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In search of new therapeutic leads, a library of 435 fractions prepared from the Irish marine biorepository was screened against 2 ABC\u2010DLBCL cell lines (TMD8 and OCI<jats:bold>\u2010<\/jats:bold>Ly10) and a non\u2010cancerous control cell line (CB33). Active fractions are prioritized based on potency and selectivity. Among them, fractions from the nudibranch <jats:italic>Antiopella cristata<\/jats:italic> and the ascidian <jats:italic>Diplosoma listerianum<\/jats:italic> exhibit the most potent and selective cytotoxicity. Bioassay\u2010guided fractionation of <jats:italic>D. listerianum<\/jats:italic> led to the identification of the known loliolide and epiloliolide. On the other hand, <jats:italic>A. cristata<\/jats:italic> yielded several bryostatin analogs, including bryostatin 13 and a new natural product, its 18\u2010demethylated analog. Both compounds demonstrated nanomolar cytotoxicity against ABC\u2010DLBCL cell lines with minimal activity in CB33. Transcriptomic profiling showed significant gene expression changes, particularly for the 18\u2010demethylated analog, implicating modulation of key signaling pathways. This study identifies <jats:italic>A. cristata<\/jats:italic> as a novel and highly enriched source of bioactive bryostatins and supports the dietary sequestration hypothesis in nudibranchs, highlighting the value of marine invertebrates as reservoirs of selective anticancer agents for drug discovery.<\/jats:p>","DOI":"10.1002\/cbic.202500500","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T08:10:31Z","timestamp":1757578231000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Screening the Irish Marine Biorepository Identifies a New Bryostatin Analog as Potent Inhibitor of Activated B\u2010Cells Diffuse Large B\u2010Cell Lymphoma"],"prefix":"10.1002","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1313-0360","authenticated-orcid":false,"given":"Laurence K.","family":"Jennings","sequence":"first","affiliation":[{"name":"School of Biological and Chemical Sciences Ryan Institute University of Galway  University Road Galway H91 TK33 Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8615-1568","authenticated-orcid":false,"given":"Filippo","family":"Spriano","sequence":"additional","affiliation":[{"name":"Institute of Oncology Research, Faculty of Biomedical Sciences USI  via F. 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