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This study demonstrates that Spn-derived H\u2082O\u2082, primarily produced by pyruvate oxidase (SpxB), inhibits key tricarboxylic acid (TCA) cycle enzymes (aconitase, glutamate dehydrogenase, and \u03b1-ketoglutarate dehydrogenase) in lung epithelial cells, leading to citrate accumulation and diminished NADH production for oxidative phosphorylation. RNA sequencing reveals SpxB-dependent upregulation of glycolytic genes (HIF1A, IER3, HK2, PFKP), restricting pyruvate entry into the TCA cycle and increasing glucose consumption and lactate\/acetate production, indicative of a Warburg-like metabolic shift that may enhance bacterial survival. Notably, mitochondrial membrane potential remains largely preserved, with minimal apoptosis despite Spn-induced stress. These findings uncover a novel mechanism of Spn-driven host metabolic reprogramming, highlighting potential therapeutic targets for pneumococcal diseases.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        <jats:italic toggle=\"yes\">Streptococcus pneumoniae<\/jats:italic>\n                        (Spn) remains a leading cause of community-acquired pneumonia worldwide, yet the mechanisms by which it manipulates host metabolism to promote its survival and pathogenesis are not fully understood. This study reveals a novel metabolic strategy whereby pneumococcus-derived hydrogen peroxide, generated by pyruvate oxidase (SpxB), disrupts the host tricarboxylic acid (TCA) cycle and drives a Warburg-like metabolic shift in lung epithelial cells. By inhibiting key TCA cycle enzymes and rewiring glycolytic gene expression, Spn effectively reprograms host cell metabolism to favor its persistence while minimizing host cell apoptosis and maintaining mitochondrial function. These insights expand our understanding of host-pathogen metabolic interactions and identify potential metabolic vulnerabilities that could be targeted to mitigate tissue damage and improve treatment outcomes in pneumococcal pneumonia.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.02019-25","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T13:48:20Z","timestamp":1761918500000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["Pneumococcal H\u2082O\u2082 reshapes mitochondrial function and reprograms host cell metabolism"],"prefix":"10.1128","volume":"16","author":[{"given":"Anna","family":"Scasny","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02teq1165","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Cell and Molecular Biology, University of Mississippi 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