SPARC activates p38γ signaling to promote PFKFB3 protein stabilization and contributes to keloid fibroblast glycolysis.

BACKGROUND: Keloids are currently challenging to treat because they recur after resection which may affect patients' quality of life. At present, no universal consensus on treatment regimen has been established. Thus, finding new molecular mechanisms underlying keloid formation is imminent. This study aimed to explore the function of secreted protein acidic and cysteine rich (SPARC) on keloids and its behind exact mechanisms. METHODS: The expression of SPARC, p38γ, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), α-SMA, and Ki67 in patients with keloid and bleomycin (BLM)-induced fibrosis mice was assessed utilizing western blot, qRT-PCR, and immunohistochemical staining. After transfected with pcDNA-SPARC, si-SPARC-1#, si-SPARC-2#, and si-p38γ, and treated with glycolytic inhibitor (2-DG) or p38 inhibitor (SB203580), CCK-8, EdU, transwell, and western blot were utilized for assessing the proliferation, migration, and collagen production of keloid fibroblasts (KFs). RESULTS: SPARC, p38γ, and PFKFB3 were highly expressed in patients with keloid and BLM-induced fibrosis mice. SPARC promoted the proliferation, migration, and collagen production of KFs via inducing glycolysis. Moreover, SPARC could activate p38γ signaling to stabilize PFKFB3 protein expression in KFs. Next, we demonstrated that SPARC promoted the proliferation, migration, collagen production, and glycolysis of KFs via regulating p38γ signaling. In addition, in BLM-induced fibrosis mice, inhibition of p38γ and PFKFB3 relieved skin fibrosis. CONCLUSIONS: Our findings indicated that SPARC could activate p38γ pathway to stabilize the expression of PFKFB3, and thus promote the glycolysis of KFs and the progression of keloid.

Twist-related protein 1 promotes transforming growth factor ß receptor 1 in keloid fibroblasts via regulating the stability of myocyte enhancer factor 2A.

Background: Keloid scarring is caused by a fibroproliferative disorder due to abnormal activation of genes, the underlying mechanism of which is still unclear. The basic helix-loop-helix transcription factor Twist-related protein 1 (TWIST1) controls cell proliferation and differentiation in tissue development and disease processes. In this study, we aimed to clarify the essential role of TWIST1 in the pathogenesis of keloids. Methods: Immunohistochemistry, cell counting kit-8 assays, western blotting, PCR, matrigel invasion assays and immunofluorescence assays were applied to demonstrate the effects and mechanisms of TWIST1 in fibroblasts derived from normal skin and keloids. Mass spectrometry, ubiquitination assays, chromatin immunoprecipitation and dual luciferase reporter assay were applied to explore the interaction of TWIST1 with downstream molecules. Results: In the present study, we confirmed that TWIST1 was upregulated in keloid tissue of patients and in keloid-derived fibroblasts (KFBs). In vitro, TWIST1 inhibition prevented KFB proliferation, invasion and activation. We also discovered a link between TWIST1 and the transforming growth factor ß (TGF-ß) signaling related molecules TGF-ß receptor 1 (TΒR1), SMAD family member 2 (Smad2) and Smad3, and the fibrosis markers α-smooth muscle actin, collagen type I and collagen type III in KFBs. Mechanistically, we uncovered a brand-new mechanism by which TWIST1 interacts with myocyte enhancer factor 2A (MEF2A) and suppresses its ubiquitination and degradation. Using chromatin immunoprecipitation and dual-luciferase reporter assay, TΒR1 was identified as a novel downstream target of MEF2A, which directly binds to its promoter. Overexpression of TWIST1 promoted the recruitment of MEF2A to the TΒR1 promoter and restored TΒR1 functional expression. Conclusions: Our research highlights a significant function of TWIST1 in the development of keloid and its related fibroblasts, partially facilitated by elevated MEF2A-dependent TΒR1 expression. Blocking the expression of TWIST1 in KFBs could potentially pave a novel therapeutic avenue for keloid treatment.

