Key Takeaways & Executive Findings
- •• Daphnetin attenuates TBHP-induced ECM degradation, oxidative stress, and NLRP3 inflammasome activation in nucleus pulposus cells. • Daphnetin facilitates mitophagy to remove damaged mitochondria, reducing mitochondrial ROS and alleviating NLRP3 inflammasome activation. • The protective effect of Daphnetin is mediated via the Nrf2/PINK1 signaling pathway. • In vivo, Daphnetin prevents intervertebral disc degeneration in a rat puncture model, suggesting its therapeutic potential.
Abstract
Intervertebral disc degeneration (IDD) is a major cause of low back pain (LBP), and effective therapies are still lacking. Reactive oxygen species (ROS) stress induces NLRP3 inflammasome activation, and this, along with extracellular matrix metabolism (ECM) degradation in nucleus pulposus cells (NPCs), plays a crucial role in the progression of IDD. Daphnetin (DAP) is a biologically active phytochemical extracted from plants of the Genus Daphne, which possesses various bioactivities, including antioxidant properties. In the present study, we demonstrate that DAP significantly attenuates tert-butyl hydroperoxide (TBHP)-induced ECM degradation, oxidative stress and NLRP3 inflammasome activation in NPCs. Furthermore, DAP could facilitate mitophagy to increase the removal of damaged mitochondria, consequently reducing mitochondrial ROS accumulation and alleviating NLRP3 inflammasome activation. Mechanistically, we unveil that DAP activates mitophagy by stimulating the Nrf2/PINK1 signaling pathway in TBHP-induced NPCs. In vivo experiments further corroborate the protective effect of DAP against IDD progression in a rat model induced by disc puncture. Accordingly, our findings reveal that DAP could be a promising therapeutic candidate for the treatment of IDD.
1. Introduction
Intervertebral disc degeneration (IDD) is a prominent contributor to the occurrence of low back pain (LBP) and is a leading cause of disability worldwide [1]. Existing IDD care options focus primarily on pain relief and often fall short of providing lasting therapeutic outcomes [2]. The peripheral annulus fibrosus (AF), the core nucleus pulposus (NP), and the cartilaginous endplates (CEP) are the three distinct components that make up the intervertebral disc (ID). Among these, nucleus pulposus cells (NPCs) play crucial roles in regulating extracellular matrix metabolism (ECM) and maintaining the equilibrium between proteoglycan and type II collagen formation [3].
NPCs inhabit a microenvironment characterized by hypoxia and limited nutrient availability as a result of the absence of a direct blood supply. This condition makes them particularly vulnerable to the accumulation of inflammatory agents and reactive oxygen species (ROS) [4], which can further impact ECM anabolism and catabolism [5]. Emerging evidence suggests that mitigating oxidative stress in NPCs represents a promising therapeutic approach for treating IVDs [6].
Previous studies have suggested that stimulation of the nucleotide-binding oligomerization domain-like pyrin domain-containing protein 3 (NLRP3) inflammasome, accompanied by interleukin-1 beta (IL-1β) secretion and excessive caspase-1 generation, substantially influences the development of IVD pathogenesis [7–9]. Additionally, NLRP3 inflammasome activation has been linked to endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and ROS in IDD [10], all of which have the potential to modulate the synthesis of diverse inflammatory cytokines, hence exacerbating IDD [8,11]. Recent research suggests that the NLRP3 inflammasome might act as a diagnostic indicator for IVD [7,9,12].
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Yiting Tu, Jiaping Ren, Weiyuan Fang, Chencheng Zhou, Binli Zhao, Tianyong Hua, Yiqi Chen, Zhenya Chen, Yongzeng Feng, Haiming Jin, Xiangyang Wang (2026). Daphnetin-mediated mitophagy alleviates intervertebral disc degeneration via the Nrf2/PINK1 pathway. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025002
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Frequently Asked Questions
What is the role of Daphnetin in intervertebral disc degeneration?
Daphnetin alleviates intervertebral disc degeneration by attenuating oxidative stress, ECM degradation, and NLRP3 inflammasome activation in nucleus pulposus cells, and by promoting mitophagy via the Nrf2/PINK1 pathway.
How does Daphnetin protect nucleus pulposus cells?
Daphnetin protects nucleus pulposus cells by facilitating mitophagy to remove damaged mitochondria, reducing mitochondrial ROS accumulation, and inhibiting NLRP3 inflammasome activation.
What is the molecular mechanism of Daphnetin's action?
Daphnetin activates the Nrf2/PINK1 signaling pathway, which promotes mitophagy and alleviates oxidative stress and inflammation in nucleus pulposus cells.
What is the significance of this study for IDD treatment?
The study suggests that Daphnetin could be a promising therapeutic candidate for treating intervertebral disc degeneration, as it shows protective effects in both cellular and rat models.
What are the key findings of the study?
Key findings include that Daphnetin reduces TBHP-induced ECM degradation, oxidative stress, and NLRP3 inflammasome activation, and that it prevents IDD progression in a rat puncture model.
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