2. Academic Validation
  3. ELAVL1 promotes ferroptosis-induced inhibition of osteogenic differentiation in diabetic osteoporosis by downregulating SIRT1

ELAVL1 promotes ferroptosis-induced inhibition of osteogenic differentiation in diabetic osteoporosis by downregulating SIRT1

  • Tissue Cell. 2025 Jul 29:97:103060. doi: 10.1016/j.tice.2025.103060.
Bi Huang 1,  Jie Jiang 2,  Xiang Ou 3,  Meng Hao 3,  Huige Shao 3
Affiliations

Affiliations

  • 1 Department of Endocrinology, Changsha Central Hospital (Changsha Central Hospital Affiliated to University of South China), No.161 Shaoshan South Road, Changsha, Hunan 410028, People's Republic of China. Electronic address: huangbi0205dl@163.com.
  • 2 Changsha Medical Emergency Center, Changsha, Hunan 410001, People's Republic of China.
  • 3 Department of Endocrinology, Changsha Central Hospital (Changsha Central Hospital Affiliated to University of South China), No.161 Shaoshan South Road, Changsha, Hunan 410028, People's Republic of China.
PMID: 40753732 DOI: 10.1016/j.tice.2025.103060
Abstract

Objective: Ferroptosis can implicate in the pathogenesis of diabetic osteoporosis (DOP). This study aimed to determine whether Sirtuin 1 (SIRT1) modulates DOP through ELAV-like RNA binding protein 1 (ELAVL1)-mediated Ferroptosis.

Methods: MC3T3-E1 cells were cultured in high glucose (HG) medium, and osteogenic differentiation was assessed by evaluating RUNX2, OCN, ALP activity, and calcium deposition via Alizarin Red S staining. Ferroptosis was evaluated by measuring GPX4, ACSL4, ROS, MDA, and Fe2 + . A DOP mouse model was established using C57BL/6 J mice fed a high-fat diet combined with 1 % streptozotocin injection. Femoral histopathology, body weight, fasting blood glucose (FBG), and Ferroptosis were analyzed.

Results: HG exposure inhibited osteogenic differentiation, characterized by the reduction in RUNX2, OCN ALP activity and calcium accumulation in MC3T3-E1 cells (P < 0.05); it induced Ferroptosis, including the decrease in GPX4 and the increase in ACSL4, ROS, MDA and Fe2+ (P < 0.05). SIRT1 overexpression or treatment with Fer-1 reversed HG-induced Ferroptosis and restored osteogenic differentiation (P < 0.05). SIRT1 was shown to bind ELAVL1, and its overexpression suppressed ELAVL1(P < 0.05). In HG-stimulated cells co-overexpressing SIRT1 and ELAVL1, both Ferroptosis and osteogenic markers resembled those in cells exposed to HG (P < 0.05). DOP mice exhibited elevated FBG, reduced body weight, increased ELAVL1, and decreased SIRT1(P < 0.05); these mice showed impaired femoral histology. Ferroptosis was evident in DOP mice (P < 0.05). Silencing ELAVL1 improved femoral tissue integrity, inhibited Ferroptosis, promoted osteogenic differentiation, restored body weigh, and upregulated SIRT1 in DOP mice (P < 0.05).

Conclusion: ELAVL1 repressed SIRT1 translation to interrupt ferroptosis-mediated osteoblastic differentiation, thereby inhibiting DOP progression.

Keywords

Diabetic osteoporosis; Ferroptosis; Osteoblast.

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