FTO-associated osteoclastogenesis promotes alveolar bone resorption in apical periodontitis male rat via the HK1/USP14/RANK pathway

Yajie Qian, Jing Wu, Weidong Yang, Ruining Lyu, Qiao You, Jingjing Li, Qin He, Yuan Zhuang, Wenmei Wang (), Yong Wang (), Yanan Zhu (), Zhiwei Wu () and Deyan Chen ()
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Yajie Qian: Nanjing University
Jing Wu: Medical School of Nanjing University
Weidong Yang: Nanjing University
Ruining Lyu: Medical School of Nanjing University
Qiao You: Medical School of Nanjing University
Jingjing Li: Nanjing University
Qin He: Nanjing University
Yuan Zhuang: Nanjing University
Wenmei Wang: Nanjing University
Yong Wang: Medical School of Nanjing University
Yanan Zhu: Nanjing University
Zhiwei Wu: College of Pharmacy, Dali University
Deyan Chen: Medical School of Nanjing University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Alveolar bone resorption (ABR) is a key pathological manifestation in the development of apical periodontitis (AP) and contributes to the AP-associated tooth loss among AP patients in the clinic. However, the underlying mechanism of ABR development is largely unknown. Here we show, the total levels of N6-methyladenosine (m6A) were reduced in AP male rat alveolar bone tissues and BMDM-derived osteoclasts (OC), which was associated with the up-regulation of obesity-associated protein (FTO). Subsequently FTO-mediated hexokinase (HK1) demethylation modification enhancing glycolytic pathway that stabilizes receptor activator of NF-κB (RANK) protein via the deubiquitination activity of ubiquitin-specific protease 14 (USP14), which further promotes osteoclastogenesis to participate in the AP-related ABR development. Finally, Dac51 (an FTO inhibitor) and 2-DG (an HK1 inhibitor) both exhibit the inhibitory activity of osteoclastogenesis. Our current study reveals a molecular mechanism on osteoclastogenesis-related ABR and provides a therapeutic target of AP via modulating the FTO/HK1/USP14/RANK axis.

Date: 2025
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DOI: 10.1038/s41467-025-56615-1

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