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

作者：Daxue Zhu, Zhaoheng Wang, Yanhu Li, Shi‐Jie Chen, Xuewen Kang · 发表于：Journal of Orthopaedic Translation · 年份：2025 · DOI：10.1016/j.jot.2024.12.002 · 被引用次数：10 · 研究领域：Spine and Intervertebral Disc Pathology、GDF15 and Related Biomarkers、TGF-β signaling in diseases

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...