A suprapubic refractory skin ulcer following keloid radiotherapy: from hyper-proliferation to hypo-proliferation.

Radiation-induced skin ulcer following cancer and/or tumour is well-documented in the literature. However, radiation-induced skin ulcer following the excision of keloid is yet to be reported. Here, we report the case of a 33-year-old female patient with a suprapubic skin ulcer of five months' duration following keloid treatment with electron beam therapy at recommended dosage. Various examinations, including a skin biopsy, metagenomic sequencing, magnetic resonance imaging and immunochemistry, indicated that the skin ulcer was induced by radiotherapy. While postoperative radiotherapy has been recommended immediately following keloid excision to reduce the risk of recurrence, the present case highlights the risk of skin refractory ulcer following keloid radiotherapy.

The mechanism of TGF-ß mediating BRD4/STAT3 signaling pathway to promote fibroblast proliferation and thus promote keloid progression.

The purpose of this study was to investigate the effect of TGF-ß on keloid and its molecular mechanism in fibroblasts. METHODS: The difference between normal tissue and keloid tissue can be detected using HE staining. Fibroblasts were treated with TGF-ß, and then treated with the BRD4 inhibitor JQ1 and the STAT3 activator Colivelin TFA. Western blot was used to measure the relative protein expression of TGF-ß, BRD4, p-STAT3, p-EZH2, C-myc, KLF2, KLF4, α-SMA, and Collagen-I. Immunofluorescence staining was used to measure the relative fluorescence intensity of BRD4, p-STAT3, α-SMA, and Collagen-I. Cell proliferation ability was evaluated by CCK-8 assay and colony formation assay. RESULTS: The expression of TGF-ß and BRD4 was significantly higher in keloid tissue compared to normal tissue. TGF-ß mediated the BRD4/STAT3 signaling pathway to inhibit p-EZH2 and promote the expression of C-myc, KLF2, KLF4, α-SMA, and Collagen-I. Additionally, TGF-ß mediated the BRD4/STAT3 signaling pathway to enhance fibroblast proliferation. CONCLUSION: TGF-ß mediates the BRD4/STAT3 signaling pathway to promote fibroblast proliferation and contribute to the progression of keloid.

Logistic regression analysis of risk factors influencing postoperative keloid scar recurrence.

OBJECTIVE: To identify risk factors of postoperative keloid scar recurrence in patients using logistic regression analysis. METHODS: A retrospective analysis was conducted with the use of clinical data collected from 132 keloid scars patients undergoing keloidectomy under local anaesthesia between January 2020 and June 2023 at The First Affiliated Hospital of the WANNAN Medical College. The recurrence of keloid scars in the included patients was analyzed, and their clinical data were subjected to univariate analysis. Factors showing significant differences were included in the multivariate logistic regression analysis. A receiver operating characteristics (ROC) curve was generated based on the independent risk factors to explore the predictive performance of joint-factor prediction for postoperative recurrence of keloid scars, and a corresponding Nomogram was generated. RESULTS: Out of the 132 patients, 38 experienced keloid scar recurrence, accounting for 28.79% of the total cases. Logistic regression analysis identified infection, family history of keloid scars, relatively large scar size and the absence of radiotherapy and local hormone therapy as independent risk factors influencing postoperative recurrence of keloid scars. The prediction for postoperative recurrence of keloid scars based on the joint independent risk factors yielded an area under the ROC curve of 0.889, with a sensitivity, a specificity, and an accuracy of 78.72%, 86.84%, and 81.06%, respectively. CONCLUSION: Infection, family history of keloid scars, relatively large scar size, and the absence of radiotherapy and local hormone treatment have been identified as independent risk factors for postoperative recurrence of keloid scars in patients.

Efficacy of photodynamic therapy combined with cross-punch technique for the treatment of keloid.

