{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:06:53Z","timestamp":1789049213637,"version":"build-2803163510"},"reference-count":55,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>NF-\u03baB p65 (RelA) is a key regulator of inflammation, immunity, and stress responses. Recent evidence indicates that alternative p65 isoforms may diversify NF-\u03baB signaling, but their functions remain largely unexplored. We previously identified a novel splice variant, p65 iso5, which contains an additional upstream exon and displays distinct molecular properties, including the ability to interact with dexamethasone in a glucocorticoid receptor-dependent manner. Here, we define the transcriptional programs regulated by p65 iso5 using RNA-seq analysis of HeLa cells expressing either p65 iso5 or canonical p65, with or without dexamethasone treatment. Under basal conditions, p65 iso5 expression was associated with reduced expression of genes involved in type I interferon and antiviral pathways as compared to the effects of canonical p65, while genes involved in translation, ribosome biogenesis, and metabolic activity were not reduced as with p65. Upon dexamethasone stimulation, p65 iso5 expression was associated with extensive transcriptome remodeling characterized by suppression of biosynthetic and proliferative programs and activation of metabolic and stress-adaptive pathways. Comparative analyses reveal that glucocorticoid responses are strongly isoform-dependent, with p65 iso5 expression being associated with distinct gene expression networks supported by distinct protein\u2013protein interaction hubs. p65 iso5 is overexpressed in cirrhotic and hepatocellular carcinoma tissues as well as in high-grade colon tumors, suggesting clinical relevance. Our findings identify p65 iso5 as a context-dependent NF-\u03baB modulator with unique transcriptional and metabolic functions and potential relevance in inflammation-associated diseases and cancer.<\/jats:p>","DOI":"10.3390\/cells15181643","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T13:04:57Z","timestamp":1789045497000},"page":"1643","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The NF-\u03baB Isoform p65 iso5 Is Associated with Distinct Transcriptional Programs and Signaling Pathways"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9767-679X","authenticated-orcid":false,"given":"Gaetano","family":"Spinelli","sequence":"first","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0214-3537","authenticated-orcid":false,"given":"Ilaria","family":"Cosentini","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3335-1726","authenticated-orcid":false,"given":"Giuseppa","family":"Biddeci","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Judit","family":"Mihaly-Bison","sequence":"additional","affiliation":[{"name":"Center for Physiology and Pharmacology, Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Schwarzspanierstra\u00dfe 17, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7710-4735","authenticated-orcid":false,"given":"Gioacchin","family":"Iannolo","sequence":"additional","affiliation":[{"name":"Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Via E. Tricomi 5, 90127 Palermo, Italy"},{"name":"Department of Medicine and Surgery, Universit\u00e0 degli Studi di Enna \u201cKore\u201d, 94100 Enna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Giovanni","family":"Duro","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1266-0017","authenticated-orcid":false,"given":"Carmela","family":"Zizzo","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2470-7030","authenticated-orcid":false,"given":"Paolo","family":"Colomba","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6586-3507","authenticated-orcid":false,"given":"Johannes A.","family":"Schmid","sequence":"additional","affiliation":[{"name":"Center for Physiology and Pharmacology, Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Schwarzspanierstra\u00dfe 17, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8085-7538","authenticated-orcid":false,"given":"Francesco","family":"Di Blasi","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. 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