N-acetylcysteine restores osteogenesis in human periodontal ligament stem cells by attenuating HIF-1α-driven oxidative stress and glycolytic reprogramming.

Authors

Xiaochi Chang, Yanghao Zhao, Yang Wang, Chang Shu, Yi Feng, Yichong Sun, Guangxun Zhu, Jianxia Hou

Published in

Journal of dental sciences. Volume 21. Issue 3. Pages 1486-1498. Epub Jul 01, 2026.

Abstract

Periodontitis-associated hypoxia signaling and oxidative stress severely impair the regenerative capacity of human periodontal ligament stem cells (hPDLSCs). This study investigated whether antioxidant intervention rescues hPDLSC osteogenesis under CoCl₂-induced HIF-1α stabilization by modulating PI3K/Akt/HIF-1α/HO-1 signaling and glycolytic reprogramming.
Primary hPDLSCs isolated from healthy premolars were characterized by flow cytometry and multilineage differentiation. To simulate periodontitis-associated stress, a CoCl₂-induced HIF-1α-stabilizing condition was established. Cells were treated with the antioxidant N-acetylcysteine (NAC), the glycolysis inhibitor 2-deoxy-d-glucose (2-DG), or the PI3K inhibitor LY294002. Redox balance (DCFH-DA, MDA, GPX activity), glycolysis-related markers (HK2, GLUT1, lactate), and osteogenic-related markers (RUNX2, ALP, OCN) were quantified via qRT-PCR, Western blot, and biochemical assays, alongside an analysis of the PI3K/ Akt/HIF-1α/HO-1 signaling axis.
CoCl₂ exposure triggered profound redox imbalance and significantly impaired hPDLSC osteogenesis. Crucially, NAC effectively reversed these damages and restored osteogenic capacity. Mechanistically, CoCl₂-induced HIF-1α stabilization activated PI3K/Akt/HO-1 signaling, a pathological cascade attenuated by either NAC or targeted PI3K inhibition. Furthermore, CoCl₂ forced a pronounced glycolytic shift characterized by upregulated HK2, GLUT1, and lactate production, which was directly intercepted by ROS clearance. Functionally, targeted glycolysis inhibition via 2-DG also successfully rescued the osteogenic potential of HIF-1α-stabilized hPDLSCs.
HIF-1α stabilization suppresses hPDLSC osteogenesis by inducing both oxidative stress and pathological glycolytic reprogramming. Targeted antioxidant intervention effectively mitigates these impairments, highlighting the ROS/PI3K/Akt/HIF-1α axis as a key link between redox imbalance and metabolic dysfunction, and suggesting a potential therapeutic target for periodontal regeneration.

PMID:
42688993
Bibliographic data and abstract were imported from PubMed on 03 Sep 2026.

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