OBJECTIVE: Keloids are characterized by abnormal activation of fibroblasts and excessive collagen deposition. Keloids are notoriously difficult to treat effectively due to their high recurrence rate after therapy. Our study explored the use of the punch technique in conjunction with photodynamic therapy, a novel approach that may swiftly reduce keloid volume, promote collagen remodeling, mitigate inflammation and enhance the wound healing process. METHODS: In our study, we conducted a retrospective analysis of 47 keloid patients who were treated with cross-punch technique combined with photodynamic therapy (punch+PDT group), compared them with a control group of 42 patients who received cross-punch therapy alone (punch group). The visual Analog Scale (VAS) scoring system, the Dermatology Life Quality Index (DLQI) questionnaire and the subjective scoring of patients were implemented to assess the improvement rate at baseline (month 0) and 12-month follow-up (month 12). RESULTS: The results demonstrated significant enhancements in both VAS scores and DLQI scores on month 12 when compared with those on month 0. Notably, the subjective scoring indicated a marked difference, with 93.62 % of patients in the punch+PDT group and 59.52 % in the punch group reporting good or excellent improvement. CONCLUSION: Patients in the punch+PDT group had a significant improvement rate than those in the punch group.

Efficacy of Nd:YAG Laser and Intralesional Triamcinolone Injection Combination Therapy in the Postoperative Management of Keloids.

BACKGROUND: Keloids, characterized by protruding scars that extend beyond the original skin damage site, cause significant emotional stress and reduced quality of life. Their exact pathogenesis remains unclear, with various hypotheses including growth factor imbalances and extracellular matrix changes. No single treatment is universally accepted, but multiple modalities like triamcinolone acetonide injection (TAC), laser therapies, and surgery are commonly used. METHODS: This retrospective study involved East Asian patients who underwent keloid scar excision between March 2019 and June 2022. Patients were divided into two groups: one receiving only TAC injections and the other a combination of TAC and Nd:YAG laser therapy. The efficacy of treatments was evaluated using the modified Vancouver Scar Scale (mVSS) and the Patient and Observer Scar Assessment Scale (POSAS), with follow-ups at six and twelve months after operation. RESULTS: The study involved 111 patients. Both treatment groups showed significant improvements in mVSS and POSAS scores, but the combination therapy group demonstrated a statistically significant improvement in POSAS scores and lower recurrence rates at 12 months compared to the TAC-only group. However, there was no significant difference in patient satisfaction between the groups. CONCLUSION: Dual therapy involving TAC injection and Nd:YAG laser treatment was more effective than TAC injection alone for managing keloid scars after surgery. This combination therapy showed better outcomes in preventing keloid recurrence and improving scar status at 12 months after operation, along with significant improvements in patient-reported outcomes. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Macrophage Polarization: A Novel Target and Strategy for Pathological Scarring.

BACKGROUND: Abnormal scarring imposes considerable challenges and burdens on the lives of patients and healthcare system. Macrophages at the wound site are found to be of great concern to overall wound healing. There have been many studies indicating an inextricably link between dysfunctional macrophages and fibrotic scars. Macrophages are not only related to pathogen destruction and phagocytosis of apoptotic cells, but also involved in angiogenesis, keratinization and collagen deposition. These abundant cell functions are attributed to specific heterogeneity and plasticity of macrophages, which also add an extra layer of complexity to correlational researches. METHODS: This article summarizes current understanding of macrophage polarization in scar formation and several prevention and treatment strategies on pathological scarring related to regulation of macrophage behaviors by utilizing databases such as PubMed, Google Scholar and so on. RESULTS: There are many studies proving that macrophages participate in the course of wound healing by converting their predominant phenotype. The potential of macrophages in managing hypertrophic scars and keloid lesions have been underscored. CONCLUSION: Macrophage polarization offers new prevention strategies for pathological scarring. Learning about and targeting at macrophages may be helpful in achieving optimum wound healing.

Sandwich Therapy with Radionuclide Combined with Intralesional Injections Based on Differences in the Spatial Structure Components of Keloids.

