2. Academic Validation
  3. Ferristatin II protects nucleus pulposus against degeneration through inhibiting ferroptosis and activating HIF-1α pathway mediated mitophagy

Ferristatin II protects nucleus pulposus against degeneration through inhibiting ferroptosis and activating HIF-1α pathway mediated mitophagy

  • Int Immunopharmacol. 2025 Feb 6:147:113895. doi: 10.1016/j.intimp.2024.113895.
Cheng Su 1,  Xingzhi Jing 2,  Xiaoyang Liu 3,  Yuandong Shao 4,  Yong Zheng 5,  Xiaodong Liu 6,  Xingang Cui 7
Affiliations

Affiliations

  • 1 Department of Spine Surgery, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong 250000, China; Department of Spine Surgery, Zhoukou Orthopaedic Hospital, Zhoukou 466000, China.
  • 2 Department of Spine Surgery, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong 250000, China; Department of Spine Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250000, China. Electronic address: jingxingzhi@sdfmu.edu.cn.
  • 3 Department of Spine Surgery, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong 250000, China; Department of Spine Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250000, China.
  • 4 Department of Spine Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250000, China; Department of Spine Surgery, Binzhou People's Hospital. Binzhou, Shandong 256600, China.
  • 5 Xinjiang Production and Construction Corps Fourth Division Hospital, Yining, Xinjiang, 835000, China.
  • 6 Department of Spine Surgery, Zhoukou Orthopaedic Hospital, Zhoukou 466000, China.
  • 7 Department of Spine Surgery, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong 250000, China; Department of Spine Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250000, China. Electronic address: cuixingang@sdfmu.edu.cn.
PMID: 39752759 DOI: 10.1016/j.intimp.2024.113895
Abstract

Background: Nucleus pulposus (NP) degeneration represents a significant contributing factor in the pathogenesis of intervertebral disc (IVD) degeneration (IVDD), and is a key underlying mechanism in several lumbar spine pathologies. Nevertheless, the precise mechanisms that govern NP degeneration remain unclear. A significant contributing factor to IVDD has been identified as Ferroptosis. Nevertheless, its function in the degeneration of NP remains uncertain. The Transferrin Receptor Inhibitor Ferristatin II (Fer-II) has been demonstrated to possess neuroprotective properties, which are conferred by its ability to suppress Ferroptosis. It is therefore crucial to investigate the mechanisms by which Fer-II exerts its protective effects against NP degradation.

Methods: In order to investigate the protective effects of Fer-II, an IVDD rat model was developed by puncturing the rat tail in vivo. Human NP cells extracted with the aid of tert-butyl hydroperoxide (TBHP) and ferric ammonium citrate (FAC) interventions mimic the IVDD pathological environment in vitro.

Results: The present study demonstrates that Fer-II can delay nucleus pulposus degeneration and IVDD by inhibiting Ferroptosis. This conclusion was reached through epidemiological studies and in vitro and in vivo experiments. Furthermore, Fer-II was observed to alleviate oxidative stress-induced NP cell degeneration by activating the HIF-1α pathway, enhancing Mitophagy, suppressing NP cell Ferroptosis.

Conclusions: The findings of our study indicate that Fer-II has the potential to safeguard nucleus pulposus cells from degeneration by triggering HIF-1α-mediated Mitophagy. The potential of Fer-II as a promising alternative therapeutic option for the management of IVDD is worthy of further investigation.

Keywords

Ferristatin II; Ferroptosis; HIF-1α; Intervertebral disc degeneration; Mitophagy; Transferrin receptor 1.

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