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

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.