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Background <p>Disruption of iron homeostasis is closely associated with ferroptosis and inflammation-related diseases. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy plays a central role in regulating intracellular iron levels and inducing ferroptosis. However, its involvement in orthodontically induced inflammatory root resorption (OIIRR) remains largely unexplored.</p> Methods&#xa0; <p>In vitro, a compressive force (CF) loading model was established using human periodontal ligament cells (hPDLCs). Western blotting and immunofluorescence staining were performed to detect the expression of ferroptosis-related proteins, including NCOA4, FTH1, and GPX4. Intracellular levels of malondialdehyde (MDA), Fe²⁺, and reactive oxygen species (ROS) were measured using a ferroptosis assay kit. JC-1 staining was used to evaluate mitochondrial membrane potential. NCOA4 was silenced via lentiviral transfection, and the small-molecule inhibitor 9a was used to further assess its functional role in ferroptosis. In vivo, an OIIRR mouse model was established. Hematoxylin and eosin (H&amp;E) staining, tartrate-resistant acid phosphatase (TRAP) staining, and micro-computed tomography (micro-CT) were used to assess root resorption. The expression of NCOA4, FTH1, and GPX4 in periodontal tissues was evaluated via immunohistochemistry and immunofluorescence. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, was administered intraperitoneally to investigate its therapeutic effect on OIIRR.</p> Results <p>CF and IL-1β stimulation induced ferroptosis in hPDLCs, as indicated by increased intracellular Fe²⁺, ROS, and MDA levels, decreased GPX4 expression, and mitochondrial damage. NCOA4 expression was markedly upregulated in both in vitro and in vivo models, leading to ferritin degradation and iron overload. Fer-1 treatment effectively reduced oxidative stress and iron accumulation in vitro and alleviated OIIRR in vivo. Compound 9a suppressed NCOA4 expression and mitigated ferritinophagy-mediated ferroptosis.</p> Conclusions <p>NCOA4/FTH1-mediated ferritinophagy promotes ferroptosis under compressive and inflammatory conditions, contributing to OIIRR pathogenesis. Targeting the NCOA4/FTH1 axis may represent a promising therapeutic strategy for preventing orthodontically induced root resorption.</p> Graphical abstract <p></p>

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Inhibition of NCOA4/FTH1-mediated ferritinophagy attenuates ferroptosis in PDLCs and alleviates orthodontically induced inflammatory root resorption

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月28日

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  • Liyan Liu,
  • Dongyang Li,
  • Zhe Zhou,
  • Hong Ding,
  • Runze Zhang,
  • Xueyuan Han,
  • Kexin Huang,
  • Chunmiao Jiang

摘要

Background

Disruption of iron homeostasis is closely associated with ferroptosis and inflammation-related diseases. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy plays a central role in regulating intracellular iron levels and inducing ferroptosis. However, its involvement in orthodontically induced inflammatory root resorption (OIIRR) remains largely unexplored.

Methods 

In vitro, a compressive force (CF) loading model was established using human periodontal ligament cells (hPDLCs). Western blotting and immunofluorescence staining were performed to detect the expression of ferroptosis-related proteins, including NCOA4, FTH1, and GPX4. Intracellular levels of malondialdehyde (MDA), Fe²⁺, and reactive oxygen species (ROS) were measured using a ferroptosis assay kit. JC-1 staining was used to evaluate mitochondrial membrane potential. NCOA4 was silenced via lentiviral transfection, and the small-molecule inhibitor 9a was used to further assess its functional role in ferroptosis. In vivo, an OIIRR mouse model was established. Hematoxylin and eosin (H&E) staining, tartrate-resistant acid phosphatase (TRAP) staining, and micro-computed tomography (micro-CT) were used to assess root resorption. The expression of NCOA4, FTH1, and GPX4 in periodontal tissues was evaluated via immunohistochemistry and immunofluorescence. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, was administered intraperitoneally to investigate its therapeutic effect on OIIRR.

Results

CF and IL-1β stimulation induced ferroptosis in hPDLCs, as indicated by increased intracellular Fe²⁺, ROS, and MDA levels, decreased GPX4 expression, and mitochondrial damage. NCOA4 expression was markedly upregulated in both in vitro and in vivo models, leading to ferritin degradation and iron overload. Fer-1 treatment effectively reduced oxidative stress and iron accumulation in vitro and alleviated OIIRR in vivo. Compound 9a suppressed NCOA4 expression and mitigated ferritinophagy-mediated ferroptosis.

Conclusions

NCOA4/FTH1-mediated ferritinophagy promotes ferroptosis under compressive and inflammatory conditions, contributing to OIIRR pathogenesis. Targeting the NCOA4/FTH1 axis may represent a promising therapeutic strategy for preventing orthodontically induced root resorption.

Graphical abstract