Targeting the JAK-STAT signaling pathway ameliorates chemotherapy-induced skin aging

Chemotherapy-induced skin aging is a clinically relevant adverse effect that significantly impairs patients' quality of life. Here, we combined in vivo mouse models, human dermal fibroblasts (HDFs), and transcriptomic analysis to investigate the underlying mechanisms. Cisplatin and gemcitabine induced pronounced skin aging phenotypes in mice, including increased transepidermal water loss, epidermal atrophy, collagen degradation, and elevated expression of senescence-associated markers and SASP factors. In HDFs, chemotherapy suppressed proliferation and induced cellular senescence, as confirmed by SA-β-Gal staining and EdU assays. Mechanistically, RNA sequencing and biochemical analyses revealed that chemotherapy-induced DNA damage activates JAK-STAT signaling, promoting fibroblast senescence and SASP production. Notably, inhibition of JAK-STAT signaling with ruxolitinib reduced skin aging phenotypes and SASP secretion, and suppressed tumor progression in an orthotopic tumor mouse model. Collectively, these findings identify a DNA damage-JAK-STAT-senescence axis underlying chemotherapy-induced skin aging and suggest that targeting this pathway may provide dual therapeutic benefits by alleviating skin toxicity while enhancing antitumor efficacy.