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Objectives To investigate the proteome of inflammatory foci in CLE, aiming to elucidate the pathological processes occurring at the site of tissue injury within the skin.Methods Skin biopsies from 5 patients with CLE, 4 healthy controls and 2 cases uninvolved skin of CLE patients were investigated (altogether controls). Inflammatory foci were excised using laser capture microdissection and analyzed by tandem mass-spectroscopy. Raw protein data was processed using R (version 4.0+) and DESeq2 package. Cluster analysis was performed using String-Db platform with integrated open AI (ChatGPT). We merged up-and downregulated proteins in search for the top aberrant clusters.Results Study detected 1385 proteins. Significant expression difference was observed in 297 proteins (adj.p<0.05). In CLE 134 proteins were up- and 113 downregulated. Seven clusters containing >2 proteins were identified. Cluster 1 included interferon type I/immune activation and nucleic acid sensing proteins, mediators of leukocyte activation, nucleic-acid metabolism and factors that might increase autoantigen exposure. Multiple stress-response proteins were upregulated; but superoxide dismutase SOD3 - a key protector against oxidative stress - was downregulated. We observed dysregulation in cytoskeleton dynamics and cell migration: proteins governing adhesion, epithelial junctions, and barrier stability were dysregulated. Cluster 2 showed increased expression of structural collagens, proteoglycans, elastic-fibre components, whereas laminins - core constituents of the basement membrane were reduced, indicating extracellular matrix reinforcement with concomitant basement-membrane weakening. Cluster 3 suggested shift in ribosome composition: multiple large subunit ribosomal proteins were abundant, while only one small subunit protein was identified (RPS27) suggesting an imbalanced ribosomal signature and possible translational reprogramming. Cluster 4 included proteins in endoplasmic-reticulum-phagosome pathway, antigen recognition, processing and presentation. Cluster 5 showed downregulation of multiple proteins in histidine metabolism. Cluster 6 included multiple upregulated proteins important for mRNA 3-end processing, pre-mRNA splicing, spliceosome components and regulators, while LSM8, involved in pre-mRNA splicing, was single downregulated. Cluster 7 showed upregulated histone proteins, but MRE11 and PHGDH, important in double-stranded DNA repair were downregulated.Conclusions Integrated analysis of protein expression in CLE inflammatory foci uncovers dysregulation of multiple pathways and offers critical insights in local aberrant biological mechanisms.