Androgenetic alopecia (AGA) is a common form of hair loss characterized by androgen-driven tissue remodeling, including progressive follicular miniaturization and dermal fibrosis, which is accompanied by low-grade immune activation. However, the molecular mechanisms underlying this fibroimmune dysfunction remain poorly understood. Dermal fibroblasts (DFs) have been suggested as androgen-responsive stromal cells and a potential source of CXCL12, a chemokine implicated in fibroimmune pathology, but their precise role in AGA has not been fully established. In this study, we performed single-cell transcriptomic profiling of a testosterone-induced mouse model of AGA, with or without treatment of CXCL12-neutralizing antibody, to elucidate the pathological role of CXCL12 in mediating stromal-immune interactions. Our analysis suggested that DFs are the primary androgen-responsive population driving CXCL12 expression. Autocrine CXCL12-ACKR3 signaling in DFs activated TGF-β pathways and promoted fibrotic extracellular matrix deposition. In parallel, paracrine CXCL12-CXCR4 signaling reprogrammed Sox2⁺Twist1⁺ dermal papilla cells (DPCs) and promoted the accumulation of pro-fibrotic Trem2⁺ macrophages, contributing to impaired hair follicle regeneration. Notably, CXCL12 blockade attenuated these stromal and immune alterations, restored the regenerative capacity of DPCs, reduced pro-fibrotic macrophage infiltration, and promoted hair regrowth. Together, these findings identify CXCL12 as a central mediator of androgen-induced fibroimmune remodeling and highlight its potential as a therapeutic target in AGA.

We have previously demonstrated that receptor-interacting serine threonine kinase 1 (RIPK1) is expressed in hair follicles and regulates the hair cycle. In a mouse model, RIPK1 inhibitors also accelerated the telogen-to-anagen transition and elongated the anagen period. Here, we first investigated the involvement of RIPK1 in alopecia areata (AA). The mRNA and protein expression of RIPK1 was increased in the skin of an AA mouse model. Single-cell RNA sequencing and immunohistochemistry showed that RIPK1 was highly increased in dendritic cells (DCs) and CD8⁺ T cells. RIPK1 inhibitors (i.e., Necrostatin-1s and GSK2982772) delayed the onset of AA in the mouse model and reduced the numbers of DCs and CD8⁺ T cells in AA skin. The RIPK1 inhibitors also increased the hair length in a mouse hair organ culture mimicking AA. Collectively, these results suggest that RIPK1 is involved in AA onset via modulating immune cells, and RIPK1 inhibitors could prevent AA onset.