Keloid Pathogenesis Research Articles

Asiatic acid inhibits keloid fibroblast migration and collagen deposition via suppression of STAT3 activation.

Keloid scars impact 4.5% to 16% of the population, causing pain, pruritus, and disfigurement. They are a common, recurrent complication in dermatologic surgery, with limited treatment options. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway has been implicated in keloid formation, presenting a potential therapeutic target. To review the literature published on the role of the JAK/STAT pathway in keloid pathogenesis and treatment. A systematic review of clinical and experimental studies was conducted on October 21, 2024, using PubMed, Cochrane, Embase, MEDLINE, and Web of Science, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies examining JAK/STAT signaling in keloids were independently reviewed. Of 109 retrieved articles, 23 met inclusion criteria (one clinical trial, 22 basic science studies). A trial of tofacitinib, a JAK1/3 inhibitor, showed reduced scar thickness, pruritus, and pain. Preclinical studies demonstrated that JAK2 and STAT3 inhibition reduced fibroblast proliferation and collagen deposition. Systemic side effects remain a concern. The JAK/STAT pathway plays a key role in keloid fibrogenesis. Although JAK inhibitors show promise, further research is needed to confirm efficacy, refine specificity, and minimize systemic risks. Targeted JAK/STAT inhibition may improve keloid treatment in dermatologic surgery.

Keloids, characterized by excessive collagen deposition and recurrence, pose significant therapeutic challenges due to limited mechanistic understanding. Mesenchymal stem cells (MSCs) exhibit potential for keloid management, but their precise mechanisms remain unclear. This study investigated how MSCs modulate extracellular matrix (ECM) remodeling in keloid pathogenesis. Using a co-culture system of human umbilical cord MSCs (UC-MSCs) and immortalized keloid fibroblasts (HDIKFs), we demonstrated that UC-MSCs significantly suppressed HDIKF proliferation (via CCK8 assay) and migration (via wound healing assay). Interestingly, UC-MSCs did not alter keloid xenograft growth in vivo. Mechanistically, quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) revealed selective downregulation of matrix metalloproteinases 9 (MMP9) in HDIKFs co-cultured with UC-MSCs, while MMP1, MMP2, and MMP3 remained unaffected. This suppression was linked to inhibition of the transforming growth factor-β1/SMAD (TGF-β1/SMAD) pathway, evidenced by reduced hypoxia‐inducible factor-1α (HIF-1α) and SMAD2 expression, alongside upregulated interleukin-10 receptor alpha (IL-10RA). Additionally, UC-MSCs did not alter collagen I/III (COL I/III) ratios or phosphatidylinositol‐3‐kinase (PI3K)/protein kinase B (AKT) signaling. These findings highlight that MSCs attenuate keloid fibroblast activity through TGF-β1/SMAD-driven MMP9 suppression and IL-10RA enhancement, offering novel insights into MSC-based strategies for ECM homeostasis. This study underscores MMP9 as a therapeutic target and provides a foundation for refining MSC efficacy in keloid treatment.

Scutellarin attenuates keloid fibroblast progression by targeting EGFR/PI3K/AKT signaling: An integrated network pharmacology and in vitro experimental study.

