Humanin reduces nucleus pulposus cells ferroptosis to alleviate intervertebral disc degeneration: An in vitro and in vivo study

Abstract

Background

Intervertebral disc degeneration (IDD) is a prevalent etiology of low back pain in the global adult population, leading to considerable morbidity and healthcare costs. Existing therapeutic modalities for IDD remain constrained. Ferroptosis in the nucleus pulposus (NP) cells emerges as a pivotal contributor to IDD. Humanin (HN), a mitochondrial-secreted peptide, is intricately linked to age-related maladies and showcases antioxidant, anti-inflammatory, and anti-apoptotic properties. Nonetheless, its precise involvement in IDD remains enigmatic.

Methods

The expression profile of HN in IDD was scrutinized utilizing human NP cell cultures and an IDD rat model (n = 5). The therapeutic efficacy of HN in rats was assessed via MRI and histological evaluation, alongside an exploration of the molecular underpinnings of HN's therapeutic actions in IDD management.

Results

This pioneering study unveiled a downregulation of HN expression in IDD patients, a finding corroborated through cell and rat IDD models. Furthermore, it was ascertained that exogenous HN could trigger endogenous HN expression, impede the JAK2/STAT3 and NF-κB pathways, thereby mitigating erastin-induced ferroptosis in NP cells, contingent upon the upregulation of HSP27 expression. Moreover, the study validated the role of HN in preserving mitochondrial homeostasis, curbing mitochondrial reactive oxygen species (mtROS) generation and mtDNA leakage, consequently hindering mtDNA binding to TLR9 and subsequent activation of the NF-κB pathway. Notably, in vivo rat experiments underscored the efficacy of HN treatment in ameliorating IDD progression induced by annulus fibrosus puncture.

Conclusion

By assuaging ferroptosis in NP cells, HN exhibits promise as a viable candidate for IDD treatment, capable of impeding disease advancement. The translational potential of this article: This study highlights the importance and effectiveness of HN in alleviating IDD by inhibiting ferroptosis in NP cells. The addition of exogenous HN may represent a potential therapeutic strategy for treating IDD.