Skin fibrosis is increasingly recognized as an important component of chronic inflammatory skin diseases, contributing to dermal thickening, tissue stiffness, and persistent functional impairment. Although transforming growth factor-β (TGF-β) has long been considered the central mediator of fibrosis, accumulating evidence indicates that interleukin-13 (IL-13), a key cytokine of type 2 immunity, plays a pivotal role in linking chronic inflammation to fibrotic remodeling. Unlike classical scar formation, IL-13-associated fibrosis is characterized by sustained immune activation, continuous extracellular matrix remodeling, and residual tissue plasticity, suggesting that it represents a dynamic and potentially reversible process. In this review, we summarize the current understanding of the mechanisms by which IL-13 promotes skin fibrosis. We discuss direct activation of fibroblasts through the IL-13Rα1/STAT6 pathway, dysregulation of extracellular matrix synthesis and degradation, neuroimmune interactions involving chronic itch and mechanotransduction, macrophage-fibroblast crosstalk, and emerging evidence for fibroblast memory mediated by epigenetic remodeling. Furthermore, we compare the pathological features of IL-13-associated fibrosis across representative skin diseases, including atopic dermatitis, prurigo nodularis, systemic sclerosis, and keloids. This conceptual framework provides a unified perspective on the diverse roles of IL-13 in cutaneous fibrosis and highlights the importance of integrating immunological, mechanical, and stromal mechanisms.

Successful tissue repair depends on the precise orchestration of phase-specific cellular responses alongside sustained activity of multifunctional immune regulators. Mast cells, which have primarily been long regarded as effector cells of allergic reactions, have emerged as pivotal modulators of wound repair. Importantly, mast cell activity exhibits a dual nature: while transient activation supports efficient repair and granulation tissue formation, sustained or excessive activation is associated with pathological fibrosis, hypertrophic scarring and keloid formation. Although many experimental studies and clinical evidences implicate a critical role for mast cells in wound repair, several key questions remain. Specifically, the contributions of distinct mast cell subtypes and the precise temporal dynamics of their mediator release, as well as the intricate molecular crosstalk between mast cells, stromal components, and other infiltrating immune cells remans a subject of active investigation. This review highlights current literature on the multifaceted roles of mast cells across the successive phases of wound-healing, and the specific mechanisms by which mast cells support or impair tissue repair, outlining unresolved questions in the field. Through this discussion, we aim to provide a framework for developing new therapeutic strategies to improve healing outcomes and facilitate better scar management.

Keloids are benign dermal tumors that arise from abnormal wound healing processes following skin lesions. Keloids are present in all human populations but occur most frequently in Africans. A significantly higher incidence is observed in female populations. Consequently, keloid patients not only endure physical burdens caused by symptoms such as pain, pruritus, and burning, but also suffer from psychological distress due to altered appearance, significantly compromising their quality of life. Surgical excision, as one of the various treatment options, demonstrates rapid efficacy but carries an unacceptably high recurrence rate of 40%-100% when used as a standalone therapy. Postoperative radiotherapy (PORT) is a clinically effective measure to reduce recurrence rates of keloid. Nevertheless, studies comparing the effectiveness and underlying mechanisms of distinct radiotherapy modalities for keloid remain absent in the literature. In our study, we performed single-cell RNA sequencing (scRNA-Seq) of primary keloid fibroblasts treated with three kinds of radiotherapy modalities, and unbiased clustering revealed the identification of seven distinct clusters. Among them, the cell proportions of Fib2-CCND1 [high], Fib3-IGFBP7 [high] and Fib 4-APCDD1 [high] increased significantly in the X-ray group, electron beam group and both [90]Sr groups, which are involved in microtubule-associated complex, extracellular matrix organization and oxidative phosphorylation, respectively. In addition, the bioinformatics analysis highlighted the alteration of immune-associated interactions, such as PVR-TNFSF9 and TNFSF9-IL13RA2, and provided a basis for the activation of interferon regulatory factor 1 (IRF1) in all radiotherapy modalities. Then, functional analysis revealed that Ad-IRF1 and pharmacological activation of IRF1 (ATRA and 9-cis-RA) significantly induced apoptosis and suppressed cell viability. Mechanistically, reciprocal regulation between the single-stranded DNA sensors SSBP1 and IRF1 was revealed. Thus, this study illustrates the molecular alterations and driving transcription factors following various radiotherapy modalities at the single-cell resolution. Notably, IRF1 is regulated by SSBP1 and identified as a novel therapeutic target for keloid.

To evaluate clinical outcomes and toxicity of a standardized protocol of immediate (<6 h postoperative) high-dose-rate (HDR) brachytherapy with volumetric planning in patients with keloids.

