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Backgrounds <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Shang-Chuan Ng,
  • Shih-Wen Kao,
  • Chih‑Jung Chen,
  • Shinn-Zong Lin,
  • Dennis Jine-Yuan Hsieh,
  • Chia-Hua Kuo,
  • Kuan-Ho Lin,
  • Chih-Yang Huang,
  • Wei-Wen Kuo

摘要

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.