Reprogramming NOX4-associated ferro-aging with an iron-chelating senescent-cell-targeted therapy for intervertebral disc degeneration.

Authors

Jinyu Wang, Qitong Chen, Jianpeng Xing, Yuheng Sun, Chen Yan, Baolian Zhao, Linhui Han, Jiuyi Sun, Jingchuan Sun, Kaiqiang Sun, Jiangang Shi

Published in

Bioactive materials. Volume 69. Pages 105-129. Epub Oct 04, 2026.

Abstract

Intervertebral disc degeneration (IVDD) has been a major contributor to chronic low back pain, yet effective disease-modifying therapies remain limited. Here, we identified a NOX4-associated ferro-aging program linking iron overload, oxidative stress, lipid peroxidation, and cellular senescence in degenerative NPCs. Clinical imaging, transcriptomic analyses, human disc specimens, iron-overloaded NPCs, and naturally aged rats consistently revealed ferro-aging-associated changes during IVDD. Mechanistically, gain- and loss-of-function, genetic rescue, and temporal analyses positioned NOX4 as an upstream oxidative regulator of ROS-dependent ACSL4 activation, lipid peroxidation, mitochondrial dysfunction, and NPC senescence. Natural-product screening identified amentoflavone (Amen) as a candidate NOX4-interacting compound that suppresses membrane-associated NADPH oxidase activity in a NOX4-dependent manner. Single-cell transcriptomic analyses showed that ferro-aging NPCs exhibited increased NKG2D ligand-related stress signals, reduced endocytic activity, and enhanced membrane-fusion features. Guided by these characteristics, we engineered SenoFAN, an Amen-loaded, iron-chelating phenolic nanozyme coated with NKG2D-engineered NPC membranes. SenoFAN integrates iron sequestration, nanozyme-mediated redox remodeling, Amen-mediated NOX4-dependent suppression of NADPH oxidase activity, and ferro-aging-cell-adapted delivery through NKG2D-ligand recognition and membrane fusion. In vitro, SenoFAN reduced labile iron and oxidative stress, restored mitochondrial and lipid homeostasis, and suppressed lipid peroxidation and senescence. In a rat puncture-induced IVDD model, SenoFAN showed preferential association with ferro-aging-associated NPCs, prolonged intradiscal retention, reduced iron deposition and senescence, preserved disc structure, and showed favorable biosafety. Collectively, our findings identify NOX4-associated ferro-aging as a therapeutically actionable pathological program in IVDD, while establishing an upstream regulatory role for NOX4 in the FAC-induced ferro-aging model.

PMID:
42876555
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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