{
  "abstract": "Host oxysterols coordinate macrophage cholesterol homeostasis and antimicrobial defense, but whether pathogens directly target oxysterol signaling is unknown. Here, we identify pathogen-mediated enzymatic oxysterol inactivation as a mechanism by which Mycobacterium tuberculosis (Mtb) subverts host cholesterol metabolism. Mtb oxidizes the endogenous oxysterols 27-hydroxycholesterol (27-HC) and 3{beta}-hydroxycholest-5-enoic acid (3{beta}-HCA) into 3-oxo-{Delta}4 metabolites. Sputum lipidomics across TB cohorts on three continents revealed an active-disease signature characterized by 27-HC depletion and accumulation of 27-hydroxycholest-4-en-3-one (27-HCO) and 3-oxocholest-4-enoic acid (3O-CA), which normalized with treatment. In infected human macrophages, Mtb 3{beta}-hydroxysteroid dehydrogenase (3{beta}-Hsd) generated 27-HCO. Unlike their parent oxysterols, 27-HCO and 3O-CA did not activate liver X receptor (LXR), and 3O-CA failed to suppress sterol regulatory element-binding protein 2 (SREBP2) target genes. Accordingly, 3{beta}-Hsd-deficient Mtb did not induce macrophage cholesterol retention, a phenotype restored by LXR antagonism. Thus, Mtb enzymatically inactivates host oxysterols, disrupting macrophage cholesterol homeostasis and generating treatment-responsive metabolic signatures in human TB.",
  "abstract_shown": true,
  "affiliations": [
    "Washington University in St. Louis School of Medicine"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "name": "A. Roth"
    },
    {
      "name": "M. Ali Asgari"
    },
    {
      "name": "P. Chandra"
    },
    {
      "name": "J. Muhammad"
    },
    {
      "name": "A. Lopez"
    },
    {
      "name": "S. Bhattacharya"
    },
    {
      "name": "I. A. Williams"
    },
    {
      "name": "B. Edelson"
    },
    {
      "name": "C. W. Goss"
    },
    {
      "name": "D. I. Kotov"
    },
    {
      "name": "M. Qian"
    },
    {
      "name": "D. F. Covey"
    },
    {
      "name": "X. Jiang"
    },
    {
      "name": "W. J. Griffiths"
    },
    {
      "name": "Y. Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "J. A. Philips"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/825m3cdam7pyq.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.04.756586",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.04.756586v1.full",
  "id": "825m3cdam7pyq",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.04.756586v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "microbiology"
    ],
    [
      "openalex",
      "2725|Tuberculosis Research and Epidemiology"
    ]
  ],
  "openalex": "W7220361546",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.04.756586v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-04",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/825m3cdam7pyq.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:07Z",
      "native_id": "10.64898/2026.10.04.756586",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.04.756586v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:microbiology",
      "subfield": "microbiology"
    }
  ],
  "title": "Mycobacterium tuberculosis inactivates host oxysterols to impair macrophage cholesterol homeostasis",
  "title_text": "Mycobacterium tuberculosis inactivates host oxysterols to impair macrophage cholesterol homeostasis",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:07Z",
  "url": "https://research.draconitic.com/paper/825m3cdam7pyq",
  "venue": "bioRxiv",
  "versions": []
}