Integrated skin-lesion transcriptomics prioritises biomarker-candidate host-response genes with pharmacological annotation in leprosy type 1 reaction.

Type 1 reaction (T1R) is an inflammatory complication of leprosy that can affect skin and peripheral nerves, but the lesion-level host-response genes distinguishing reactional from non-reactional borderline disease remain incompletely defined. This study analysed the GSE74481 skin-lesion transcriptomic dataset to compare T1R_R1 lesions with borderline non-reaction lesions and used an evidence-guided prioritisation approach to organise the lesion-derived expression signal. Differential expression analysis of 44 skin-lesion samples identified 3630 differentially expressed genes, including 1979 upregulated and 1651 downregulated genes in T1R_R1 lesions. T1R_R1-upregulated genes were enriched for immune-cell recruitment, interleukin-related signalling, neutrophil activation and extracellular matrix organisation, whereas borderline non-reaction lesions showed stronger epithelial and skin-development programmes. Co-expression and candidate-prioritisation analyses identified 23 final Tier 1 candidates within this broader inflammatory and tissue-remodelling response, including genes linked to myeloid activity, oxidative response, cytokine-interferon-related signalling, endothelial interaction and matrix remodelling. The final candidate signature showed within-cohort separation of T1R_R1 from borderline non-reaction lesions, with an apparent internal AUC of 0.955. Most detected skin-derived candidates also showed the same direction of change in the blood-based GSE269151 T1R contrast, supporting partial cross-tissue direction-of-effect concordance. DGIdb and ChEMBL analyses linked representative candidates, including JAK2, ICAM1 and TNF, to existing drug-gene or target-level annotations, providing pharmacological context for hypothesis generation. These findings define a discovery-stage lesion-derived T1R host-response profile and prioritise candidate genes for future validation in independent lesion cohorts and experimental systems.