An SSK1-loaded decellularized annulus fibrosus matrix-based PD hydrogel alleviates intervertebral disc degeneration through modulation of NF-κB signaling and ferroptosis.

Background: Intervertebral disc degeneration (IDD) is a major cause of low back pain and is closely associated with inflammatory activation, extracellular matrix (ECM) degradation, cellular senescence, and ferroptosis in nucleus pulposus cells (NPCs). In this study, we aimed to clarify the therapeutic effects and underlying mechanisms of SSK1 and to develop an injectable SSK1-loaded hydrogel for localized and sustained treatment of IDD. Methods: An interleukin-1β (IL-1β)-induced NPC degeneration model was established to evaluate ECM metabolism, ferroptosis, senescence, and inflammatory signaling. Ferroptosis-related rescue experiments, pharmacological modulation of NF-κB and PPARγ, and PPARγ knockdown were performed to investigate the underlying mechanism. SSK1 was incorporated into a poly (ethylene glycol) diacrylate/decellularized annulus fibrosus matrix hydrogel (SSK1@PD). The physicochemical properties, cytocompatibility, sustained-release behavior, and therapeutic efficacy of SSK1@PD were evaluated in vitro and in a puncture-induced rat model of IDD using radiographic, histological, immunohistochemical, and biochemical analyses. Results: SSK1 markedly attenuated IL-1β-induced degenerative changes in NPCs, including ECM degradation, iron accumulation, lipid peroxidation, GPX4 loss, and cellular senescence. Mechanistically, SSK1 restored PPARγ expression and suppressed NF-κB activation. PPARγ silencing largely abolished the protective effects of SSK1, whereas pharmacological activation of PPARγ partially reproduced them. The SSK1@PD hydrogel exhibited favorable physicochemical properties, good cytocompatibility, and sustained drug release. In vivo, local injection of SSK1@PD preserved disc height and histological architecture, improved ECM homeostasis, and reduced ferroptosis-, senescence-, and NF-κB-related changes in degenerated discs. Conclusion: SSK1@PD alleviates IDD by enabling sustained local delivery of SSK1 and modulating degenerative cellular responses, at least in part through the PPARγ/NF-κB/ferroptosis axis. This injectable biomaterial-based platform represents a promising minimally invasive therapeutic strategy for IDD. The translational potential of this article: In this study, we propose an injectable hydrogel system for localized delivery of SSK1 to treat intervertebral disc degeneration. By targeting ferroptosis and inflammation while enabling sustained drug release, this strategy effectively alleviates disc degeneration in vivo. The combination of mechanistic targeting and biomaterial-based delivery highlights its potential as a minimally invasive and clinically translatable therapy for IDD.