Keloids are an inflammatory cutaneous condition, which are characterized by fibroproliferative overgrowth of the skin. Although keloids are not life‑threatening, their incidence and recurrence are relatively high, thus decreasing the quality of life of patients due to pain, pruritus and cosmetic reasons. Additionally, the precise molecular mechanisms underlying the pathogenesis of keloids remain largely unexplored, thus limiting the development of therapeutic interventions. To screen the key molecules in keloids, microarray data were selected from three different datasets obtained from the Gene Expression Omnibus database, namely GSE145725, GSE7890 and GSE44270. One differentially expressed gene was identified, periostin (POSTN), which was upregulated in keloid fibroblasts (KFs) compared with normal fibroblasts. Its high expression was further validated in KFs using reverse transcription‑quantitative PCR (RT‑qPCR), western blotting and immunofluorescence staining. Its potential function were explored in keloids through loss-of-function assay. Notably, the EdU incorporation assay and cell cycle assay indicated that POSTN knockdown had limited effects on the proliferation of KFs; however, the RT‑qPCR, western blotting, and RNA sequencing results suggested that POSTN inhibition blocked the JAK‑STAT signaling pathway and decreased the expression levels of various proinflammatory factors in KFs. Additionally, the RT‑qPCR and western blotting results demonstrated that IL‑4 and IL‑13, two significant mediators of T helper 2 (Th2) signaling, could induce POSTN expression in KFs. Notably, IL‑4 receptor (IL‑4R), a receptor for both IL‑4 and IL‑13, could be positively modulated by POSTN through the Reactome enrichment, RT‑qPCR and western blotting analysis. Furthermore, IL‑4R was essential for IL‑4/IL‑13‑induced POSTN upregulation in KFs, thus indicating a positive feedback loop between POSTN and Th2 signaling. Overall, the current study uncovered a novel mechanism of POSTN, which could be associated with keloid inflammation, thus highlighting the POSTN/Th2 feedback loop as a potential therapeutic target for patients with keloids.

Keloids are dermal fibroproliferative skin disorders caused by abnormal wound healing, resulting in impaired skin function and aesthetic defects. Abnormal fibroblast proliferation and excessive collagen deposition are involved in keloid formation. This study investigated the role of fibroblast differentiation in keloid development. Single-cell and bulk RNA sequencing data of keloids were comprehensively analyzed, and 25 clinically relevant differentially expressed fibroblast-differentiation-related genes (DEFDRGs) were identified. Based on DEFDRGs, a keloid diagnostic classification system comprising three subtypes was constructed, indicating that DEFDRGs could serve as therapeutic targets. Additionally, multiple microarray datasets, protein sequencing data, and immunohistochemical analyses of key markers in clinical keloid samples were used for further verification. In conclusion, this study established a molecular classification of keloids based on fibroblast differentiation, contributing to the further understanding of keloid pathogenesis and providing new insights for diagnosis and treatment.

IntroductionKeloids are a complex pathological condition of the skin characterized by abnormal proliferation of fibrous tissue and excessive accumulation of extracellular matrix, typically following inflammation after skin injury. Understanding the regulatory mechanisms of immune cells involved in keloid formation is essential for the development of effective treatments.MethodsThis study integrated publicly available single-cell RNA sequencing (scRNA-seq) data with our own keloid scRNA-seq samples to investigate the role of triaptosis in shaping the immune microenvironment of keloids. We analyzed the composition and functional status of fibroblast and immune cell subpopulations.ResultsImmune cells in keloids, especially CD8+ T cells and macrophages, showed significant heterogeneity under the influence of triaptosis regulatory patterns. These triaptosis-associated immune cell clusters exhibited distinct signaling interference compared to mesenchymal fibroblasts and contributed to keloid development. Furthermore, ELMO2 was identified as a key gene with a potential causal relationship to keloids using Summary-data-based Mendelian Randomization and validated through immunofluorescence staining.ConclusionOur findings reveal the complexity of cell–cell interactions in the keloid immune microenvironment and highlight triaptosis as a potential regulatory mechanism in keloid pathogenesis. The identification of ELMO2 as a key factor offers a promising therapeutic target. This study lays a foundation for developing novel therapeutic strategies and encourages future investigations into the clinical application of triaptosis-related interventions for keloid treatment.

Secreted clusterin inhibits keloid formation by promoting fibroblast apoptosis.

