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Adipose-derived mesenchymal stem cells (ASCs) represent a promising therapeutic option due to their regenerative and immunomodulatory properties, which may be further enhanced through specific priming strategies. In this study, primary human ASCs were exposed to interleukin-1 beta (IL1\u03b2), interferon-gamma (IFN\u03b3), or hypoxic priming, and subsequently analyzed using a multi-omics approach integrating RNA sequencing, proteomics of secretome, and exosomal miRNA profiling. Differential gene expression, protein abundance, and miRNA signatures were assessed together with functional enrichment and network analyses. IL1\u03b2 priming induced marked transcriptional reprogramming of ASCs, while hypoxia and IFN\u03b3 priming produced limited changes. IL1\u03b2 also profoundly reshaped the ASC secretome and exosomal miRNA cargo, revealing coordinated regulation of pathways involved in immune modulation and cartilage remodeling. In contrast, the other priming conditions showed minimal and less integrated molecular effects. Overall, IL1\u03b2 priming consistently generated a multi-layered molecular signature linking immunoregulatory and regenerative pathways. These findings suggest that IL1\u03b2 priming enhances the functional properties of ASCs and provides mechanistic insight supporting their potential use in osteoarthritis therapy.<\/jats:p>","DOI":"10.3390\/cells15121056","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:58:12Z","timestamp":1781053092000},"page":"1056","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Multi-Omics Approach Reveals Interleukin 1 Beta Priming as a Key Driver of Immunomodulatory and Regenerative Programs in Adipose-Derived Stem Cells for Osteoarthritis Therapy"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8922-9909","authenticated-orcid":false,"given":"Vitale","family":"Miceli","sequence":"first","affiliation":[{"name":"Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia Emanuela","family":"Ligotti","sequence":"additional","affiliation":[{"name":"Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4658-722X","authenticated-orcid":false,"given":"Vincenzo","family":"Raffo","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina di Precisione e Rigenerativa e Area Jonica (Di.Me.Pre-J), Universit\u00e0 Degli Studi di Bari, Valenzano, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0410-5814","authenticated-orcid":false,"given":"Silvia","family":"Lopa","sequence":"additional","affiliation":[{"name":"Cell and Tissue Engineering Laboratory, IRCCS Galeazzi-Sant\u2019Ambrogio Hospital, Via Cristina Belgioioso 173, 20157 Milan, 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