HIF-1α attenuates ferroptosis-associated dermal fibroblast senescence via modulation of NF-κB–DPP4 signaling

BACKGROUNDS: Skin aging is characterized by progressive structural and functional decline driven in part by chronic oxidative stress. Ferroptosis-associated processes have been increasingly implicated in cellular senescence and are linked to dipeptidyl peptidase-4 (DPP4). Although hypoxia-inducible factor-1α (HIF-1α) is essential for skin homeostasis, its role in dermal fibroblast aging remains incompletely understood. This study aimed to determine whether HIF-1α modulates ferroptosis-associated senescence in human dermal fibroblasts (HDFs) and to explore the involvement of NF-κB-DPP4 signaling. METHODS: HIF-1α expression was examined in aged HDFs and sun-exposed human skin. Transcriptomic profiling was performed to assess pathways associated with hypoxia in aging models. Pharmacological modulators of ferroptosis, DPP4, and HIF-1α were applied in vitro to evaluate effects on senescence and ferroptotic markers. NF-κB activity and DPP4 transcription were analyzed using molecular assays. Potential in vivo relevance was evaluated in aged mice treated with a HIF-1α activator or a ferroptosis inhibitor. RESULTS: HIF-1α expression was reduced in aged HDFs and photoaged skin, and its depletion accelerated cellular senescence. Transcriptomic analysis suggested downregulation of ferroptosis-related pathways under hypoxic conditions. Induction of ferroptosis-associated stress promoted senescence phenotypes in HDFs, whereas hypoxia-induced HIF-1α activation attenuated these effects. Mechanistically, NF-κB functioned as a transcriptional regulator of DPP4, and hypoxia was associated with reduced NF-κB activity, decreased DPP4 expression, and lower secretion of soluble DPP4 (sDPP4). Inhibition of DPP4 mitigated ferroptosis-associated senescence and restrained sDPP4-mediated paracrine propagation to neighboring young fibroblasts. In aged mice, topical treatment with a HIF-1α activator or a ferroptosis inhibitor was associated with improved dermal structure and reduced senescence markers. CONCLUSION: These findings support a model in which HIF-1α is associated with suppression of NF-κB-dependent DPP4 expression and attenuation of ferroptosis-associated fibroblast senescence. Targeting the HIF-1α/NF-κB/DPP4 axis may represent a potential strategy for mitigating skin aging.