Background:Keloids, benign skin tumors due to connective tissue overgrowth, can be exacerbated by ubiquitin-proteasome system abnormalities through uncontrolled inflammation. This study aimed to use Mendelian randomization (MR) analysis to explore keloid pathogenesis and identify target drugs for treatment.Methods:The single-nucleotide polymorphism identifiers of keloid were obtained from the Open Genome-Wide Association Study database, and ubiquitin-related genes from GeneCards database. Five techniques were used for MR analysis during the research, with the accuracy of MR results evaluated by sensitivity analysis. Then, the R software package coloc was used for colocalization analysis of ubiquitin-related genes and keloid. Subsequently, the Comparative Toxicogenomics Database was used to predict skin complications related to keloid-associated target genes. Also, the Drug-Gene Interaction Database was used to study potential target drugs for target genes, and the mechanism of drug inhibition of keloid formation was explored using the DrugBank, Therapeutic Target Database, and STRING databases.Results:IFNGR1 and RNF187 were significant risk factors for keloid formation. A causal relationship exists between IFNGR1 and chronic skin ulcers (a keloid complication). Moreover, indole-3-carbinol, interferon gamma-1b, and pretomanid (targeting IFNGR1) are potential keloid treatments. Tretinoin can affect the IFNGR1 protein via the AKT1 pathway, inhibiting keloid proliferation.Conclusions:IFNGR1 was associated with the pathogenesis of keloids. Interferon gamma-1b targeting IFNGR1 might be a potential strategy for the treatment of keloids, and this discovery opened up a new direction for the treatment of keloids.

ABSTRACT Background Long non-coding RNAs (lncRNAs) are increasingly recognized in keloid pathogenesis. This study investigates the role and mechanisms of HOXA11-AS in keloid formation. Methods Expression levels of HOXA11-AS and related proteins were measured in keloid tissues and fibroblasts using qRT-PCR, Western blot, and ELISA. Functional assays assessed cell proliferation, migration, fibrosis, and oxidative stress. RIP, ChIP, Co-IP, FISH, and luciferase assays were used to explore interactions among HOXA11-AS, YY1, Nrf2, EZH2, and DNMT1. An in vivo mouse xenograft model validated the findings. Results HOXA11-AS was upregulated in keloids. Silencing HOXA11-AS reduced fibroblast proliferation, migration, fibrosis, and oxidative stress. Its overexpression had the opposite effect, which was reversed by Nrf2 pathway inhibition. HOXA11-AS promoted the methylation of the Nrf2 promoter via DNMT1 recruitment, mediated by EZH2. YY1 enhanced HOXA11-AS transcription by binding to its promoter. The YY1/HOXA11-AS axis was confirmed in vivo. Conclusion YY1-induced HOXA11-AS drives keloid formation by promoting oxidative stress and inflammation through epigenetic suppression of Nrf2 signaling.

