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Previously, we have detailed that human B-lp biology is remarkably conserved in the zebrafish using an in vivo chemiluminescent reporter of ApoB (LipoGlo) that does not disrupt ApoB function. Thus, the LipoGlo model is an ideal system for identifying novel mechanisms of ApoB modulation and, due to the ability of zebrafish to generate many progeny, is particularly amenable to large-scale phenotypic drug screening. Here, we report a screen of roughly 3000 compounds that identified 49 unique ApoB-lowering hits. Nineteen hits passed orthogonal screening criteria, and seven were subjected to extensive phenotyping. A licorice root component, enoxolone, significantly lowered B-lps only in animals that express a functional allele of the nuclear hormone receptor Hepatocyte Nuclear Factor 4\u237a (HNF4\u237a). Consistent with this result, inhibitors of HNF4\u237a also reduce B-lp levels. These data demonstrate that mechanism(s) of action can be rapidly determined from a whole-animal zebrafish phenotypic screen. Given the well-documented role of HNF4\u237a in human B-lp biology, these data validate the LipoGlo screening platform for identifying small-molecule modulators of B-lps that play a critical role in a leading cause of worldwide mortality.<\/jats:p>","DOI":"10.7554\/elife.105314","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T12:30:15Z","timestamp":1749126615000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.105314","source":"Crossref","is-referenced-by-count":0,"title":["A whole-animal phenotypic drug screen identifies suppressors of atherogenic lipoproteins"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7383-5530","authenticated-orcid":true,"given":"Daniel J","family":"Kelpsch","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, Johns Hopkins University","place":["Baltimore, United 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