Aug 2026· International Journal of Biological Macromolecules· Vol 380, pp.
153997
· 0 citations· 36 references
Medicine
TL;DR
In a needle puncture-induced IVDD rat model, intra-disc injection of Ti3C2@PtAu@TFE3 alleviated structural deterioration and prevented ECM destruction and the potential application of Ti3C2@PtAu@TFE3 against IVDD is demonstrated.
Abstract
Intervertebral disc (IVD) degeneration (IVDD) is a major cause of lower back pain, characterized by oxidative stress accumulation and impaired autophagic flux leading to nucleus pulposus cell (NPC) degeneration. Transcription factor E3 (TFE3) is crucial in autophagy regulation. MXene, a nanomaterial known for its antioxidant capability, exhibits satisfactory therapeutic effects in various diseases. This study investigates the role of TFE3 and evaluates the therapeutic potential of Ti3C2 MXene-based nanocomposites in IVDD. The Ti3C2@PtAu@TFE3 nanocomposite was designed, with properties of anti-oxidation and pro-autophagic flux, alleviated extracellular matrix (ECM) degradation and senescence in NPCs. In a needle puncture-induced IVDD rat model, intra-disc injection of Ti3C2@PtAu@TFE3 alleviated structural deterioration and prevented ECM destruction. This study highlights the critical role of TFE3 in IVDD pathogenesis and demonstrates the potential application of Ti3C2@PtAu@TFE3 against IVDD.
In vitro and in vivo evidence confirms that this dual-functional hydrogel attenuates NP cell inflammation and significantly retards the progression of IDD, offering a synergistic strategy that couples nanozyme-mediated antioxidant therapy with targeted FPR1 blockade, holding substantial promise for intervertebral disc repair.
Zhiwei Liao, Guoqiang Yin, Jing-Pei Liu et al.· Journal of Controlled Releas...· 0 citations
Intervertebral disc degeneration (IDD) is a primary cause of low back pain, characterized by cell loss, extracellular matrix (ECM) degradation, and a harsh microenvironment with excessive oxidative stress, creating an urgent need for regenerative therapies. This study aimed to develop and evaluate a multifunctional injectable hydrogel (Gel@MnO2/GDF6) co-delivering growth differentiation factor 6 (GDF6) for anabolic stimulation and manganese dioxide (MnO2) nanozymes for reactive oxygen species (ROS) scavenging to treat IDD. The MnO2 nanorods and the chitosan-arginine/oxidized dextran-based hydrogel were synthesized and characterized, demonstrating sustained GDF6 release and pH-responsive degradation. In vitro, Gel@MnO2/GDF6 protected nucleus pulposus (NP) cells from H2O2-induced oxidative stress by reducing ROS, upregulating antioxidant enzymes, promoting anabolic ECM metabolism (increasing Aggrecan and Collagen II while decreasing ADAMTS-4 and MMP-13), reducing key inflammatory cytokine expression (TNF-α and IL-6), and activating the Smad pathway. In vivo, intra-discal injection of Gel@MnO2/GDF6 into a rat IDD model significantly attenuated disc degeneration over 12 weeks, as evidenced by improved histological scores, preserved disc height and hydration on radiological and MRI assessments, restoration of ECM protein homeostasis, reduced cellular apoptosis, mitigated inflammatory marker expression, and activated Smad pathway, with these therapeutic effects being superior to those achieved with hydrogels containing only MnO2 or GDF6. Importantly, all tested hydrogel formulations, including Gel@MnO2/GDF6, demonstrated good systemic biocompatibility. These findings collectively demonstrate that the multifunctional Gel@MnO2/GDF6 hydrogel effectively promotes intervertebral disc regeneration by concurrently mitigating oxidative stress and fostering an anabolic, anti-inflammatory microenvironment, validating its potential as a promising therapeutic method for IDD.