0968 Shared gene signatures in keloid pathogenesis across ethnically diverse populations: Insights from scRNA-seq

0908 Unveiling the inflammatory and cardiovascular signatures in keloid pathogenesis through multiomic analysis

0867 The role of schwann cell - macrophage interactions in keloid pathogenesis

Keloids are scars that grow abnormally due to excessive extracellular matrix production by fibroblasts and increased angiogenesis. Chronic tension is implicated in their growth, but the exact pathology remains unclear. This study investigated the increased expression of molecules responsible for sensing pressure in keloids compared with lymphedema, which is also a non‐tumorous fibroproliferative disease caused by another etiology. Higher expression levels of COL1A2, PIEZO2, and POSTN were observed in the keloid group compared with the lymphedema group. PIEZO2 expression levels showed a strong correlation with both COL1A2 (r = 0.9252, 95% CI 0.8474–0.9641, p < 0.001) and POSTN (r = 0.9118, 95% CI 0.8213–0.9575, p < 0.001). Additionally, PIEZO2 expression levels were significantly higher in recurrent keloids than in non‐recurrent keloids (3,032.5 ± 1,090.2 versus 1,241.9 ± 860.7, p = 0.032). Analysis of gene expression at the single‐cell level found upregulation of PIEZO2 in vascular and lymphatic endothelial cells, and a subgroup of fibroblasts. Additionally, COL1A1, COL1A2, COL3A1, and POSTN expression was also increased in the fibroblast subgroup. Furthermore, in fibroblasts with high PIEZO2 expression, extracellular matrix collagen production signaling was augmented. Histological analysis confirmed the presence of PIEZO2‐positive cells in the perivascular stroma active area of keloid tissue, together with inflammatory cells. Therefore, since PIEZO2‐positive cells are highly expressed specifically in keloids and are deeply involved in their recurrence and activity, we propose that the pathogenesis of keloids is constructed by PIEZO2‐positive cells. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Background: Keloids are a challenging fibrotic disorder with limited treatment options. The study sought to examine the underlying mechanisms of keloid pathogenesis, emphasizing the influence of dermal adipocytes and ferroptosis resistance in driving fibrosis.Methods: Single-cell RNA sequencing (scRNA-seq) was employed for determining essential cell populations in keloid tissue. Mechanistic studies assessed iron overload, Reactive Oxygen Species (ROS) exhaustion, and interferon responses in ferroptosis-resistant adipocytes. Glutathione peroxidase 4 (GPX4) expression and TGF-β signaling activation were evaluated in adipocyte-mesenchymal transition (AMT). Paracrine signaling and metabolic symbiosis between adipocytes and fibroblasts were analyzed. Therapeutic interventions (ferroptosis inducer RSL3 and iron chelator deferoxamine DFO) were tested in vivo.Results: Through single-cell RNA sequencing, we identified ferroptosis-resistant dermal adipocytes as key contributors to keloid pathogenesis, exhibiting iron overload, ROS suppression, and impaired interferon responses. These adipocytes demonstrated elevated GPX4 expression, which mechanistically drove AMT via iron-dependent activation of TGF-β signaling pathways. GPX4-activated adipocytes promoted fibroblast collagen production through paracrine signaling while establishing a metabolic symbiosis: adipocytes exported iron via solute carrier family 40 member 1 (SLC40A1) to neighboring fibroblasts, which reciprocally supplied cystine through cystathionine beta-synthase (CBS)/cystinosin, lysosomal cystine transporter (CTNS) to sustain GPX4 activity. This vicious cycle was further amplified by iron/ROS-mediated suppression of interferon signaling, creating a pro-fibrotic feedback loop. Therapeutic targeting with either the ferroptosis inducer RSL3 or iron chelator deferoxamine (DFO) effectively disrupted this pathological network, suppressing GPX4/AMT while restoring interferon responses and attenuating keloid growth in vivo. This study clarifies a new adipocyte-focused mechanism in keloid development and identifies ferroptosis regulation as a potential treatment approach for this persistent condition.Conclusions: This study reveals a novel adipocyte-centered mechanism in keloid pathogenesis driven by GPX4-mediated ferroptosis resistance, metabolic symbiosis, and disrupted interferon signaling. The findings establish ferroptosis modulation (via RSL3 or iron chelation) as a promising therapeutic strategy for keloids, offering potential new treatments for this recalcitrant condition.

Keloids are fibroproliferative scars influenced by genetic predisposition, notably involving the ASAH1 gene, which encodes acid ceramidase. A prior study identified a pathogenic ASAH1 variant (NM_004315.6:c.1202 T > C;NP_004306.3:p.(L401P)) in a Yoruba family with keloids. To investigate ASAH1 variant prevalence, we screened 291 Black patients with keloids in the Genetic Causes of Keloid Formation Study. Although the original variant was not detected, four novel rare ASAH1 variants were identified.None of the fourwerepresent in 718 race-matched controls. Functional predictions using SIFT and PolyPhen were used to predict which rare variants may be damaging. ASAH1 dysfunction is implicated in Farber disease, a lipid storage disorder affecting wound healing. These findings support further investigation into ASAH1's role in keloid pathogenesis and the development of personalized therapeutic approaches.

