Increased melanin induces aberrant keratinocyte − melanocyte − basal − fibroblast cell communication and fibrogenesis by inducing iron overload and ferroptosis resistance in keloids

作者：Xiangguang Shi, Xueyi Xia, Yang Xiao, Ying Zhang, Yiyi Gong, Yahui Chen, Chenyi Shi, Wei Wang, Jian-Lan Liu, Jia Huang, Mengguo Liu, Zhuoya Xu, Yanyun Ma, Mengkun Shi, Jiucun Wang, Wenyu Wu · 发表于：Cell Communication and Signaling · 年份：2025 · DOI：10.1186/s12964-025-02116-z · 被引用次数：14 · 研究领域：Dermatologic Treatments and Research、Hair Growth and Disorders、melanin and skin pigmentation

Keloid 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. The 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. We 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 k...