Single-cell atlas of photoaged skin reveals JAK-STAT blockade as a strategy to reverse dermal remodeling.

INTRODUCTIONChronic ultraviolet (UV) exposure superimposes inflammatory and matrix-degenerative insults on intrinsic aging to produce cutaneous photoaging, yet the cell-type-resolved circuits and druggable nodes driving this process remain poorly defined.

METHODSChronic We established a chronic UVA+UVB-induced mouse model of photoaging and performed single-cell RNA sequencing of control, UV-exposed, and UV + ruxolitinib-treated dorsal skin to map photoaging and therapeutic response at cellular resolution.

RESULTSChronic Across 14 major lineages, UV exposure preserved overall cellular composition but induced a coordinated transcriptional network shift, marked by activation of JAK-STAT/IRF/AP-1-driven inflammatory and oxidative-stress programs and suppression of developmental, DNA-repair, and differentiation modules. Fibroblast reclustering resolved eight states and identified a papillary-to-reticular transitional continuum with the highest transcriptional burden, integrating senescence-associated secretory phenotype and extracellular-matrix disassembly signatures and skewing pseudotime toward late, terminal states. Topical JAK1/2 inhibition with ruxolitinib attenuated clinical and histological photoaging phenotypes, restored collagen and elastic fiber architecture, and rebalanced fibroblast trajectories by suppressing inflammatory/stress pathways while reactivating basement-membrane, extracellular-matrix, adhesion, and wound-healing programs. Cross-lineage analysis further revealed reversal of conserved stress-metabolic axes, including Hmox1, Gpx3, Ucp2, and Nr4a2, restoration of structural-matrix programs involving Dcn, Gsn, and Nup210l, normalization of aging regulators such as Cdkn1a and Trp53, and re-establishment of dermal-epidermal crosstalk through collagen IV-syndecan and fibronectin/laminin-CD44/αvβ1 signaling.

DISCUSSIONChronic These findings identify transitional fibroblasts as central executors of UV-driven dermal remodeling and support JAK1/2 inhibition as a network-level strategy to restore dermal-epidermal homeostasis in photoaged skin.