HACE1 alleviates intervertebral disc degeneration by inhibiting ferroptosis in nucleus pulposus cells.

HACE1 (HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1) is an antioxidant gene that plays a key role in activating antioxidant pathways to maintain cellular homeostasis. Recent studies suggest that the antioxidant gene HACE1 may be a potential therapeutic target for age-related degenerative diseases. However, its role in intervertebral disc degeneration (IDD) has not been reported in any study. To clarify the role of HACE1 in IDD, we performed in vivo and in vitro basal experiments. The MRI results indicated that the degeneration grade of intervertebral discs in old rats was significantly higher compared to that in juvenile rats. Additionally, the expression of HACE1 in the degenerated intervertebral discs of aged rats was reduced. In cellular experiments, HACE1 overexpression could restore IL-1β-induced apoptosis, mitochondrial damage and iron overload. In animal experiments, HACE1 activated antioxidant signaling pathways, attenuated oxidative stress, and increased the expression of ECM and anti-ferroptosis proteins. In summary, HACE1 alleviates the progression of IDD by inhibiting oxidative stress and ferroptosis in nucleus pulposus cells. Its protective effect may be related to the activation of the Nrf2/ARE signaling pathway. In conclusion, our results support that the antioxidant gene HACE1 could serve as a novel potential target for treating IDD.