OX40 and Regulatory Marker Alterations in Lesional and Non‐Lesional Keloid Tissues

ABSTRACT Introduction Keloids are pathologic scars that result from abnormal wound healing processes following skin trauma, with a higher prevalence in the Black population. The pathogenesis of keloids is not fully understood, hindering effective treatment options for this highly disfiguring and distressing condition. Methods Biopsies from lesional and non‐lesional skin from keloid patients and healthy skin from age/gender/race‐matched controls were collected and analyzed using RNA‐sequencing, RT‐qPCR, and immunohistochemistry. Spearman analysis was used to evaluate the correlations between biomarker expressions and clinical severity measurements. Results Both keloidal lesions and non‐lesional skin showed a distinct transcriptomic profile compared to healthy skin. Keloids demonstrated significant upregulation of fibrosis‐related markers (e.g., COL10A1, COL11A1, and BMP1). Lesional and/or non‐lesional samples showed significant upregulation of key immune biomarkers belonging to T‐cells (e.g., CD2, CD3D, and CD3E), T‐cell/NK‐cell activation/migration (e.g., CCL19, CCR7, GZMA, GZMB, and GZMK), Th1 (e.g., OASL, MX1, CCL4), Th2 (e.g., IL4R, OX40/TNFRSF4, and OX40L/TNFSF4), and Th17/22 (e.g., S100A7, S100A8, S100A9, and CCL20). Multiple immune biomarkers expression (e.g., CCL2, CXCL1, and S100A7) in lesional and/or non‐lesional skin significantly and positively correlated with keloid severity parameters (e.g., keloid size, distensibility, and number). Conclusion Both lesional and non‐lesional keloid skin show distinct upregulation of immune axes, underscoring the role of inflammation in keloid pathogenesis and pointing to potential novel therapeutic targets.