BACKGROUNDKeloid is a benign skin tumor that result from abnormal wound healing and excessive collagen deposition. The pathogenesis is believed to be linked to genetic predisposition and immune imbalance, although the precise mechanisms remain poorly understood. Current therapeutic approaches may not consistently yield satisfactory outcomes and are often accompanied by potential side effects and risks. The high recurrence rate and refractory nature of keloid nodules present significant challenges and uncertainties in their management. Given the lack of effective treatment strategies, it is essential to identify key molecular pathways and potential therapeutic targets for keloid.OBJECTIVEThis study aimed to identify the potential pathogenic mechanisms, hub genes, and immune cell involvement in keloid formation, with the goal of providing novel insights for targeted therapies.METHODSWe utilized a combination of bulk RNA sequencing to analyze gene expression profiles in keloid tissues. Differentially expressed genes (DEGs) were identified and subjected to pathway enrichment analysis to reveal key biological processes involved in keloid pathogenesis. Mendelian randomization was performed to investigate the causal relationship between genetic factors and keloid formation, identifying potential hub genes. Immune infiltration analysis was conducted to determine the role of specific immune cells in keloid development. Subsequently, Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were performed to investigate the functional pathways associated with the hub genes. Network analysis was employed to identify transcription factors, miRNAs, and potential drugs in the Connectivity Map associated with the hub genes. Single-cell RNA sequencing was also used to identify cell-specific expression patterns of these genes.RESULTSPathway enrichment analysis highlighted the association of keloid pathogenesis with cell proliferation and division, providing insights into the molecular processes involved. Mendelian randomization revealed that DUSP1 acts as an inhibitor of keloid formation, while HOXA5 promotes keloid pathogenesis. Immune infiltration analysis suggested that mast cells and macrophages play critical roles in the disease's progression. Based on hub gene analysis, the IL17 signaling pathway emerged as a key pathway implicated in keloid development. Further drug prediction models identified 9-methyl-5H-6-thia-4, 5-diaza-chrysene-6, 6-dioxide, zebularine, temozolomide and valproic acid targeting these hub genes.CONCLUSIONDUSP1 and HOXA5 are hub genes in keloid pathogenesis, with DUSP1 acting as an inhibitor and HOXA5 as a promoter of disease progression. Targeting the regulatory networks associated with these genes could provide novel therapeutic strategies. Mast cells and macrophages are identified as critical immune cell types involved in the disease process. Additionally, the IL17 signaling pathway plays a crucial role in keloid development, highlighting its potential as a therapeutic target. These findings suggest that a multi-target approach focusing on these pathways could offer effective treatment options for keloid patients.