BACKGROUND: Complications such as ulceration, depigmentation, and recurrence limit the use of intralesional injections and brachytherapy in keloid treatment. We designed a modified "sandwich" therapy based on the spatial distribution of keloid components to reduce the incidence of these complications. METHODS: First, we analyzed the spatial distribution pattern of scar tissue through single-cell sequencing analysis, ultrasound, and pathology. Subsequently, a "sandwich" therapy combining radionuclide and intralesional injections was designed based on the pattern found in the previous stage. Finally, 40 patients with keloid scars at 41 sites were included in the clinical trial. RESULTS: Single-cell sequencing identified two significant cellularly highly expressed genes and enriched pathways in the keloid vascular wall that primarily play essential roles in angiogenesis and promoting collagen synthesis, thereby promoting scar growth. Color ultrasound showed that there were hierarchical differences in the blood supply of the keloid, and further H&E, CD34, and eNOS staining showed that there were hierarchical differences in the spatial structure of blood vessels, fibroblasts, and collagen in the keloid. In clinical studies, the complication rate of "sandwich" therapy is lower than that of conventional treatment. CONCLUSION: The distribution of blood vessels and collagen in keloid scars is characterized by spatial variability. The "sandwich" therapy of radionuclide combined with intralesional injections is a modified type of precisely targeted therapy designed based on this variability; it has fewer complications and good clinical efficacy and is worthy of popularization. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

PTB Regulates Keloid Fibroblast Migration and Proliferation Through Autophagy.

BACKGROUND: Keloid disease is a chronic fibroproliferative disease that occurs after tissue injury, and the currently available treatments are unsatisfactory. OBJECTIVES: We aimed to explore the level of autophagy in keloid fibroblasts (KFbs) and adjacent normal fibroblasts (NFbs). In addition, whether polypyrimidine tract-binding protein (PTB) regulates the biological functions of KFbs via autophagy was also investigated. METHODS: The morphology of fibroblasts in normal skin and keloids was observed transmission electron microscopy. We silenced PTB with PTB-specific siRNA to determine whether PTB-regulated KFb proliferation. Acridine orange and LysoTracker Red staining was performed to label acidic compartments. Interestingly, when autophagy was inhibited by wortmannin, the PTB knockdown-mediated decrease in KFb migration and proliferation was abolished, while the collagen I and III levels were not altered; these results indicated that PTB regulated the migration and proliferation of KFbs via autophagy, while collagen synthesis occurred independently of PTB regulation. RESULTS: Many activities related to the survival and function of KFbs are controlled by PTB. Transmission electron microscopy revealed more autophagosomes and autolysosomes in KFbs than in NFbs. PTB induced autophagy in KFbs, as demonstrated by the significantly greater number of autophagosomes in KFbs after PTB knockdown, which was revealed by acridine orange and LysoTracker staining. CONCLUSIONS: Our study is the first to show that PTB regulates the migration and proliferation of KFbs via autophagy and that PTB regulates collagen synthesis in KFbs in an autophagy-independent manner. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Increased Susceptibility to Mechanical Stretch Drives the Persistence of Keloid Fibroblasts: An Investigation Using a Stretchable PDMS Platform.

BACKGROUND: Keloids are a common fibrotic disease of the skin, with the pathological hallmark of excessive extracellular matrix synthesis due to abnormal fibroblast activity. Since keloids clinically arise in areas of high mechanical tension, the mechanotransductory pathway may be attributed to its pathogenesis. We aimed to establish a preclinical platform to elucidate the underlying mechanism of keloid development and its clinical persistence. METHODS: We fabricated a mechanically stretchable polydimethylsiloxane cell culture platform; with its mimicry of the in vivo cyclic stretch of skeletal muscles, cells showed higher proliferation compared with conventional modalities. RESULTS: In response to mechanical strain, TGF-ß and type 1 collagen showed significant increases, suggesting possible TGF-ß/Smad pathway activation via mechanical stimulation. Protein candidates selected by proteomic analysis were evaluated, indicating that key molecules involved in cell signaling and oxidative stress were significantly altered. Additionally, the cytoskeletal network of keloid fibroblasts showed increased expression of its components after periodic mechanical stimulation. CONCLUSIONS: Herein, we demonstrated and validated the existing body of knowledge regarding profibrotic mechanotransduction signaling pathways in keloid fibroblasts. Cyclic stretch, as a driving force, could help to decipher the tension-mediated biomechanical processes, leading to the development of optimized therapeutic targets.

