{
  "abstract": "Macrophages are the predominant cell type infected by Mycobacterium tuberculosis (Mtb) in tuberculosis (TB). Death of Mtb‐infected macrophages promotes tissue pathology and releases Mtb to infect other cells, suggesting that inhibiting the death of Mtb‐infected macrophages could be an adjunctive treatment of TB. Prospects for such an intervention depend on identifying the molecular pathways leading to cell death. We previously reported that the death of Mtb‐infected mouse macrophages in vitro depends on type I interferons (IFNs) and lysosomal membrane permeabilization contributes to cell death. Here, we report that the death of Mtb‐infected primary mouse macrophages in vitro became necroptotic in the presence of a pan‐caspase inhibitor, benzyloxycarbonyl‐Val‐Ala‐Asp‐fluoromethylketone (z‐VAD‐FMK, hereafter called z‐VAD) acting on a target other than caspase‐8. Macrophages infected with Mycobacterium kansasii or Rhodococcus equi likewise underwent z‐VAD‐dependent necroptosis. In TB‐resistant C57BL/6 mice, the deficiency of the key necroptosis executioner, mixed lineage kinase domain‐like (MLKL), did not affect bacterial burden or pulmonary pathology. In contrast, in mice lacking the IFN repressor SP140, which express high levels of type I IFNs after Mtb infection and develop necrotic pulmonary lesions, MLKL‐deficiency reduced bacterial burden and pathology after high‐dose infection. This report illustrates that off‐target action(s) of a caspase‐8 inhibitor can switch the cell death pathway to necroptosis in macrophages infected with several Gram‐positive pathogens and highlights that necroptosis can exacerbate TB. Identifying the target of z‐VAD may help to delineate how necrotic lesions form in TB.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Immunology and Microbiology, School of Life Sciences Southern University of Science and Technology Shenzhen China",
    "Shenzhen Third People's Hospital The Second Affiliated Hospital of Southern University of Science and Technology Shenzhen China",
    "Department of Microbiology and Immunology Weill Cornell Medicine New York New York USA",
    "Department of Immunology University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USA",
    "Tumor Microenvironment Center, UPMC Hillman Cancer Center University of Pittsburgh Pittsburgh Pennsylvania USA",
    "Cancer Immunology and Immunotherapy Program UPMC Hillman Cancer Center Pittsburgh Pennsylvania USA",
    "National Clinical Research Center for Infectious Diseases (SHENZHEN) Shenzhen China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Rong Hu"
    },
    {
      "affs": [
        0
      ],
      "name": "Pei Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Jie Han"
    },
    {
      "affs": [
        1
      ],
      "name": "Jiamin Huang"
    },
    {
      "affs": [
        1
      ],
      "name": "Guoyi Huang"
    },
    {
      "affs": [
        2
      ],
      "name": "Xiuju Jiang"
    },
    {
      "affs": [
        2
      ],
      "name": "Daniel Pfau"
    },
    {
      "affs": [
        1
      ],
      "name": "Guobao Li"
    },
    {
      "affs": [
        3,
        4,
        5
      ],
      "name": "Yi‐Nan Gong"
    },
    {
      "affs": [
        2
      ],
      "name": "Carl F. Nathan"
    },
    {
      "affs": [
        0,
        6
      ],
      "name": "Li Zhang",
      "orcid": "0000-0003-0853-8473"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8cy9r4m9x9bds.bib",
  "cited_by": 0,
  "doi": "10.1002/mlf2.70101",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13628176/",
  "id": "8cy9r4m9x9bds",
  "issns": [
    "2097-1699",
    "2770-100X"
  ],
  "landing_url": "https://doi.org/10.1002/mlf2.70101",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2725|Tuberculosis Research and Epidemiology"
    ]
  ],
  "openalex": "W7215101656",
  "pdf_url": "https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/mlf2.70101",
  "pmcid": "PMC13628176",
  "pmid": "42824841",
  "published": "2026-10-01",
  "publisher": "Wiley",
  "ris": "https://research.draconitic.com/paper/8cy9r4m9x9bds.ris",
  "sources": [
    {
      "first_seen": "2026-11-02T12:23:13Z",
      "native_id": "PMC13628176",
      "source": "pmc",
      "url": "https://doi.org/10.1002/mlf2.70101"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2725|Tuberculosis Research and Epidemiology",
      "subfield": "infectious-disease"
    }
  ],
  "title": "z‐VAD‐FMK triggers macrophage necroptosis during mycobacterial infection via a non‐canonical off‐target mechanism",
  "title_text": "z‐VAD‐FMK triggers macrophage necroptosis during mycobacterial infection via a non‐canonical off‐target mechanism",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:20:20Z",
  "url": "https://research.draconitic.com/paper/8cy9r4m9x9bds",
  "venue": "mLife",
  "versions": []
}