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Death of Mtb\u2010infected macrophages promotes tissue pathology and releases Mtb to infect other cells, suggesting that inhibiting the death of Mtb\u2010infected 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\u2010infected mouse macrophages\n                    <jats:italic>in vitro<\/jats:italic>\n                    depends on type I interferons (IFNs) and lysosomal membrane permeabilization contributes to cell death. Here, we report that the death of Mtb\u2010infected primary mouse macrophages\n                    <jats:italic>in vitro<\/jats:italic>\n                    became necroptotic in the presence of a pan\u2010caspase inhibitor, benzyloxycarbonyl\u2010Val\u2010Ala\u2010Asp\u2010fluoromethylketone (z\u2010VAD\u2010FMK, hereafter called z\u2010VAD) acting on a target other than caspase\u20108. Macrophages infected with\n                    <jats:italic>Mycobacterium kansasii<\/jats:italic>\n                    or\n                    <jats:italic>Rhodococcus equi<\/jats:italic>\n                    likewise underwent z\u2010VAD\u2010dependent necroptosis. In TB\u2010resistant C57BL\/6 mice, the deficiency of the key necroptosis executioner, mixed lineage kinase domain\u2010like (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\u2010deficiency reduced bacterial burden and pathology after high\u2010dose infection. This report illustrates that off\u2010target action(s) of a caspase\u20108 inhibitor can switch the cell death pathway to necroptosis in macrophages infected with several Gram\u2010positive pathogens and highlights that necroptosis can exacerbate TB. Identifying the target of z\u2010VAD may help to delineate how necrotic lesions form in TB.\n                  <\/jats:p>","DOI":"10.1002\/mlf2.70101","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:14:04Z","timestamp":1790838844000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["z\u2010VAD\u2010FMK triggers macrophage necroptosis during mycobacterial infection via a non\u2010canonical off\u2010target mechanism"],"prefix":"10.1002","author":[{"given":"Rong","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, School of Life Sciences Southern University of Science and Technology Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, School of Life Sciences Southern University of Science and Technology Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, School of Life Sciences Southern University of Science and Technology Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamin","family":"Huang","sequence":"additional","affiliation":[{"name":"Shenzhen Third People's Hospital The Second Affiliated Hospital of Southern University of Science and Technology Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoyi","family":"Huang","sequence":"additional","affiliation":[{"name":"Shenzhen Third People's Hospital The Second Affiliated Hospital of Southern University of Science and Technology Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuju","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Weill Cornell Medicine New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Pfau","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Weill Cornell Medicine New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guobao","family":"Li","sequence":"additional","affiliation":[{"name":"Shenzhen Third People's Hospital The Second Affiliated Hospital of Southern University of Science and Technology Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Nan","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Immunology University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USA"},{"name":"Tumor Microenvironment Center, UPMC Hillman Cancer Center University of Pittsburgh Pittsburgh Pennsylvania USA"},{"name":"Cancer Immunology and Immunotherapy Program UPMC Hillman Cancer Center Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl F.","family":"Nathan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Weill Cornell Medicine New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0853-8473","authenticated-orcid":false,"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, School of Life Sciences Southern University of Science and Technology Shenzhen China"},{"name":"National Clinical Research Center for Infectious Diseases (SHENZHEN) Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/nrmicro2387","article-title":"Evasion of innate immunity by Mycobacterium tuberculosis: is death an exit 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