biostudies-literatureUnknown27(3)Zhou SPathogenic mycobacteria orchestrate the complex cell populations known as granuloma that is the hallmark of tuberculosis. Foam cells, a lipid-rich cell-type, are considered critical for granuloma formation; however, the causative factor in foam cell formation remains unclear. Atherosclerosis is a chronic inflammatory disease characterized by the abundant accumulation of lipid-laden-macrophage-derived foam cells during which cholesterol 25-hydroxylase (CH25H) is crucial in foam cell formation. Here, we show that <i>M</i>. <i>marinum</i> (<i>Mm</i>), a relative of <i>M</i>. <i>tuberculosis</i>, induces foam cell formation, leading to granuloma development following CH25H upregulation. Moreover, the <i>Mm</i>-driven increase in CH25H expression is associated with the presence of phthiocerol dimycocerosate, a determinant for <i>Mm</i> virulence and integrity. CH25H-<i>null</i> mice showed decreased foam cell formation and attenuated pathology. Atorvastatin, a recommended first-line lipid-lowering drug, promoted the elimination of <i>M. marinum</i> and concomitantly reduced CH25H production. These results define a previously unknown role for CH25H in controlling macrophage-derived foam cell formation and Tuberculosis pathology.iScience109204https://www.ebi.ac.uk/biostudies/studies/S-EPMC10901098biostudies-literaturePathogenic mycobacterium upregulates cholesterol 25-hydroxylase to promote granuloma development via foam cell formation.PMC10901098Xia XZhang DLi DDing CZhou SWang DWang HZhang LHan SJin ZSong JZhou ZHuang WYan BGonzales JVia LEfalsePathogenic mycobacterium upregulates cholesterol 25-hydroxylase to promote granuloma development via foam cell formation.Pathogenic mycobacteria orchestrate the complex cell populations known as granuloma that is the hallmark of tuberculosis. Foam cells, a lipid-rich cell-type, are considered critical for granuloma formation; however, the causative factor in foam cell formation remains unclear. Atherosclerosis is a chronic inflammatory disease characterized by the abundant accumulation of lipid-laden-macrophage-derived foam cells during which cholesterol 25-hydroxylase (CH25H) is crucial in foam cell formation. Here, we show that <i>M</i>. <i>marinum</i> (<i>Mm</i>), a relative of <i>M</i>. <i>tuberculosis</i>, induces foam cell formation, leading to granuloma development following CH25H upregulation. Moreover, the <i>Mm</i>-driven increase in CH25H expression is associated with the presence of phthiocerol dimycocerosate, a determinant for <i>Mm</i> virulence and integrity. CH25H-<i>null</i> mice showed decreased foam cell formation and attenuated pathology. Atorvastatin, a recommended first-line lipid-lowering drug, promoted the elimination of <i>M. marinum</i> and concomitantly reduced CH25H production. These results define a previously unknown role for CH25H in controlling macrophage-derived foam cell formation and Tuberculosis pathology.2024-01-01T00:00:00Z2024 Mar2025-04-22T06:39:59.371Z2025-04-05T21:49:10.025ZS-EPMC109010983842059110.1016/j.isci.2024.109204