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RanBP3, as a potential regulator, participates in cell stress, but its specific mechanism of action in TBTB has not been clarified. The mouse and bone marrow-derived macrophages (BMDMs) models were constructed by infecting with\n                    <jats:italic>M. smegmatis<\/jats:italic>\n                    . RanBP3 protein level and the levels of pyroptosis-related proteins were measured by Western blotting (WB). The levels of inflammatory factors were measured by ELISA. Pearson\u2019s correlation analysis was employed to evaluate their correlation with RanBP3, and the interaction of RanBP3\/CCAR2\/SIRT1 was verified by Co-immunoprecipitation (Co-IP). The detection of macrophage pyroptosis and mitophagy was done using flow cytometry, and mitophagy was further assessed by transmission electron microscopy. Bacterial survival in BMDMs was evaluated by colony-forming unit assays. Hematoxylin and eosin (H&amp;E) and Masson staining were used to assess lung tissue damage. RanBP3 was down-regulated in TBTB mucosa. At the cellular level, RanBP3 overexpression alleviated BMDM\u2019s pyroptosis by promoting mitophagy and reduced intracellular bacterial survival, whereas RanBP3 knockdown exacerbated pyroptosis and increased bacterial survival. Mechanistically, RanBP3 competitively binds to CCAR2, disrupts the CCAR2-SIRT1 interaction, and promotes SIRT1 release, thereby activating mitophagy. At the animal level, RanBP3 overexpression promoted mitophagy, alleviated macrophage pyroptosis, and alleviated TBTB, but the SIRT1 inhibitor reversed these effects. RanBP3 mediates the release of SIRT1 through the CCAR2-SIRT1 axis, thereby activating mitophagy and inhibiting pyroptosis, providing a new target for TBTB treatment.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-55696-2","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T13:45:32Z","timestamp":1781185532000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["RANBP3 promotes mitophagy through the CCAR2\/SIRT1 pathway to alleviate pyroptosis in macrophages in TBTB"],"prefix":"10.1038","volume":"16","author":[{"given":"Lei","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin-Zi","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Bin","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Long","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limei","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang-Bao","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"55696_CR1","doi-asserted-by":"publisher","unstructured":"Zhang, Q. et al. 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Science 381, 851\u2013857. https:\/\/doi.org\/10.1126\/science.ade0522 (2023).","journal-title":"Science"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-55696-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-55696-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-55696-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T22:42:02Z","timestamp":1787697722000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-55696-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,11]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["55696"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-55696-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,11]]},"assertion":[{"value":"23 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Approval for this study was obtained from the Ethics Review Committee of Hunan Institute for Tuberculosis Control (Hunan Chest Hospital) (Approval No. LS2024052901), and all patients or their legal guardians provided informed consent for sample collection. The research was conducted according to the World Medical Association Declaration of Helsinki. All experimental procedures and animal handling were performed with the approval of the Animal Care and Use Committee of the Hunan Institute for Tuberculosis Control (Hunan Chest Hospital) (Approval No. LS2024052901), in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.","order":2,"name":"Ethics","label":"Ethical Considerations","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"26707"}}