Keloid disease (KD) is a fibroproliferative skin disorder resulting from abnormal scar formation that causes pain, itching, and decreased quality of life. While multiple KD transcriptomic studies exist, the influence of cell type composition on bulk tissue gene expression is unknown. We characterized fibroblast subtype and immune cell enrichment using bulk RNA-Seq of head and neck keloid and matched adjacent normal skin tissue (MANST) from 14 patients (10 African American and 4 European American). Cell type enrichment was calculated by single sample gene set enrichment analysis. Linear mixed-effects models were employed for 1) differential cell type enrichment across tissue, 2) tissue type-specific associations between fibroblast subtypes and immune cells, and 3) differentially expressed genes (DEGs) across tissue. Validation was conducted in an independent cohort of 8 African Americans. Three fibroblast subtypes and 14 immune cell types were differentially enriched across tissue type. Further, 17 tissue type-specific fibroblast subtype-immune cell enrichment associations were identified, with 14 exhibiting decreased association in keloid tissue relative to MANST. After adjustment for cell type enrichment, MIR31HG and NR4A2 were significant DEGs with the largest positive and negative fold-changes, respectively. By considering cell type enrichment, underlying keloid tissue-specific cell type and gene expression associations were revealed.

Keloid is a fibroproliferative disorder with high recurrence and unclear pathogenesis, lacking effective therapeutic targets. Recent evidence suggests metabolic reprogramming, particularly in heme metabolism, may drive fibrosis. This study investigates the role of heme metabolism, focusing on feline leukemia virus subgroup C receptor 1 (FLVCR1), in keloid pathogenesis and explores its diagnostic and therapeutic potential. We analyzed bulk RNA-seq datasets and single-cell RNA-seq data (scRNA-seq). Differential expression, least absolute shrinkage and selection operator (LASSO), and random forest (RF) models identified heme metabolism-related diagnostic biomarkers. Immune infiltration, single-cell mapping, microRNA (miRNA) network construction, and molecular docking with traditional Chinese medicine compounds were performed. Six heme metabolism-related biomarkers were identified, forming a diagnostic nomogram with high accuracy. FLVCR1, enriched in endothelial cells and melanocytes, correlated negatively with T follicular helper cells, suggesting immunometabolic crosstalk. MiRNA regulatory network analysis revealed five miRNAs co-targeting all six biomarkers. Molecular docking identified (+)-gallocatechin as a high-affinity FLVCR1 ligand. These findings suggest an association between FLVCR1-related heme metabolism and immune alterations in keloid pathogenesis. The biomarker panel showed exploratory diagnostic potential, and (+)-gallocatechin was identified as a candidate FLVCR1-interacting compound requiring further validation. This study reframes keloid within the metabo-fibrotic spectrum and proposes metabolic-immune intervention as a novel therapeutic strategy.

Pathological cutaneous fibrosis, exemplified by hypertrophic scarring and keloid formation, imposes substantial disease burden through persistent pruritus, pain and contracture-induced functional impairment. While the antifibrotic role of gp130 signaling inhibition has been established in visceral organ fibrosis, its therapeutic efficacy in pathological cutaneous fibrosis remains unexplored. Herein, we investigated the effectiveness of gp130 inhibition on cutaneous fibrosis by leveraging the application of Bazedoxifene, a clinically approved selective estrogen receptor modulator recently identified as a gp130 signaling inhibitor. We demonstrate that gp130 signaling is aberrantly activated in human keloid tissues and fibroblasts. In vitro, Bazedoxifene suppressed the fibroblast activation of disease-derived fibroblasts, featured by attenuated cell migration, myofibroblast differentiation and ECM production. In vivo, Bazedoxifene ameliorated dermal fibrosis and ECM deposition in both bleomycin-induced cutaneous fibrosis and keloid xenograft models. Notably, spatial transcriptomic analysis revealed reduced myofibroblast differentiation within fibrotic regions, providing tissue-level evidence for inhibition of fibroblast activation. Transcriptomic analysis revealed suppression of multiple fibrosis-associated signaling pathways following Bazedoxifene treatment, including the PI3K-AKT-mTOR, JAK-STAT, and MAPK pathways, with the PI3K-AKT-mTOR pathway showing the most prominent inhibition. Collectively, these findings establish Bazedoxifene repurposing as a promising therapeutic strategy for cutaneous fibrosis.

Pathological scars (PSs) are characterized by excess dermal collagen deposition and primarily manifest as hypertrophic scars and keloids. The microenvironment of PSs is shaped by a diverse array of cells, collectively forming a profibrotic and proangiogenic niche. Recent advances in high-throughput sequencing have enhanced our understanding of the cellular heterogeneity, transcriptional changes, and intercellular communication within the PS microenvironment. This review comprehensively describes the cellular landscape of PSs, including mesenchymal cells, endothelial cells, epithelial cells, and immune cells. Additionally, we evaluate precision medicine strategies ranging from biomarker-driven diagnostics to targeted biological therapies and innovative drug delivery systems. We aim to provide a mechanistic framework that accelerates the translation of basic experimental research into effective and personalized treatments for pathological scarring.