CXCL2 ‐ PI3K / AKT / NF ‐ κB Signalling Axis Drives Neutrophil Activation and Inflammation in Systemic Lupus Erythematosus: Implications for Targeted Therapeutic Strategies

ABSTRACT Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by chronic inflammation and immune dysregulation, with neutrophils playing a critical role in disease pathogenesis. In this study, we elucidated the involvement of the CXCL2‐PI3K/AKT/NF‐κB 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‐inflammatory cytokines and chemokines. In vitro and in vivo experiments confirmed that CXCL2 promotes the transcription of inflammatory factors by activating the PI3K/AKT/NF‐κB pathway, and inhibitors targeting this signalling axis effectively reduced inflammation. Furthermore, neutrophils from SLE patients exhibited a ‘pre‐activated’ state under CXCL2 stimulation, potentially due to epigenetic or metabolic alterations. The functional relevance of CXCL2 was further validated in vivo, where knockout of CXCL2 or depletion of neutrophils reduced tissue damage and inflammatory responses. This study highlights the importance of the CXCL2‐PI3K/AKT/NF‐κB signalling axis in SLE and suggests that targeting CXCL2 or neutrophil‐specific 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.