Targeting fibroimmune remodeling in androgenetic alopecia: emerging opportunities for RNA-based drug discovery

Current treatments for androgenetic alopecia (AGA) primarily suppress androgen signaling or stimulate hair growth. Recent single-cell and spatial transcriptomic studies identify fibroimmune remodeling as a potential source of new AGA targets.

This review integrates transcriptomic and mechanistic evidence linking androgen-responsive fibroblasts, immune-cell recruitment, and extracellular matrix remodeling, in male and female pattern hair loss. Herein, the authors assessed published human scalp, cell and animal studies of JAK/STAT, TGF-β, CXCL12-CXCR4/ACKR3, and DKK3-CKAP4, and evaluated RNA therapeutic modalities and delivery barriers. Literature was identified primarily through PubMed in the last 20 years.

Fibroimmune remodeling should be viewed as a complementary, rather than alternative, framework to androgen biology. The most promising drug discovery strategy is to identify molecularly defined patient subsets and locally inhibit nodal mediators that couple fibroblast activation to inflammation and matrix remodeling. RNA therapeutics are well suited to otherwise difficult-to-drug intracellular targets, but progress will require human spatial validation, rigorous target prioritization, reproducible delivery, and pharmacodynamic biomarkers demonstrating restoration of the regenerative follicular niche.