Esculetin Alleviates IL-1β-Evoked Nucleus Pulposus Cell Death, Extracellular Matrix Remodeling, and Inflammation by Activating Nrf2/HO-1/NF-kb.

Inflammation, extracellular matrix metabolic dysfunction, and oxidative stress are key pathogenic characteristics of intervertebral disk degeneration (IVDD), a major pathogenic cause of low back pain. Esculetin possesses anti-injury, anti-inflammation, and antinociceptive properties. This study aimed to explore its role in IVDD. In this research, esculetin exhibited little cytotoxicity to human nucleus pulposus cells (NPCs). Moreover, esculetin increased cell viability under IL-1β stimulation but attenuated IL-1β-induced cell apoptosis and caspase-3 activity. Furthermore, IL-1β-evoked increases in intracellular reactive oxygen species and malondialdehyde (MDA) levels, and decreases in superoxide dismutase (SOD) activity were reversed after esculetin treatment, indicating the antioxidative stress efficacy of esculetin. Esculetin alleviated the inhibitory effects of IL-1β on the transcription and protein expression of anabolic biomarkers (collagen II and aggrecan), accompanied by decreases in expression and release of catabolic biomarkers MMP-3 and MMP-13 from NPCs. Moreover, IL-1β exposure enhanced the expression levels of the inflammatory mediator nitric oxide and inflammatory cytokine IL-6 and TNF-α, which were overturned after esculetin treatment. Additionally, esculetin activated the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) to inhibit the activation of nuclear factor κB (NF-κB) signaling in NPCs. Importantly, suppression of Nrf2 signaling reversed the protective efficacy of esculetin against IL-1β-mediated oxidative injury, matrix metabolism disruption, and inflammatory response in NPCs. Together, esculetin may alleviate IL-1β-induced dysfunction in NPCs by regulating the Nrf2/HO-1/NF-kb signaling, indicating its potential as a promising therapeutic agent against IVDD.