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Although reduced production of reactive oxygen species (ROS) by neutrophils correlates with severe SLE, the specific mechanisms linking ROS deficiency to heightened renal inflammation remain unknown. We aimed to elucidate the role of NOX2-derived ROS in LN pathogenesis and identify potential therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted an in vivo study using a pristane-induced lupus model in\n                      <jats:italic>Ncf1<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      (NOX2-deficient) mice and wild-type controls. We assessed LN severity and characterized renal immune infiltration using flow cytometry and single-cell RNA sequencing (scRNA-seq). We performed transcriptomic analysis to evaluate the function of NOX2-deficient neutrophils. Finally, we tested the therapeutic efficacy of an IL-1 receptor antagonist in ameliorating disease severity in the NOX2-deficient mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      NOX2 deficiency exacerbated LN severity compared to wild-type controls, demonstrated by increased serum anti-dsDNA antibody titers and worsened LN scores. Through scRNA-seq, we identified a distinct, activated neutrophil subset in\n                      <jats:italic>Ncf1<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice featuring a robust interferon signature and high\n                      <jats:italic>Nlrp3<\/jats:italic>\n                      expression. Transcriptomic analysis confirmed the upregulation of core NLRP3 pathway within these cells. Crucially, treating NOX2-deficient mice with an IL-1 receptor antagonist reduced LN activity scores.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our results showed that NOX2 deficiency was associated with the expansion of a highly inflammatory renal neutrophil subset that may contribute to aggravated renal inflammation. These findings suggest that NOX2 functions as a negative regulator of the NLRP3 inflammasome and IL-1\u03b2 blockade represents a promising precision therapeutic strategy for patients with LN who exhibit impaired ROS production.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12929-026-01287-2","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T12:38:44Z","timestamp":1787143124000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NOX2 deficiency exacerbates lupus nephritis through activation of NLRP3 inflammasome in neutrophils"],"prefix":"10.1186","volume":"33","author":[{"given":"Chun-Hsin","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang-Yu","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao-Shan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Yi","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Ren","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Ching","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Kai","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-An","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng-Chieh","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siao-Muk","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daw-Yang","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junne-Ming","family":"Sung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yau-Sheng","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin","family":"Ling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Chang","family":"Shieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"issue":"8","key":"1287_CR1","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1038\/s41590-024-01898-7","volume":"25","author":"GC Tsokos","year":"2024","unstructured":"Tsokos GC. 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