Establishing the role of vitamin D signalling through metabolomic profiles and adaptive immune markers in keloid pathogenesis in a cohort of dark-skinned South Africans

Abstract

Keloid disease is a chronic fibroproliferative skin disorder characterised by excessive collagen deposition and scar tissue extension beyond the original wound boundaries. It disproportionately affects individuals with darker skin tones, with a particularly high prevalence in African populations; however, region-specific data from South Africa remain limited. While genetic, inflammatory, and fibroblast-mediated mechanisms have been extensively studied, the precise pathways underlying keloid formation remain poorly defined. Emerging evidence highlights vitamin D as a potential immunomodulatory and anti-fibrotic factor influencing both fibroblast function and immune regulation. Given the increased risk of vitamin D deficiency in individuals with darker skin due to reduced cutaneous synthesis, this study investigated the interplay between vitamin D status, immune dysregulation, and metabolic alterations in South African patients with keloid disease. This cross-sectional analytical study included 102 dark-skinned South African patients who were clinically diagnosed with keloid disease. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured using electrochemiluminescence, and participants were categorised into low (<20 ng/mL) and normal (≥20 ng/mL) vitamin D groups. Detailed demographic and phenotypic data were collected, and disease severity was assessed using a validated, clinical scoring system. A subset of 57 patients underwent bead-based multiplex immunoassay profiling of adaptive immune markers, including cytokines, costimulatory molecules, and ligands. Untargeted serum metabolomic analysis was performed on 96 patients using comprehensive two-dimensional gas chromatography–time-of-flight mass spectrometry (GC×GC-TOFMS), with metabolite identification based on the Human Metabolome Database. Non-parametric statistical methods were applied because of data skewness. Comparative analyses between the vitamin D groups and clinical subgroups (based on severity, recurrence, pain, and lesion size) employed Wilcoxon rank-sum and Kruskal–Wallis tests, while partial least squares–discriminant analysis (PLS-DA) was used for metabolomic clustering. The integrated systems biology approach has positioned vitamin D signalling as a central axis linking immune modulation, fibroblast activity, and metabolic homeostasis in keloid disease. This study represents the first integrated assessment of vitamin D status, adaptive immune responses, and metabolomic profiles in South African patients with keloids. By contextualising the findings within an underrepresented high-risk population, this study aimed to identify potential biomarkers and mechanistic pathways relevant to disease susceptibility and progression. Overall, in this study, no association was found between vitamin D status, clinical parameters, altered adaptive immune responses, and metabolic profiles in dark-skinned Africans with keloids. In addition, this study provides novel insights into the immune-metabolic landscape of keloid disease and lays the groundwork for a deeper exploration of metabolic drivers, such as lipids, and immune contributors, including IL-10, IL-7, CD62P, and CD40L, in the pathogenesis of keloids. It also supports the development of personalised therapeutic and preventative strategies for high-risk populations.