2. Academic Validation
  3. Activation of PI3K-AKT pathway prevents steroid-induced osteonecrosis of the femoral head via inhibiting Cuproptosis

Activation of PI3K-AKT pathway prevents steroid-induced osteonecrosis of the femoral head via inhibiting Cuproptosis

  • Sci Rep. 2025 Mar 15;15(1):8950. doi: 10.1038/s41598-025-93555-8.
Shihua Gao # 1,  Haoran Zhu # 2,  Hongxing Chen 3,  Hongduo Lu 2,  Moshan Wen 2,  Yinuo Fan 2,  Deqiang Yang # 4,  Hu Li # 5
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, 528400, Guangdong, China.
  • 2 Guangzhou University of Chinese Medicine, 12 Jichang Road, Baiyun District, Guangzhou, 510405, Guangdong, China.
  • 3 Jinan Fifth People's Hospital, No. 24297, Jingshi Road, Huaiyin District, Jinan, 250022, Shandong, China.
  • 4 Jinan Fifth People's Hospital, No. 24297, Jingshi Road, Huaiyin District, Jinan, 250022, Shandong, China. wutai.deqiang@163.com.
  • 5 Jinan Fifth People's Hospital, No. 24297, Jingshi Road, Huaiyin District, Jinan, 250022, Shandong, China. 1083121926@qq.com.
  • # Contributed equally.
PMID: 40089548 DOI: 10.1038/s41598-025-93555-8
Abstract

This study delved into the role of the PI3K/Akt signaling pathway and Cuproptosis in steroid-induced osteonecrosis of the femoral head (SIONFH), assessing the therapeutic potential of the PI3K agonist 740Y-P. We analyzed femoral head specimens from SIONFH patients using DIA proteomics, identifying differentially expressed proteins linked to Cuproptosis. In vitro, MC3T3-E1 cells treated with dexamethasone (DEX) exhibited hallmarks of Cuproptosis, including downregulation of DLAT, PDHB, SLC25A3, and FDX1, increased copper ions, and reduced osteogenic potential, as shown by decreased ALP activity and RUNX2/BMP2 expression. The PI3K/Akt pathway's modulation of FDX1 was key to Cuproptosis regulation; activating it with 740Y-P restored FDX1 levels and partially recovered osteogenic capacity. An in vivo rat model of SIONFH treated with 740Y-P demonstrated improved bone parameters, reversed osteogenic suppression, and upregulated PI3K/Akt/FDX1 expression, validating the pathway's role in Cuproptosis and the agonist's therapeutic potential for treating SIONFH and glucocorticoid-associated bone disorders.

Keywords

740Y-P; Cuproptosis; Dexamethasone; PI3K/AKT signaling pathway; Steroid-induced osteonecrosis of the femoral head.

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