JAK Inhibitor Ruxolitinib Reverses UV-Driven Skin Aging at Single-Cell Resolution

Photoaging—the accelerated skin deterioration caused by chronic UV exposure—superimposes persistent inflammation and extracellular matrix (ECM) degradation onto intrinsic aging. Despite its prevalence, the cell-type-specific circuits driving this process and the druggable nodes within them have remained poorly defined, largely because bulk tissue analyses obscure cellular heterogeneity. This study addresses that gap with single-cell resolution.

The team established a chronic UVA+UVB mouse photoaging model and performed single-cell RNA sequencing (scRNA-seq) on dorsal skin from three groups: untreated controls, UV-exposed mice, and UV-exposed mice treated topically with ruxolitinib (a JAK1/2 inhibitor). UV-exposed skin displayed classic photoaging hallmarks including epidermal thickening, hyperkeratosis, fragmented dermal collagen, neutrophil and lymphocyte infiltration, and accumulation of p16-INK4a+ senescent cells. qRT-PCR confirmed elevated IL-6, IL-1β, and γH2AX alongside reduced TGF-β1.

ScRNA-seq resolved 14 major skin cell lineages including fibroblasts, basal and suprabasal keratinocytes, endothelial cells, melanocytes, immune cells, and others. UV exposure did not dramatically alter overall cellular composition but induced a sweeping transcriptional shift across all lineages: JAK-STAT, IRF, and AP-1 inflammatory and oxidative-stress programs were broadly upregulated, while developmental, DNA-repair, and differentiation modules were suppressed. Fibroblasts were reclustered into eight distinct states spanning a papillary-to-reticular transitional continuum. The transitional subpopulations FB2 and FB3 carried the highest transcriptional burden, integrating senescence-associated secretory phenotype (SASP) signatures with ECM disassembly programs and skewing pseudotime trajectories toward late, terminal states.

Topical ruxolitinib produced a directional cellular rescue. Clinically and histologically, it attenuated epidermal hyperplasia, dermal inflammation, and senescent cell accumulation, and restored collagen and elastic fiber architecture. At the single-cell level, it suppressed JAK-STAT/IRF/AP-1 and SASP modules while reactivating basement-membrane, ECM, adhesion, and wound-healing programs—with the most pronounced effects in FB2 and FB3. Cross-lineage analysis revealed reversal of conserved stress-metabolic genes (Hmox1, Gpx3, Ucp2, Nr4a2), restoration of structural matrix genes (Dcn, Gsn, Nup210l), normalization of aging regulators (Cdkn1a, Trp53), and re-establishment of dermal-epidermal crosstalk through collagen IV–syndecan and fibronectin/laminin–CD44/αvβ1 signaling axes.

These results establish transitional fibroblasts as central orchestrators of UV-driven dermal remodeling and demonstrate that JAK1/2 blockade can reverse this process at a network level. Because ruxolitinib is already FDA-approved as a topical formulation for inflammatory skin conditions, this study provides a strong mechanistic rationale and preclinical proof-of-concept for its repurposing in photoaging. Caveats include the mouse-to-human translational gap and the need for clinical validation.