Deciphering the contributions of cuproptosis in the development of hypertrophic scar using single-cell analysis and machine learning techniques

Abstract

Hypertrophic scar (HS) is a chronic inflammatory skin disease characterized by excessive deposition of extracellular matrix, but the exact mechanisms related to its formation remain unclear, making it difficult to treat. This study aimed to investigate the potential role of cuproptosis in the information of HS. To this end, we used single-cell sequencing and bulk transcriptome data, and screened for cuproptosis-related genes (CRGs) using differential gene analysis and machine learning algorithms (random forest and support vector machine). Through this process, we identified a group of genes, including ATP7A, ULK1, and MTF1, as novel therapeutic targets for HS. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to confirm the mRNA expression of ATP7A, ULK1, and MTF1 in both HS and normal skin (NS) tissues. We also constructed a diagnostic model for HS and analyzed the immune infiltration characteristics. Additionally, we used the expression profiles of CRGs to perform subgroup analysis of HS. We focused mainly on fibroblasts in the transcriptional profile at single-cell resolution. By calculating the cuproptosis activity of each fibroblast, we found that cuproptosis activity of normal skin fibroblasts increased, providing further insights into the pathogenesis of HS. We also analyzed the cell communication network and transcription factor regulatory network activity, and found the existence of a fibroblast-centered communication regulation network in HS, where cuproptosis activity in fibroblasts affects intercellular communication. Using transcription factor regulatory activity network analysis, we obtained highly active transcription factors, and correlation analysis with CRGs suggested that CRGs may serve as potential target genes for transcription factors. Overall, our study provides new insights into the pathophysiological mechanisms of HS, which may inspire new ideas for the diagnosis and treatment.

Machine learning and single‐cell transcriptome profiling reveal regulation of fibroblast activation through THBS2/TGFβ1/P‐Smad2/3 signalling pathway in hypertrophic scar

“…HS is a chronic skin condition characterized by the formation of fibrous lesions due to the excessive accumulation of fibroblasts and collagen 28 . This disease is caused by a combination of genetic, biomechanical, metabolic, endocrine and immunological factors 29 .…”

“…HS is a chronic skin condition characterized by the formation of fibrous lesions due to the excessive accumulation of fibroblasts and collagen. 28 This disease is caused by a combination of genetic, biomechanical, metabolic, endocrine and immunological factors. 29 Given its impact on physical, mental and social well‐being, HS has been recognized as a major challenge to global health in terms of unmet functional and psychosocial needs.…”

HSFAS mediates fibroblast proliferation, migration, trans-differentiation and apoptosis in hypertrophic scars via interacting with ADAMTS8

“…Hypertrophic scar (HS), a pathogenic form of scar formation, forms within the original wounded area developed from burns, surgeries or traumatic injuries [23] . Substantial evidence suggests that HS formation is closely related to the abnormally increased activity of fibroblasts [ 24 , 25 ]. However, the detailed mechanism is not fully understood in fibroblasts.…”