CEMIP induces TGF-ß/Smad signaling to promote keloid development by binding to SPARC.

BACKGROUND: Cell Migration Inducing Hyaluronidase 1 (CEMIP) is a protein that plays regulatory functions in a variety of cellular processes in many diseases. Nevertheless, its role and molecular mechanism in keloid hyperplasia are still elusive. METHODS: Expressions of CEMIP and Secreted Protein acidic and Rich in Cysteine (SPARC) were detected by qRT-PCR and western blot. CCK-8 assay, along with immunofluorescence staining, was applied for the assessment of cell proliferation. The capabilities of cells to migrate and invade were evaluated utilizing wound healing and Transwell, while Extracellular Matrix (ECM) deposition was measured by immunofluorescence and western blot. The interaction of CEMIP and SPARC was predicted by the Coexpedia and PPA-red databases and verified by co-IP. Western blot was adopted for the estimation of TGF-ß/Smad pathway-related proteins. RESULTS: The data demonstrated that CEMIP expression was elevated in Keloid Fibroblasts (KF). CEMIP interference suppressed cell proliferative, migrative and invasive capabilities and ECM deposition in KF. Mechanistically, bioinformatics analysis revealed that CEMIP was co-expressed with SPARC and CEMIP protein could bind to SPARC. SPARC expression was reduced in CEMIP-silenced cells. SPARC overexpression counteracted the impacts of CEMIP silencing on cell proliferative, migrative and invasive capabilities and ECM deposition in KF. In addition, the expressions of TGF-ß/Smad signaling-related proteins were decreased by CEMIP silencing via the inhibition of SPARC. CONCLUSION: In summary, this study revealed that CEMIP modulated KF proliferation, migration, invasion and ECM deposition by TGF-ß/Smad signaling through binding to SPARC.

Pulsed dye laser in jellyfish-induced keloids.

Jellyfish stings can cause acute inflammatory skin lesions that may hesitate in keloids. Pulsed dye laser (PDL) represents one of the most effective treatments for newly developed keloids. Aim of this study was to evaluate the efficacy of PDL on newly developed keloids specifically induced by jellyfish stings in pediatric patients.We conducted a retrospective observational study on pediatric patients with newly developed keloids from jellyfish stings, treated in the last two years with 595 nm wavelength PDL with a duration of 0.45-1.5 msec, spot-size 7 mm and fluence 8.5-9.5 J/cm2. PDL therapy was administered for a mean of 7.4 treatment sessions, every 1-3 months. Two expert dermatologists evaluated the vascularity, pigmentation, height, and pliability of keloids, according to the Vancouver Scar Scale (VSS), pre-and-post treatment. A total of 17 patients (7 males, 10 females) were included in the study, mean age of 11 years. Overall, mean pre-treatment global VSS was 11.0 ± 1.50. After treatment, global VSS was 3.88 ± 1.87. At paired t-test, the difference between pre-treatment and post-treatment was highly statistically significant (p < .0001). Commonly, manipulation and therapeutic intervention on jellyfish scars and keloids is feared. The present study supports the use of PDL in keloids secondary to jellyfish stings, though conducted on a limited number of patients.

Future Directions About Keloid Scars Based on Pathogenesis and Therapies.