There is a significant gap in multi-omics studies on keloids, especially concerning the interaction between fibroblasts and super-enhancers (SEs). Identifying novel biomarkers within the epigenetic landscape could greatly improve keloid management. In this study, we investigated gene expression at both transcriptional and translational levels to identify potential biomarkers and employed CUT&Tag technology to validate SE-associated genes and upstream transcription factors (TFs). Through integrated analyses of transcriptomics and proteomics, 10 hub genes that associated with ECM, immune, and metabolic pathways were found. Given the crucial role of fibroblasts in keloid pathogenesis, we further identified five SE-associated genes (SERPINH1 SE, MMP14 SE, COL5A1 SE, COL16A1 SE, and SPARC SE) that exhibit characteristic upregulation in keloids. Analysis of upstream TFs and core transcription regulatory circuitry (CRC) revealed potential master TFs (FOSL2, BACH2, and FOXP1), with FOXP1 emerging as the core TF likely driving pro-fibrotic development through its anti-senescence function. In summary, we anticipate that the outcomes of the integrative omics analysis will facilitate further investigation into the underlying molecular mechanisms of keloid formation and lead to novel strategies for its prevention and management. Specifically inhibiting the anti-senescence function of FOXP1 brings new promise for the treatment of fibrosis-related diseases. Supplementary InformationThe online version contains supplementary material available at 10.1186/s11658-025-00763-1.

Keloids are skin lesions caused by excessive fibrotic reactions, and their pathogenesis is not yet fully understood. Recent studies have shown that the immune microenvironment plays a significant role in the development of keloids. This article reviews the distribution and functions of immune microenvironment-related cells in keloids, including keratinocytes, fibroblasts, mast cells, macrophages, T cells, and stem cells, as well as the interactions between these cells and local cells. The article also explores the impact of several signaling pathways within the immune microenvironment on keloid formation, including the transforming growth factor β pathway (TGF-β), PI3K/Akt/mTOR signaling pathway, Wnt/β-catenin signaling pathway, and Notch signaling pathway. These pathways recruit more immune cells by secreting various cytokines and inflammatory mediators, stimulate fibroblast proliferation and collagen synthesis, ultimately leading to the formation of keloids. By deeply analyzing the roles of cells and their signaling pathways within the immune microenvironment, we can provide potential new targets for the treatment of keloids.

Introduction: Keloid, a fibroproliferative tumor characterized by excessive collagen deposition and fibroblast hyperplasia, lacks effective therapeutic strategies due to unclear molecular mechanisms. Objective: This study aims to elucidate keloid pathogenesis and identify diagnostic biomarkers through multi-omics integration. Methods: Single-cell RNA sequencing (ScRNA-seq) data (GSE163973) and bulk RNA sequencing datasets (GSE162904/GSE145725) were analyzed. Fibroblast subpopulations were identified using the Seurat R package, and cell&amp;ndash;cell interactions were explored using the CellChat R package. Weighted gene co-expression network analysis (WGCNA) was employed to identify key gene modules in fibroblasts. Hub genes were screened using Lasso regression and validated through machine learning algorithms and a gene-immune convolutional neural network (CNN). Immune infiltration patterns were evaluated using the MCP-counter and Immuno-Oncology Biological Research R packages. Results: ScRNA-seq analysis revealed eight distinct cell subtypes within keloid tissues, with fibroblasts significantly enriched compared to normal skin. Fibroblast clusters 1 and 5 exhibited elevated midkine&amp;ndash;low-density lipoprotein receptor-related protein 1-mediated interactions and enhanced differentiation activity. WGCNA identified three critical modules&amp;mdash;&amp;ldquo;brown,&amp;rdquo; &amp;ldquo;cyan,&amp;rdquo; and &amp;ldquo;yellow&amp;rdquo;&amp;mdash;linked to fibroblast activation. Lasso regression produced an eight-gene signature that effectively distinguished keloid from normal skin (area under the curve = 0.885 &amp;ndash; 0.889). Nonnegative matrix factorization classified keloids into four subtypes, each with distinct immune infiltration profiles correlated with hub gene expression. The gene-immune CNN model achieved 100% sensitivity and 88.9% specificity in diagnostic classification. Conclusion: This study elucidates the molecular mechanisms underlying keloid formation through integrated single-cell and transcriptomic analysis, proposing an eight-gene signature as a potential diagnostic and therapeutic target. The identified keloid subtypes and associated immune infiltration patterns provide novel insights for advancing precision medicine approaches in keloid management.

Secreted phosphoprotein 1 promotes the activation of keloid fibroblasts via the CD44/TGF-β1/Smad pathway.