Chao Wei, Qin Tang, Yanlin Tan et al.· Free Radical Biology & Medic...· 0 citations
BACKGROUND
Oxidative stress and ferroptosis play critical roles in the pathogenesis of intervertebral disc degeneration (IVDD). Thonningianin A (TA) is a complex polyphenolic ellagitannin found in plants like Thonningia sanguinea, and it exhibits free radical scavenging, anti-superoxide anion generation and metal-chelating activities. However, whether it can inhibit oxidative stress, ferroptosis and the progression of IVDD remains unclear.
PURPOSE
This study aimed to elucidate the molecular mechanism by which TA alleviates IVDD, specifically regarding oxidative stress and ferroptosis, and to validate these mechanisms in both cellular and animal models.
METHODS
An RSL3-induced nucleus pulposus cells (NPCs) ferroptosis model was established, with rescue using Fer-1, DFO and various concentrations of TA along with siRNA validation. Ferroptosis, oxidative stress and extracellular matrix (ECM) related proteins were assessed by western blot, immunofluorescence, fluorescent probes, molecular docking, molecular dynamics simulations and DFT binding energy analysis. In vivo, a rat tail puncture IVDD model was treated with TA or Fer-1, and evaluated by X-ray, MRI, Safranin-O/fast green (S-O) staining, Hematoxylin and Eosin (HE) staining and immunohistochemistry.
RESULTS
Mechanistic studies revealed that TA activates adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and promotes the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and subsequently upregulates the expression of glutathione peroxidase 4 (GPX4), thereby inhibiting oxidative stress, ECM degradation and ferroptosis. Additionally, TA modulates intracellular iron homeostasis by chelating Fe²⁺, thereby further attenuating ferroptosis. In a rat model, local intradiscal injection and intraperitoneal administration of TA effectively inhibited the progression of IVDD.
CONCLUSION
TA inhibits oxidative stress, ECM degradation and ferroptosis in NPCs by activating the AMPK/Nrf2/GPX4 axis and chelating Fe²⁺, thereby suppressing the progression of IVDD.
This study clarifies the molecular mechanism by which the USP5/MATN3 axis regulates cellular senescence and affects IVDD progression, opening up new potential targets for the intervention strategy of IVDD.
Chunyang Fan, Jie-yun Xia, Yao Zhang et al.· Cellular Signalling· 0 citations
Intervertebral disc degeneration pathogenesis involves chronic inflammation and cell death, highlighting the need for targeted therapeutic strategies. Extracellular vesicles (EVs) have emerged as promising bioactive materials for designing therapeutic approach. In this study, we demonstrate that youthful-state EVs (Y-EVs) outperform aged donor-derived EVs (O-EVs) in resolving inflammatory cascades within nucleus pulposus (NP) cells. EVs from young rats significantly suppressed TNF-α-induced inflammation in NP cells by reducing pro-inflammatory cytokine secretion, inhibiting extracellular matrix catabolism, and ameliorating rat disc degeneration in vivo. Mechanistically, CD55 enrichment in Y-EVs attenuated NF-κB pathway activation, thereby disrupting inflammatory transcriptional programs. CD55 knockdown abrogated the anti-inflammatory efficacy of Y-EV, confirming its functional necessity. Besides, we identified thioredoxin (TRX) as a critical suppressor of NLRP1 inflammasome activation via direct protein binding, which inhibited NP cell pyroptosis. Crucially, CD55 in Y-EVs facilitated TRX-mediated NLRP1 suppression, whereas O-EVs failed to upregulate TRX or suppress the NLRP1 inflammasome. This study highlights the age-dependent functional divergence of EV bioactivity and establishes CD55 as a key determinant of their therapeutic superiority. The TRX–NLRP1 interaction represents a novel target for disc degeneration intervention, positioning youthful-state EVs as an optimized bioactive material for disc regeneration strategies.
Zhiwei Liao, Kun Wang, M. Lei et al.· Biomedical Materials· 0 citations
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