ArticleCell communication and signaling : CCS2025
Increased melanin induces aberrant keratinocyte - melanocyte - basal - fibroblast cell communication and fibrogenesis by inducing iron overload and ferroptosis resistance in keloids.
Article in Cell communication and signaling : CCS, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed.
- Research advances in the pathogenesis and photodynamic therapy of pathological scars.Lasers in medical science · 2026Review
- Metabolic reprogramming and ferroptosis in keloid pathogenesis: new insights for targeted therapy.Molecular biology reports · 2026Review
- Dissecting the boundary of quiescence and activation of murine melanocyte stem cells in the hair follicle niche.NPJ Regenerative medicine · 2026Review
- Exploring hub genes related to adipocytokines in keloids: a combined analysis integrating single-cell, Mendelian randomization and bulk transcriptome data with experimental verification.Frontiers in molecular biosciences · 2026Article
- A panoramic analysis of keloid pathogenesis: multidimensional network regulation of genetics-immunity-metabolism-mechanical force.Frontiers in immunology · 2026Review
- Deciphering the cellular landscape of pathological scars.Burns & trauma · 2026Article
- AMP-activated protein kinase-driven lipid droplet dynamics govern melanoma sensitivity to polyunsaturated fatty acid and iron-induced ferroptosis.Nature communications · 2025Article
- Article
- Natural protection against oxidative stress in human skin melanocytes.Communications biology · 2025Review
- Impact of nicotine-free and nicotine-rich flavored electronic cigarette refill liquids on primary human melanocyte function.Toxicology reports · 2025Article
- Molecular Insights into Oxidative-Stress-Mediated Cardiomyopathy and Potential Therapeutic Strategies.Biomolecules · 2025Review
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16 authors.
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Abstract
backgroundKeloid is a typical skin fibrotic disease with unclear mechanisms and limited therapeutic options. Fibroblast-induced fibrogenesis is a crucial cause of KD. However, the types of cells involved in fibroblast fibrogenesis in KD and the specific mechanisms are unclear. This study aimed to investigate the role of melanocyte-secreted melanin in promoting fibroblast fibrogenesis and its mechanism and to evaluate the potential therapeutic effect of intervening melanin in treating keloid.
methodsThe activity of pigmentation-related pathways in KD melanocytes was examined using single-cell RNA-sequence (scRNA-seq) analysis. Masson-Fontana staining or isolated melanin quantification detected the melanin levels and distribution in the skin and cells. Collagen deposition, wounding healing, and proliferation analysis were employed to integratively assess fibroblast fibrogenesis. After melanin treatment, bulk-seq identified fibroblasts' differentially expressed genes (DEGs). The iron levels were detected by Perl's staining or isolated iron quantification. Cell viability, LipidROS, and malondialdehyde assay accessed the ferroptosis levels. The therapeutic potential of ML329 was evaluated in keloid-bearing mice.
resultsWe found the enriched skin pigmentation-related pathways in the melanocytes of keloid by single-cell RNA-sequence (scRNA-seq) analysis. We further validated increased melanin levels in keloid patients. Additionally, melanin positively correlated with the Keloid Area and Severity Index in keloid. Furthermore, melanocyte-secreted melanin significantly promoted fibroblast proliferation, migration, and collagen synthesis. Mechanically, melanin increased basal cell permeability and inflammation to facilitate its transfer to the dermis, where it further activated fibroblasts by evoking iron overload and ferroptosis resistance. Consistently, iron overload and ferroptosis resistance were validated in primary fibroblasts and skin tissues of keloid patients. Inhibition of iron overload and ferroptosis resistance effectively diminish melanin-induced fibrogenesis. Interestingly, melanin induced iron overload and ferroptosis resistance in melanocytes in an autocrine manner and further stimulated keratinocytes to take up melanin to deepen skin color by upregulating the F2R-like trypsin receptor 1 (F2RL1). In vivo, the delivery of ML329, a microphthalmia-associated transcription factor (MITF) inhibitor, could suppress melanogenesis and alleviate keloid in human keloid-bearing nude mice. Meanwhile, ML329 decreased the iron content and restored the sensitivities of ferroptosis.
conclusionCollectively, melanin-lowing strategies may appear as a potential new therapeutic target for keloid.
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