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RNA\u2010Seq of in vitro differentiated healthy macrophages (<jats:italic>n<\/jats:italic>\u00a0=\u00a08) after sustained myelin\u2010loading to assess the metabolic shift associated with foam cell formation. RNA\u2010Seq analysis of genes linked to lipid degradation and export in MS\u2010275\u2010treated human HAP1 cells and RT\u2010qPCR analysis of HAP1 cells knocked out for individual members of class I HDACs or the corresponding enzymatically inactive knock\u2010in mutants. Investigation of intracellular lipid\/myelin content after MS\u2010275 treatment of myelin\u2010laden human foam cells. Analysis of disease characteristic very long\u2010chain fatty acid (VLCFA) metabolism and inflammatory state in MS\u2010275\u2010treated X\u2010ALD macrophages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Enlarged foam cells coincided with a pro\u2010inflammatory, lesion\u2010promoting phenotype in <jats:italic>postmortem<\/jats:italic> tissue of MS and cerebral ALD patients. Healthy in vitro myelin laden foam cells upregulated genes linked to LXR<jats:italic>\u03b1<\/jats:italic>\/PPAR<jats:italic>\u03b3<\/jats:italic> pathways and mimicked a program associated with tissue repair. Treating these cells with MS\u2010275, amplified this gene transcription program and significantly reduced lipid and cholesterol accumulation and, thus, foam cell formation. In macrophages derived from X\u2010ALD patients, MS\u2010275 improved the disease\u2010associated alterations of VLCFA metabolism and reduced the pro\u2010inflammatory status of these cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These findings identify class I\u2010HDAC inhibition as a potential novel strategy to prevent disease promoting foam cell formation in CNS inflammation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51200","type":"journal-article","created":{"date-parts":[[2020,9,30]],"date-time":"2020-09-30T16:46:36Z","timestamp":1601484396000},"page":"2161-2177","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Targeting foam cell formation in inflammatory brain diseases by the histone modifier 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