Keloids are pathologic scars that pose a significant functional and cosmetic burden. While the literature on keloid management continues to expand, the absence of standardized guidelines or treatment protocols endorsed by academic governing bodies remains a significant challenge. The pathogenesis of keloid scars is not fully elucidated. This review delves into the intricate pathogenesis of keloids, exploring the molecular and cellular mechanisms underlying their formation. Conventional therapies are analyzed in-depth considering their efficacy and limitations, including surgical excision, pharmacotherapies, radiotherapy, cryotherapy, silicone-based product, pressure therapy, and light-based therapy. The emergence of novel therapeutic approaches is discussed, including pharmacotherapies, physical therapies, and biological therapies, shedding light on their potential in treating keloid scars. We also contemplate future directions in the field, encompassing the application of targeted therapies, gene-editing tools, tissue engineering, and regenerative medicine, together with psychosocial support and patient education. In synthesizing current knowledge, scrutinizing therapeutic modalities, and envisioning future avenues, this review aims to provide a comprehensive reference for clinicians, researchers, and stakeholders engaged in the intricate field of keloid management.

Genistein inhibited endocytosis and fibrogenesis in keloid via CTGF signaling pathways.

BACKGROUND: This study aimed to evaluate soy isoflavones' effect and potential use-specifically genistein-in treating human keloid fibroblast cells (KFs) and in a keloid tissue culture model. METHODS: To investigate the effects of genistein on keloid, a wound-healing assay was performed to detect cell migration. Flow cytometry was used to measure apoptosis. Western blotting and immunofluorescence staining were performed to detect the expression of target proteins. KF tissues were isolated, cultured, and divided into the control, silenced connective tissue growth factor (CTGF) proteins, and shNC (negative control) groups. RESULTS: Genistein suppressed cell proliferation and migration, triggering the cell cycle at the G2/M phase and increasing the expression of p53 dose-dependent in keloids. Genistein inhibited the expression of COL1A1, FN, and CTGF mRNA and protein. Knockdown CTGF reduced the migrated ability in KFs. Genistein also abated TGF-ß1-induced keloid fibrosis through the endocytosis model. Separated and cultured the keloid patient's tissues decreased the cell migration ability by genistein treatment and was time-dose dependent. CONCLUSIONS: This study indicated that genistein-induced p53 undergoes cell cycle arrest via the CTGF pathway-inhibited keloid cultured cells, and genistein suppressed the primary keloid cell migration, suggesting that our research provides a new strategy for developing drugs for treating keloids.

Development of a Simvastatin-Loaded Copolymer Acid-Sensitive Nanocarrier and Its Experimental Use in the Treatment of Keloids.

OBJECTIVE: The lipid-lowering simvastatin (SIM) has been shown to be an effective inhibitor of keloid proliferation. However, due to its low water solubility and short half-life, simvastatin aggregates to the liver and does not reach the skin lesions after oral administration, which restricts its widespread clinical use. The development of nanomedicine provides the possibility for us to break through this bottleneck problem clinically. The objective of this study was to investigate the feasibility of using complex nanocontrolled delivery system (CNDS), simvastatin-loaded polyethylene glycol-poly lactic-co-glycolic acid (PEG-PLGA), in the treatment of keloids. METHODS: In the in vitro study, the release of simvastatin in fibroblasts by CNDS@Simvastatin and its effect on inhibition of the proliferation of fibroblasts, Col Ι, and CTGF by the slow release of simvastatin were assessed. The efficacy of CNDS@Simvastatin in improving keloids and the biocompatibility and safety of CNDS@Simvastatin were examined in vivo by establishing a murine ear keloid model. RESULTS: CNDS@Simvastatin showed sustained and uniform inhibition of the proliferation of fibroblasts, Col Ι, and CTGF via the gradual release of simvastatin over 72 h. It was efficient in the treatment of the murine ear keloid with no observable toxic side effects on various organs. CONCLUSION: Simvastatin-loaded copolymer acid-sensitive nanocarriers, CNDS@Simvastatin nanospheres, were successfully developed in this study, and these were characterized by favorable physicochemical properties and biocompatibility.

Single-cell sequencing analysis and bulk-seq identify IGFBP6 and TNFAIP6 as novel differential diagnosis markers for postburn pathological scarring.

