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

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.