{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:54:39Z","timestamp":1791262479360,"version":"4.1.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Brucellar arthritis is the most common complication of brucellosis, and its chronic progression is closely associated with immune cell dysfunction. Natural killer (NK) cells play a central role in anti-infective immunity; however, their functional status and regulatory mechanisms in brucellar arthritis remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Peripheral blood and synovial tissue samples were collected from healthy controls, as well as from patients with acute-phase and chronic-phase brucellar arthritis. Single-cell RNA sequencing (scRNA-seq), flow cytometry, quantitative real-time PCR (qPCR), JC-1 mitochondrial membrane potential assay, Seahorse metabolic analysis, and Western blotting were employed to systematically evaluate NK cell phenotypes, functions, metabolic profiles, and HIF-1\u03b1\/mTOR pathway activity.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , heat-killed Brucella melitensis 16M (HKBA) was used to stimulate NK-92 cells and HIF-1\u03b1-knockout (KO) cell lines, with mTOR inhibitor intervention, to dissect the regulatory mechanism of the HIF-1\u03b1\/mTOR axis in NK cell metabolic reprogramming.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      scRNA-seq revealed enrichment of NK cells in the synovium of brucellar arthritis patients, with aberrant expression of oxidative phosphorylation (OXPHOS)-related genes. Clinical sample analyses showed that, compared with healthy controls, the proportion of peripheral blood NK cells increased in both acute- and chronic-phase patients; however, NK cells from chronic-phase patients exhibited significantly reduced IFN-\u03b3, Granzyme B, and CD107a degranulation levels. HIF-1\u03b1 protein was consistently overexpressed in patient NK cells, whereas phosphorylated mTOR-pathway proteins (p-PI3K, p-AKT, p-mTOR) were markedly suppressed.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , HKBA treatment inhibited mTOR pathway activity in NK-92 cells in a dose- and time-dependent manner and reduced mitochondrial membrane potential as shown by JC-1 staining. HIF-1\u03b1 knockout significantly restored NK cell cytotoxic function, upregulated OXPHOS- and glycolysis-related gene expression, and improved mitochondrial membrane potential. Transcriptomic sequencing confirmed enrichment of mTOR signaling and energy metabolism gene sets after knockout. Importantly, mTOR pathway inhibition completely blocked the HIF-1\u03b1-knockout-mediated restoration of NK cell function and mitochondrial fitness, indicating that HIF-1\u03b1 primarily drives NK cell metabolic and functional abnormalities through mTOR suppression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Brucella infection induces HIF-1\u03b1 overexpression, which suppresses mTOR signaling and drives metabolic reprogramming of NK cells characterized by impaired OXPHOS and functional exhaustion, thereby promoting chronicity of brucellar arthritis. Targeting the HIF-1\u03b1\/mTOR axis may offer a novel therapeutic strategy for brucellar arthritis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1961240","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:26:29Z","timestamp":1791260789000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic reprogramming of NK cells in chronic brucellar arthritis: role of the HIF-1\u03b1\/mTOR axis"],"prefix":"10.3389","volume":"17","author":[{"given":"Ganggang","family":"Sheng","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, The First Affiliated Hospital of Shihezi 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University","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyu","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengbo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University.","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuejie","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University.","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanxuan","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nannan","family":"Pang","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, 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