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Oxidative stress plays a critical role in the host defense against\n                    <jats:italic>Mtb<\/jats:italic>\n                    . However, the mechanisms by which\n                    <jats:italic>Mtb<\/jats:italic>\n                    modulates redox homeostasis to evade immune responses remain poorly understood. In this study, we primarily identified a pathogen-responsive long noncoding RNA, LINC02528, which was selectively upregulated in peripheral blood mononuclear cells (PBMCs) from tuberculosis (TB) patients. In\n                    <jats:italic>Mtb<\/jats:italic>\n                    -infected macrophages, LINC02528 dynamically relocalizes from the nucleus to the cytoplasm. Functionally, CRISPR-Cas9-mediated knockout (KO) of LINC02528 in macrophages resulted in reduced\n                    <jats:italic>Mtb<\/jats:italic>\n                    survival concurrent with an elevated IL-1\u03b2 expression. Importantly, these antimicrobial effects were abrogated by IL-1 receptor antagonist (IL-RA) treatment. Interestingly, LINC02528 was found to directly bind to TOMM22, a mitochondrial outer membrane translocase, as validated by co-localization analysis using in situ hybridization of lung tissue sections from a TB patient. The ECAR results revealed that LINC02528 deficiency significantly increased glycolysis and elevated\n                    <jats:italic>Mtb<\/jats:italic>\n                    -induced mitochondrial ROS (mtROS) production. Notably, TOMM22 knockdown phenocopied LINC02528 deletion effects, suggesting functional interdependence in modulating mitochondrial dynamics and the host\u2019s anti-TB immunity. Collectively, our findings reveal a novel strategy wherein\n                    <jats:italic>Mtb<\/jats:italic>\n                    hijacks the lncRNA-mitochondrial axis to rewire redox-metabolic checkpoints to favor immune evasion. Targeting LINC02528 could dually disrupt the pathogen-permissive redox balance and activate mtROS-IL-1\u03b2-mediated antimicrobial defense, offering novel therapeutic avenues for TB.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013810","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T18:35:20Z","timestamp":1766514920000},"page":"e1013810","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Mycobacterium tuberculosis manipulates LINC02528 in macrophages to modulate anti-tuberculosis metabolic immunity"],"prefix":"10.1371","volume":"21","author":[{"given":"Yuzhong","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kehong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siwei","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenfei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialou","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningjian","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyan","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlong","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2101-9013","authenticated-orcid":true,"given":"Xinchun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"ppat.1013810.ref001","unstructured":"WHO. 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