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In this study, we elucidated the involvement of the CXCL2\u2010PI3K\/AKT\/NF\u2010\u03baB signalling axis in the abnormal activation of neutrophils in SLE using transcriptome analysis and functional experiments. Transcriptomic profiling revealed that CXCL2 expression is significantly upregulated in SLE patients, contributing to the activation of key inflammatory pathways and the expression of pro\u2010inflammatory cytokines and chemokines. In\u00a0vitro and in\u00a0vivo experiments confirmed that CXCL2 promotes the transcription of inflammatory factors by activating the PI3K\/AKT\/NF\u2010\u03baB pathway, and inhibitors targeting this signalling axis effectively reduced inflammation. Furthermore, neutrophils from SLE patients exhibited a \u2018pre\u2010activated\u2019 state under CXCL2 stimulation, potentially due to epigenetic or metabolic alterations. The functional relevance of CXCL2 was further validated in\u00a0vivo, where knockout of CXCL2 or depletion of neutrophils reduced tissue damage and inflammatory responses. This study highlights the importance of the CXCL2\u2010PI3K\/AKT\/NF\u2010\u03baB signalling axis in SLE and suggests that targeting CXCL2 or neutrophil\u2010specific markers could provide novel therapeutic strategies for managing SLE. Future research should explore the heterogeneity of neutrophil subpopulations in SLE and the role of metabolic reprogramming in exacerbating inflammation, further refining potential targeted therapies.<\/jats:p>","DOI":"10.1111\/imm.70060","type":"journal-article","created":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T13:47:44Z","timestamp":1762609664000},"page":"512-525","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp>CXCL2<\/scp>\n                    \u2010\n                    <scp>PI3K<\/scp>\n                    \/\n                    <scp>AKT<\/scp>\n                    \/\n                    <scp>NF<\/scp>\n                    \u2010\n                    <scp>\u03baB<\/scp>\n                    Signalling Axis Drives Neutrophil Activation and Inflammation in Systemic Lupus Erythematosus: Implications for Targeted Therapeutic Strategies"],"prefix":"10.1111","volume":"177","author":[{"given":"Chang","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Dermatology The Second Affiliated Hospital of Kunming Medical University  Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Dermatology The Second Affiliated Hospital of Kunming Medical University  Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinwei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Dermatology The Second Affiliated Hospital of Kunming Medical University  Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun jing","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Dermatology Kunming Children's Hospital  Kunming 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