BACKGROUND: If not accurately diagnosed and treated, postburn pathological scars, such as keloids and hypertrophic scars, can lead to negative clinical outcomes. However, differential diagnosis at the molecular level for postburn pathological scars remains limited. Using single-cell sequencing analysis, we investigated the genetic nuances of pathological scars at the cellular level. This study aimed to identify molecular diagnostic biomarkers to distinguish between postburn keloids and hypertrophic scars. METHODS: Single-cell sequencing, differential expression, and weighted co-expression network analyses were performed to identify potential key genes for discriminating between keloids and hypertrophic scars. Postburn clinical samples were collected from our centre to validate the expression levels of the identified key genes. RESULTS: Single-cell sequencing analysis unveiled 29 and 30 cell clusters in keloids and hypertrophic scars, respectively, predominantly composed of fibroblasts. Bulk differential gene analysis showed 96 highly expressed genes and 69 lowly expressed genes in keloids compared to hypertrophic scars. By incorporating previous research, Gene Set Enrichment Analysis was conducted to select fibroblasts as the focus of research. According to the single-cell data, 301 genes were stably expressed in fibroblasts from both types of pathological scars. Consistently, Weighted Gene Co-expression Network Analysis revealed that the blue module genes were mostly hub genes associated with fibroblasts. After intersecting fibroblast-related genes in single-cell data, Weighted Gene Co-expression Network Analysis-hub module genes, and bulk differential expression genes, insulin-like growth factor binding protein 6 and tumour necrosis factor alpha-induced protein 6 were identified as key genes to distinguish keloids from hypertrophic scars, resulting in diagnostic accuracies of 1.0 and 0.75, respectively. Immunohistochemical Staining and Quantitative Reverse Transcription PCR revealed that the expression levels of tumour necrosis factor alpha induced protein 6 and insulin-like growth factor binding protein 6 were significantly lower in postburn keloids than in hypertrophic scars- CONCLUSIONS: Tumour necrosis factor alpha induced protein 6 and insulin-like growth factor binding protein 6, exhibiting high diagnostic accuracy, provide valuable guidance for the differential diagnosis and treatment of postburn pathological scars.

The Causal Role of Uterine Fibroid in Keloid and Hypertrophic Scar: A Bidirectional Mendelian Randomization Study on European Populations.

BACKGROUND: The relationship between uterine fibroids and keloid/hypertrophic scars has been contradictory. Our research employs a bidirectional Mendelian Randomization (MR) approach to establish a clearer understanding of this potential causal link. OBJECTIVE: This study aimed to determine the effect of uterine fibroids on keloid/hypertrophic scars and the effect of keloid/hypertrophic scars on uterine fibroids. PURPOSE: We aimed to demonstrate the relationship between uterine fibroids and keloid/ hypertrophic scars. METHOD: Our bidirectional MR study utilized summarized data from genome-wide association studies (GWAS) focused on European populations. Our primary tool for establishing causality was the Inverse-Variance Weighted (IVW) method. To reinforce the IVW findings, we also applied four alternative MR methods: MR-Egger, Maximum Likelihood, Weighted Mode, and Weighted Median. RESULT: The IVW method indicated a significant causal link, with uterine fibroids greatly raising the likelihood of developing keloids (Odds Ratio [OR] = 1.202, 95% Confidence Interval [CI]: 1.045-1.381; P=0.010) and hypertrophic scars (OR = 1.256, 95% CI: 1.039-1.519; P=0.018). Parallel results were observed with the MR-Egger, Maximum Likelihood, Weighted Mode, and Weighted Median methods. Sensitivity analyses indicated robustness in these findings, with no evidence of heterogeneity or horizontal pleiotropy. Conversely, the reverse MR analysis did not demonstrate an increased risk of uterine fibroids due to keloids or hypertrophic scars. CONCLUSION: This study elucidates a significant causal effect of uterine fibroids on the development of keloid and hypertrophic scars, offering valuable insights into their pathogenesis and potential therapeutic targets.