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Pyroptosis is a proinflammatory form of programmed cell death that is important in response to pathogen infection. The role of pyroptosis in Cp infection and the related mechanisms are still unclear. Here, we reveal that Cp infection induces pyroptosis in macrophages. The inhibition of pyroptosis by disulfiram (DSF) or dimethyl fumarate (DMF) decreases the pathogenicity of Cp in mice and prevents the escape of this pathogen from infected macrophages. In contrast, LPS treatment achieves the opposite results in mice and macrophages infected with Cp. In addition, we revealed that phospholipase D (PLD) is a key virulence factor that induces pyroptosis and subsequently promotes Cp escape and spread in macrophages and confirmed that mutation of the enzyme active site at D66S, G80I, K114N, and G242P weakens PLD-induced pyroptosis. Furthermore, the indispensable role of the NLRP3-GSDMD axis in PLD-induced pyroptosis was confirmed using <jats:italic>Nlrp3<\/jats:italic> knockout (<jats:italic>Nlrp3<\/jats:italic>\n            <jats:sup>\n              <jats:italic>\u2212\/\u2212<\/jats:italic>\n            <\/jats:sup>) and <jats:italic>Gsdmd<\/jats:italic> knockout (<jats:italic>Gsdmd<\/jats:italic>\n            <jats:sup>\n              <jats:italic>\u2212\/\u2212<\/jats:italic>\n            <\/jats:sup>) macrophages. Mechanistically, the PLD of Cp targets mitochondrial sphingomyelins within macrophages, induces cardiolipin externalization to the outer mitochondrial membrane, and releases mtROS, leading to pyroptosis. In conclusion, our data indicate that Cp infection induces mitochondrial dysfunction in macrophages through the secretion of PLD, which targets mitochondrial sphingomyelins and induces NLRP3-GSDMD axis-dependent pyroptosis. Inducing pyroptosis is one of the mechanisms underlying the pathogenesis and transmission of Cp, and inhibiting pyroptosis may be an important strategy for controlling this pathogen.<\/jats:p>","DOI":"10.1186\/s13567-025-01640-7","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T19:34:31Z","timestamp":1760643271000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Corynebacterium pseudotuberculosis phospholipase D targets mitochondrial sphingomyelin and induces NLRP3-GSDMD axis-mediated pyroptosis in macrophages to promote infection"],"prefix":"10.1186","volume":"56","author":[{"given":"Xincan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanyu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hexian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxin","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyue","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongfeng","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangquan","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rendong","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5098-1367","authenticated-orcid":false,"given":"Zuoyong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"1640_CR1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2023.1206187","volume":"14","author":"W Meng","year":"2023","unstructured":"Meng W, Chen S, Huang L, Yang J, Zhang W, Zhong Z, Zhou Z, Liu H, Fu H, He T, Peng G (2023) Isolation, characterization, and pathogenicity assessment of Corynebacterium pseudotuberculosis biovar equi strains from alpacas (Vicugna pacos) in China. 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