012","journal-title":"Expert Rev. 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