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

Abstract

Keloid is a typical skin fibrotic disease with unclear mechanisms and limited therapeutic options. In this study, 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 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 micropthalmia-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. Collectively, melanin-lowing strategies may appear as a potential new therapeutic target for keloid.