2. Academic Validation
  3. The YAP1/GPX4 axis alleviates osteoporosis by affecting ferroptosis in osteoblasts

The YAP1/GPX4 axis alleviates osteoporosis by affecting ferroptosis in osteoblasts

  • Mol Med. 2025 Oct 21;31(1):315. doi: 10.1186/s10020-025-01374-4.
Mingsi Deng # 1 2,  Yong Zhou # 3,  Gengyan Liu 4,  Ruimin Tang 1,  Liangrong Hu 5,  Jia Luo 6,  Zhipeng Tang 7,  Liangjian Chen 1,  Zhengguang Wang 8
Affiliations

Affiliations

  • 1 Department of Stomatology, The Third Xiangya Hospital of Central South University, 138 Tongzipo Road, Yuelu District, Changsha City, Hunan Province, P.R. China.
  • 2 Department of Orthodontics, Changsha Stomatology Hospital, Changsha City, Hunan Province, P.R. China.
  • 3 Department of Spinal Surgery, The Third Xiangya Hospital of Central South University, 138 Tongzipo Road, Yuelu District, Changsha City, Hunan Province, 410013, P.R. China.
  • 4 Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha City, 410013, Hunan Province, P.R. China.
  • 5 Department I of Orthopedics, Wugang Light Textile Orthopedic Hospital, Wugang City, Hunan Province, 422400, P.R. China.
  • 6 Changsha Blood Center, Changsha City, Hunan Province, 410000, P.R. China.
  • 7 Jinshi Hospital of Traditional Chinese Medicine, Changde City, Hunan Province, 415400, P.R. China.
  • 8 Department of Spinal Surgery, The Third Xiangya Hospital of Central South University, 138 Tongzipo Road, Yuelu District, Changsha City, Hunan Province, 410013, P.R. China. wangzhengguang0208@163.com.
  • # Contributed equally.
PMID: 41120907 DOI: 10.1186/s10020-025-01374-4
Abstract

Background: Osteoporosis (OP) is a disease in which weak bones increase the risk of fracture. It has been reported that the occurrence of Ferroptosis accelerated the progression of OP. However, the underlying mechanism of Ferroptosis in OP remains unclear.

Methods: Clinical samples from OP patients were collected and ovariectomized (OVX)-induced mouse models with GPX4 knockout was established. The expression of genes and proteins was determined by RT-qPCR, western blot, IHC and IF. Bone mineral density (BMD) of the lumbar vertebrae was evaluated using DXA. Pearson correlation analysis was used to analyze the relationship between GPX4 expression and BMD. The femoral morphology was detected by HE staining. Images and relevant parameters of the femur were acquired using micro-CT. Ultrastructural changes in mitochondria were observed using TEM. MDA and GSH levels in mice and cells were examined using commercial kits. Lipid peroxidation was detected using Bodipy-C11 fluorescent probe. ALP activity was measured using ALP staining and calcified nodules were examined using ARS staining. The interaction between YAP1 and GPX4 promoter was validated using ChIP and dual-luciferase reporter gene assay.

Results: GPX4 expression was downregulated in clinical samples of OP and positively correlated with BMD. GPX4 knockout exacerbated bone loss and promoted Ferroptosis in OVX-induced mice. Besides, GPX4 overexpression inhibited Ferroptosis and enhanced osteogenic potential of osteoblasts. Moreover, YAP1 positively regulated GPX4 expression in osteoblasts through activating transcriptional activity of GPX4 promoter and YAP1 overexpression suppressed Ferroptosis and enhanced osteogenic potential of osteoblasts via enhancing GPX4 expression.

Conclusion: GPX4 was positively regulated by YAP1, which in turn inhibited Ferroptosis and enhanced osteogenic potential of osteoblasts, thereby alleviating OA progression.

Keywords

Ferroptosis; GPX4; Osteoblasts; Osteoporosis; YAP1.

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